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Neuropsychiatric symptoms in Alzheimer’s disease
Alzheimer's & Dementia
Abstract
Neuropsychiatric symptoms (NPS) are core features of Alzheimer's disease and related dementias. Once thought to emerge primarily in people with late-stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia-associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimer's Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimer's disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.
... The majority of patients with dementia experience "Behaviour And Psychological Symptoms Of Dementia" (BPSD) at some point: when community dwelling individuals with dementia have undergone assessment in longitudinal studies, up to 97% are affected [9] neuropsychiatric disorders include impairments in motivation, interest, social behaviour and awareness, mood disorders, anxiety, agitation, impulsivity, and hallucinations and delusions, all of which often require clinical intervention. Among psychotic symptoms, hallucinations and delusions are the most clinically relevant, and are associated with hospitalization or institutionalization, cognitive and functional impairment, accelerated cognitive decline and mortality, as well as caregiver distress [10,11] on cognitive symptoms as behavioural and psychological symptoms of dementia are distressing for people with AD but also for their caregivers, with poor outcomes in terms of function, quality of life, disease course, mortality, and economic cost [12,13]. The biopsychosocial approach has proposed that neuropsychiatric disturbances which usually appear earlier than the cognitive symptoms, are the effects of the interactions between an individual's biology, prior experiences, and current environment. ...
... The evolutionary burden (S) (item 6-10) is the isolation perception of the caregiver, also considering the expectations and opportunities of their peers. The physical burden (F) (item [11][12][13][14] describes the feeling of chronic fatigue and somatic health problems while the social burden (D) examines the perception of a role's conflict. The emotional burden (E) (items 20-24) describes the feelings towards the patient, which can be induced by behavioural disorders of the latter. ...
Alzheimers Disease AD accounts for 54% of cases of dementia. The risk of Alzheimer increases with age and women seem to be more easily affected.
... Alzheimer's disease (AD) is a neurodegenerative condition primarily dominating the population over 65 years [1], being associated with cognitive disturbances and severe progression [2]. As novel drug candidates for AD keep failing in different phases of clinical trials, it can be claimed that the field of AD drug discovery reached its limit. ...
... To classify a compound as CNS-active, its BBB score should typically fall within the range of [4][5][6]. In general, amiridine heterodimers BBB score values fell into two categories: [2][3][4] and [4,5]. Out of them, 5a-d exhibited high BBB scores (4.8 and 4.9, respectively). ...
... In der mit steigendem ▶tab. 2 Versorgungssituation in Hinblick auf die tatsächlich erfolgte gegenwärtige Nutzung ("expressed need"), auf den Wunsch nach gegenwärtig intensiverer Nutzung ("felt need I") und auf den Wunsch nach einer zukünftigen Nutzung ("felt need II"). Betreuungsgruppe (ja) b 162 (16,9) 31 (16,3) 25 (18,4) 53 (16,8) 41 (19,4) 12 (11,3) 0,550 0,57 c Kurzzeitpflege (ja) b 250 (26,1) 47 (24,7) 39 (28,7) 84 (26,7) 60 (28,4) 20 (18,9) 0,516 0,58 c Angehörigenberatung (ja) b 231 (24,1) 56 (29,5) 37 (27,2) 72 (22,9) 47 (22,3) 19 (17,9) 0,611 0,58 c Angehörigengruppe(ja) b 109 (11,4) 28 (14,7) 15 (11,0) 33 (10,5) 23 (10,9) 10 ( [20]. Weiterhin kommen Einschränkungen im Bereich IADL bei Menschen über 65 Jahrenund zwar unabhängig von der Pflegeursache -insgesamt etwa doppelt so häufig vor wie ADLEinschränkungen [21,22]. ...
... In der mit steigendem ▶tab. 2 Versorgungssituation in Hinblick auf die tatsächlich erfolgte gegenwärtige Nutzung ("expressed need"), auf den Wunsch nach gegenwärtig intensiverer Nutzung ("felt need I") und auf den Wunsch nach einer zukünftigen Nutzung ("felt need II"). Betreuungsgruppe (ja) b 162 (16,9) 31 (16,3) 25 (18,4) 53 (16,8) 41 (19,4) 12 (11,3) 0,550 0,57 c Kurzzeitpflege (ja) b 250 (26,1) 47 (24,7) 39 (28,7) 84 (26,7) 60 (28,4) 20 (18,9) 0,516 0,58 c Angehörigenberatung (ja) b 231 (24,1) 56 (29,5) 37 (27,2) 72 (22,9) 47 (22,3) 19 (17,9) 0,611 0,58 c Angehörigengruppe(ja) b 109 (11,4) 28 (14,7) 15 (11,0) 33 (10,5) 23 (10,9) 10 ( [20]. Weiterhin kommen Einschränkungen im Bereich IADL bei Menschen über 65 Jahrenund zwar unabhängig von der Pflegeursache -insgesamt etwa doppelt so häufig vor wie ADLEinschränkungen [21,22]. ...
Zusammenfassung
Hintergrund In Deutschland können pflegebedürftige Personen durch Leistungen der Pflegekassen unterstützt werden. Dafür ist die offizielle Feststellung der Pflegebedürftigkeit notwendig, die seit Inkrafttreten des zweiten Pflegestärkungsgesetzes durch die Zuweisung von Pflegegraden – 1 bis 5 – erfolgt. Mit der Einführung der Pflegegrade sollten unter anderem Menschen mit Demenz stärker berücksichtigt werden. In diesem Beitrag werden die Pflegegrade durch Merkmale der Angehörigen- und Versorgungssituation beschrieben, um den Ist-Zustand abzubilden und Ansatzpunkte zur bedarfsorientierten Versorgung zu bieten.
Methodik Die Datenerhebung erfolgte im Rahmen der Querschnittsstudie „Benefits of being a caregiver“ durch eine bayernweite schriftliche Befragung pflegender Angehöriger zu Aspekten der Pflegesituation und dem gegenwärtigen und zukünftig gewünschtem Nutzungsverhalten von 15 Versorgungsangeboten. Zum Vergleich der Pflegegrade wurden Gruppenunterschiede mittels χ2-Tests und einfaktoriellen Varianzanalysen ermittelt. Die Effektstärkenmaße Odds Ratio und Cohen’s d wurden bei signifikanten Gruppenunterschieden zum Vergleich zwischen den Pflegegraden 1 und 4 angegeben. Die Stichprobe umfasste 958 Fälle pflegebedürftiger Personen im Alter von mindestens 65 Jahren.
Ergebnisse Der Anteil von Menschen mit Demenz stieg mit dem Pflegegrad signifikant an. Bei den pflegenden Angehörigen nahmen die subjektive Belastung, funktionale Copingstrategien und das Pflegemotiv die pflegebedürftige Person nicht in ein Heim geben zu wollen, mit dem Pflegegrad zu. Bei höherem Pflegegrad wandten pflegende Angehörige signifikant mehr Zeit für die Unterstützung bei Aktivitäten des täglichen Lebens und für Beaufsichtigung auf; sie erhielten häufiger informelle Hilfe und wohnten häufiger mit der pflegebedürftigen Person zusammen. Bei 9 der 15 untersuchten Versorgungsangebote (z. B. 24-h-Betreuung) stieg der gegenwärtige Nutzungsgrad signifikant mit Zunahme des Pflegegrads an. Insgesamt lag die Nutzungsrate der Angebote jedoch über alle Pflegegrade hinweg auf einem niedrigen Niveau (M=2,20; SD=1,90).
Schlussfolgerung Infolge des zweiten Pflegestärkungsgesetzes wird ein guter Zugang zu Leistungen der Pflegekasse für Menschen mit Demenz ermöglicht. Der steigende Zeitaufwand für die Unterstützung bei Aktivitäten des täglichen Lebens und für Beaufsichtigung wird durch die Pflegegrade abgebildet. Trotz steigender Belastung wurden Entlastungsangebote selten genutzt. Es empfiehlt sich, Maßnahmen zur Erhöhung der Inanspruchnahme von Entlastungs- und Beratungsangeboten auszubauen.
... Neuropsychiatric symptoms such as apathy, aggression, disinhibition, and irritability are known to affect social cognition and social functioning (Lyketsos et al., 2011). Facial recognition of emotion, integrated with other social information, allows the observer to make assumptions about what an individual is thinking or feeling and responds to their needs accordingly. ...
... Few studies have compared the facial recognition abilities of patients with mild cognitive impairment (MCI) and AD at different stages Lavenu & Pasquier, 2005;Sheardova et al., 2014;Spoletini et al., 2008;Weiss et al., 2008). Although there is some evidence that impairment in recognizing emotions increases with progression in the AD stage (Adolphs, 2009;Lyketsos et al., 2011;Spoletini et al., 2008), studies have shown that it is preserved in severe stages of the disease (Sheardova et al., 2014), indicating that this issue needs to be clarified. ...
Background
Although deficits in facial emotion recognition (FER) significantly affect interpersonal communication and social functioning, there is no consensus on how FER affects Alzheimer's disease (AD). In this study, we aimed to investigate the clinical and neuropsychological factors affecting the possible deficits in the FER abilities of patients with AD.
Methods
This cross‐sectional study included 37 patients with mild [clinical dementia rating (CDR) scale score = 1] or moderate (CDR = 2) AD, in whom vascular dementia and depression were excluded, and 24 cognitively normal (CDR = 0) subjects. FER ability was determined using the facial emotion identification test (FEIT) and facial emotion discrimination test (FEDT). All participants underwent mini‐mental state examination (MMSE), frontal assessment battery (FAB), and geriatric depression scale (GDS). The neuropsychiatric inventory‐clinician rating scale (NPI‐C), Katz index of independence in activities of daily living, and Lawton instrumental activities of daily living were also administered to patients with AD.
Results
The FEIT and FEDT total scores showed that patients with mild and moderate AD had significant FER deficits compared to healthy controls. However, no significant difference was observed between patients with mild and moderate AD in the FEIT and FEDT total scores. FEIT and FEDT scores were not correlated with the MMSE and NPI‐C total and subscales scores in patients with AD. Linear regression indicated that FEIT and FEDT total scores were significantly related to age and FAB scores. The GDS score negatively moderated the relationship between FAB and FEDT.
Conclusions
This study demonstrated a decreased FER ability in patients with AD. The critical point in FER deficits is the presence of dementia, not the dementia stage, in AD. It has been determined that executive functions and depression (even at a subsyndromal level), which have limited knowledge, are associated with FER abilities.
... This development of a comprehensive testing battery addresses several missed opportunities within the aging research field that may contribute to the lack of translational success from animal models to clinical studies. First, the ability to study cognitive development and decline across the lifespan within the same individual; second, the integration of multiple cognitive domains to facilitate a more refined understanding of how pathological aging perturbs the trajectory of typical cognitive aging; and third, data from the battery of cognitive assessments can be integrated with a broad range of tests already established in marmosets that capture negative and positive valence, which are relevant to the spectrum of neuropsychiatric features of aging and AD that are diagnostic for dementia (Granholm et al., 2008;Lyketsos et al., 2011;Oikonomidis et al., 2017). Some of the earliest cognitive changes reported with aging in humans is age-related decline in processing speeds, which is a relative measure from an individual's peak performance and includes both speed of motor responses and speed at which cognitive activities are performed (reviewed in Salthouse, 2010; Harada et al., 2013 ;Murman, 2015). ...
... These data may be indicative of selective impairments in memory for subject #21 independent of impairments in attention, although additional data will be required, including ongoing longitudinal assessments, which are currently in progress for this subject as well as all others in our colony. Moreover, as part of the testing battery, the progressive ratio test assesses motivation; reduced motivation as measured by decreases in breakpoint, may be indicative of anhedonia, an important neuropsychiatric symptom of aging and AD, and which also is assessed for each subject (Granholm et al., 2008;Lyketsos et al., 2011;Oikonomidis et al., 2017). While indeed the primary symptom of AD is traditionally cognitive decline and memory loss, there are also other non-cognitive aging-related changes in mood as well as alterations in sleep, anxiety, depression, apathy, and social withdrawal which may also be exacerbated or have an accelerated progression of change as a consequence of disease (Granholm et al., 2008;Masters et al., 2015). ...
Concerns about poor animal to human translation have come increasingly to the fore, in particular with regards to cognitive improvements in rodent models, which have failed to translate to meaningful clinical benefit in humans. This problem has been widely acknowledged, most recently in the field of Alzheimer’s disease, although this issue pervades the spectrum of central nervous system (CNS) disorders, including neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Consequently, recent efforts have focused on improving preclinical to clinical translation by incorporating more clinically analogous outcome measures of cognition, such as touchscreen-based assays, which can be employed across species, and have great potential to minimize the translational gap. For aging-related research, it also is important to incorporate model systems that facilitate the study of the long prodromal phase in which cognitive decline begins to emerge and which is a major limitation of short-lived species, such as laboratory rodents. We posit that to improve translation of cognitive function and dysfunction, nonhuman primate models, which have conserved anatomical and functional organization of the primate brain, are necessary to move the field of translational research forward and to bridge the translational gaps. The present studies describe the establishment of a comprehensive battery of touchscreen-based tasks that capture a spectrum of domains sensitive to detecting aging-related cognitive decline, which will provide the greatest benefit through longitudinal evaluation throughout the prolonged lifespan of the marmoset.
... Neuropsychiatric symptoms are core features of dementia [1]. Behavioral and psychological symptoms (BPS), which are a combination of various symptoms, are some of the most common neuropsychiatric symptoms [2]. ...
... MMSE is a questionnaire for evaluating cognitive function [21]. It consists of 11 items as follows (maximum score of each item): orientation to time (5), orientation to place (5), registration of three words (3), attention and calculation (serial sevens or spelling) (5), recall (3), naming (2), repetition (1), comprehension of verbal (3), comprehension of written (1), writing (1), and construction (1). The maximum score is 30 points, with a higher score representing greater cognitive function. ...
This retrospective cross-sectional study is aimed at investigating the prevalence and characteristics of behavioral and psychological symptoms (BPS) in subacute stroke patients with cognitive impairment. The Neuropsychiatric Inventory-Questionnaire (NPI-Q) was used to assess BPS. A total of 358 consecutive patients with first-ever stroke admitted to rehabilitation wards and with Mini-Mental State Examination (MMSE) scores < 24 on admission were included. BPS was defined as a total NPI-Q Severity or Distress score ≥ 1 . Differences between the severity and presence of BPS among patients with severe cognitive impairment (MMSE scores 0–17) and those with mild cognitive impairment (MMSE scores 18–23) were analyzed using the Mann–Whitney U test and chi-squared test, respectively. Eighty-one patients (mean (standard deviation) age, 73.5 (13.1) years) were enrolled for analysis. BPS were observed in 69.1% and 74.1% of patients when assessed with NPI-Q Severity and NPI-Q Distress, respectively. The most frequently observed BPS was apathy, followed by depression (approximately 44% and 40%, respectively). The severity and frequency of delusions, euphoria, apathy, and disinhibition were significantly higher in the severe cognitive impairment group than in the mild cognitive impairment group. However, the severity, distress, and frequency of depression were not dependent on the severity of cognitive impairment. The presence of BPS, especially apathy and depression, in subacute stroke patients with cognitive impairment is high. The severity and frequency of some BPS are higher in patients with severe cognitive impairment than in those with mild cognitive impairment. However, depression is highly prevalent among the patients regardless of the severity of cognitive impairment.
... Major challenges in old age psychiatry include both the differential diagnostic separation from dementia especially against depression and somatic comorbidities, which can contribute to considerable variations between patients. The clinical phenotype alone is often misleading because virtually all psychiatric symptoms are transnosological: cognitive symptoms appear in major depression (9), affective and other non-cognitive symptoms appear in AD with high frequencies (10). Patients in old age psychiatry present "unfolded lives" with the opportunity to identify unique biographical and environmental characteristics. ...
Elderly patients show us unfolded lives with unique individual characteristics. An increasing life span is associated with increasing physical and mental disease burden. Alzheimer’s disease (AD) is an increasing challenge in old age. AD cannot be cured but it can be treated. The complexity of old age and AD offer targets for personalized medicine (PM). Targets for stratification of patients, detection of patients at risk for AD or for future targeted therapy are plentiful and can be found in several omic-levels.
... Typical symptoms of dementia are loss of memory, impaired orientation, loss of judgment and reasoning ability, and loss of speech (Atri 2019). Behavioral changes, such as apathy, avoidance of social interaction, and loss of affect control are also common (Lyketsos et al. 2011). All of these symptoms interfere with individual planning and problem-solving abilities (Atri 2019). ...
Monitoring and assistive technologies (MATs) are being used more frequently in healthcare. A central ethical concern is the compatibility of these systems with the moral preferences of their users—an issue especially relevant to participatory approaches within the ethics-by-design debate. However, users’ incapacity to communicate preferences or to participate in design processes, e.g., due to dementia, presents a hurdle for participatory ethics-by-design approaches. In this paper, we explore the question of how the value preferences of users in the field of dementia care can be integrated into AI-based MATs. First, we briefly introduce different ethics-by-design approaches and explain the challenges they face in dementia care. Next, we introduce a novel approach for addressing these challenges. Through a qualitative content analysis of interviews with persons with dementia and their family caregivers (n = 27), we identified multiple ideal–typical value preference profiles. We then applied these profiles in a computer simulation, by which we also introduce the concept of ethical compliance quantification to scale the moral preferences of the interviewees for the simulation. Finally, we discuss study results, the advantages of using computer simulations, and general study limitations before drawing conclusions for further research. The study contributes to the ongoing debate on participatory ethics-by-design by defining on the basis of empirical data ideal–typical value preference frameworks that can be used to guide MAT actions and their outcomes. Going forward, MAT end-users with dementia and other communication-impaired persons could be enabled to choose a value profile that best fits their moral preferences.
... Additional challenges for PwD are the deterioration in cognitive function and communication abilities which may have a negative influence on medication adherence [21,22]. Furthermore, up to 90% of PwD experience one or more non-cognitive symptoms which require prescribing of one or more psychoactive medications [23,24]. For example, the prescribing of three or more psychoactive medications concurrently for more than one month was reported in 13.9% community dwelling PwD in the United States in 2018 [25]. ...
Background
Studies have shown that potentially inappropriate prescribing (PIP) is highly prevalent among people with dementia (PwD) and linked to negative outcomes, such as hospitalisation and mortality. However, there are limited data on prescribing appropriateness for PwD in Saudi Arabia. Therefore, we aimed to estimate the prevalence of PIP and investigate associations between PIP and other patient characteristics among PwD in an ambulatory care setting.
Methods
A cross-sectional, retrospective analysis was conducted at a tertiary hospital in Saudi Arabia. Patients who were ≥ 65 years old, had dementia, and visited ambulatory care clinics between 01/01/2019 and 31/12/2021 were included. Prescribing appropriateness was evaluated by applying the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria. Descriptive analyses were used to describe the study population. Prevalence of PIP and the prevalence per each STOPP criterion were calculated as a percentage of all eligible patients. Logistic regression analysis was used to investigate associations between PIP, polypharmacy, age and sex; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Analyses were conducted using SPSS v27.
Results
A total of 287 PwD were identified; 56.0% (n = 161) were female. The mean number of medications prescribed was 9.0 [standard deviation (SD) ± 4.2]. The prevalence of PIP was 61.0% (n = 175). Common instances of PIP were drugs prescribed beyond the recommended duration (n = 90, 31.4%), drugs prescribed without an evidence-based clinical indication (n = 78, 27.2%), proton pump inhibitors (PPIs) for > 8 weeks (n = 75, 26.0%), and acetylcholinesterase inhibitors with concurrent drugs that reduce heart rate (n = 60, 21.0%). Polypharmacy was observed in 82.6% (n = 237) of patients and was strongly associated with PIP (adjusted OR 24.1, 95% CI 9.0–64.5).
Conclusions
Findings have revealed a high prevalence of PIP among PwD in Saudi Arabia that is strongly associated with polypharmacy. Future research should aim to explore key stakeholders’ experiences and perspectives of medicines management to optimise medication use for this vulnerable patient population.
... FDA-approved drugs including donepezil, rivastigmine, and galantamine are mainly used to treat b-amyloid deposition and tau fiber tangles, but the effect is not significant (3,4). More and more studies showed that neuroinflammation played a key role in AD neurodegeneration, and how to control the inflammatory response caused by Ab protein provides a new research direction for the treatment of AD (5)(6)(7). ...
Background
Acanthopanax senticosus (AS) can improve sleep, enhance memory, and reduce fatigue and is considered as an effective drug for Alzheimer’s disease (AD). The therapeutic effect and mechanism need to be further investigated.
Methods
To confirm the AS play efficacy in alleviating memory impairment in mice, 5×FAD transgenic mice were subjected to an open-field experiment and a novelty recognition experiment. Network pharmacology technique was used to analyze the information of key compounds and potential key targets of AS for the treatment of AD, molecular docking technique was applied to predict the binding ability of targets and compounds, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were also performed on the targets to derive the possible metabolic processes and pathway mechanisms of AS in treating AD. Quantitative real-time PCR (qRT-PCR) and western blot technique were carried out to validate the candidate genes and pathways.
Results
In the open-field experiment, compared with the wild-type (WT) group, the number of times the mice in the AD group crossed the central zone was significantly reduced (P< 0.01). Compared with the AD group, the number of times the mice in the AS group crossed the central zone was significantly increased (P< 0.001). In the new object recognition experiment, compared with the WT group, the percentage of times the AD group explored new objects was significantly reduced (P< 0.05). Compared with the AD group, the AS group had an increase in the percentage of time spent exploring new things and the number of times it was explored (P< 0.05). At the same time, the donepezil group had a significantly higher percentage of times exploring new things (P< 0.01). By using network pharmacology technology, 395 common targets of AS and AD were retrieved. The Cytoscape software was used to construct the protein–protein interaction (PPI) network of common targets. Using the algorithm, nine key targets were retrieved: APP, NTRK1, ESR1, CFTR, CSNK2A1, EGFR, ESR2, GSK3B, and PAK1. The results of molecular docking indicate that 11 pairs of compounds and their corresponding targets have a significant binding ability, as the molecular binding energies were less than -7.0. In comparison to the AD group, the mRNA expression of the key target genes was significantly decreased in the AS treatment group (P< 0.001). The KEGG analysis showed that the MAPK signaling pathway was significantly enriched, and Western blot confirmed that the TRAF6 protein decreased significantly (P< 0.0001). Meanwhile, the levels of MAP3K7 and P38 phosphorylation increased, and there was also an increase in the expression of HSP27 proteins.
Conclusion
Our study indicates that the multi-component and multi-target properties of AS play an important role in the alleviation of anxiety and memory impairment caused by AD, and the mechanism is involved in the phosphorylation and activation of the MAPK signaling pathway. The results of this study could provide a novel perspective for the clinical treatment of AD.
... Age and duration of therapy emerged as two main modulators of AD risk associated with CNS-active drugs, where AD risk reduction was apparent after 3 years of drug exposure and reduction of AD risk was greater with increasing age. During early stages of AD pathology, a misdiagnosis of a neuropsychiatric disorder can occur as a consequence of the common symptomatology of both diseases (69,70). Thus, the increased AD risk observed in patients receiving CNS-active drugs for less than 3 years may be the result of AD pathology already established in this group of patients, but not yet diagnosed. ...
Objective
As neuropsychiatric conditions can increase the risk of age-related neurodegenerative diseases (NDDs), the impact of CNS-active drugs on the risk of developing Alzheimer’s Disease (AD), non-AD dementia, Multiple Sclerosis (MS), Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) was investigated.
Research design and methods
A retrospective cohort analysis of a medical claims dataset over a 10 year span was conducted in patients aged 60 years or older. Participants were propensity score matched for comorbidity severity and demographic parameters. Relative risk (RR) ratios and 95% confidence intervals (CI) were determined for age-related NDDs. Cumulative hazard ratios and treatment duration were determined to assess the association between CNS-active drugs and NDDs at different ages and treatment duration intervals.
Results
In 309,128 patients who met inclusion criteria, exposure to CNS-active drugs was associated with a decreased risk of AD (0.86% vs 1.73%, RR: 0.50; 95% CI: 0.47-0.53; p <.0001) and all NDDs (3.13% vs 5.76%, RR: 0.54; 95% CI: 0.53-0.56; p <.0001). Analysis of impact of drug class on risk of AD indicated that antidepressant, sedative, anticonvulsant, and stimulant medications were associated with significantly reduced risk of AD whereas atypical antipsychotics were associated with increased AD risk. The greatest risk reduction for AD and NDDs occurred in patients aged 70 years or older with a protective effect only in patients with long-term therapy (>3 years). Furthermore, responders to these therapeutics were characterized by diagnosed obesity and higher prescriptions of anti-inflammatory drugs and menopausal hormonal therapy, compared to patients with a diagnosis of AD (non-responders). Addition of a second CNS-active drug was associated with greater reduction in AD risk compared to monotherapy, with the combination of a Z-drug and an SNRI associated with greatest AD risk reduction.
Conclusion
Collectively, these findings indicate that CNS-active drugs were associated with reduced risk of developing AD and other age-related NDDs. The exception was atypical antipsychotics, which increased risk. Potential use of combination therapy with atypical antipsychotics could mitigate the risk conferred by these drugs. Evidence from these analyses advance precision prevention strategies to reduce the risk of age-related NDDs in persons with neuropsychiatric disorders.
... The prodromal phase of AD is thought to involve NPS, in the absence of detectable cognitive symptoms. 3,17 Among the preclinical symptoms, anxiety and depression are the most commonly observed and are considered robust indicators of subsequent AD development. 30,31,45,46 While NPS is frequently observed throughout all stages, preclinical symptoms may include heightened agitation or impaired social functioning. ...
... There are correlations between delusions and decreased glucose metabolism in specific brain regions, and altered glucose metabolism has been linked to non-cognitive psychiatric symptoms (NPS) such as anxiety, apathy, agitation, and disinhibition citation). Mild cognitive impairment (MCI) and other symptoms including apathy, anxiety, irritability, and depression may be present in the early stages of the disease (Hashimoto et al., 2006;Lyketsos et al., 2011). ...
Approximately 50 million people live with Alzheimer’s (Alz) and 50,000 people are living with Transthyretin Amyloidosis (ATTR) worldwide. Both Alz and ATTR are types of amyloidosis, a disease where amyloid protein builds up in the body’s organs. Alz and ATTR are conditions with no known cures and similar etiologies but different manifestations in the brain and heart, respectively. Alzheimer’s disease is irreversible, which causes lifelong suffering for patients and their families. ATTR is a potentially fatal disease that causes heart problems for patients. Amyloidosis arises due to genetic mutations in the amyloid precursor protein (APP) or proteins involved in the generation of APP such as BACE1, PSEN1, PSEN2, APOE and transthyretin (TTR) genes, which result in the overexpression and accumulation of amyloid protein. CRISPR-Cas9 is a breakthrough gene editing technology that is capable of editing mutations in multiple genes with high specificity. This technology has the capability of treating both Alz and ATTR through targeted gene editing of the mutations that contribute to these diseases. This review will focus on BACE1, PSEN1, PSEN2, and APOE as targets for Alz and TTR as a treatment for ATTR through the use of CRISPR-Cas9. Various delivery mechanisms and current clinical trials will be discussed to identify the best delivery route of these treatments for the respective disease . A CRISPR-Cas9 derived treatment would bring new hope for patients with these diseases and could propel cures for other types of amyloidosis.
... Neuropsychiatric symptoms (NPS) are non-cognitive manifestations of neurodegenerative diseases that include mood disturbances, abnormal perceptions, and problematic behaviors. 1,2 Although cognitive impairment is a hallmark symptom of dementia, NPS can occur several years before dementia onset. 3 Later-life NPS may emerge before detectable cognitive decline and are associated with a higher risk of clinical progression to mild cognitive impairment (MCI) or dementia. ...
Background:Quality of life is an essential outcome parameter in geriatric research; however, research to date offers mixed evidence about the factors associated with health-related quality of life (HRQOL) among people with dementia (PWDs). We aimed to identify factors relating to HRQOL among PWDs living in long-term care (LTC) facilities.
Methods:A total of 299 from 1,607 registered long-term care facilities were randomly selected in every administrative region of Taiwan. A cross-sectional two-phase survey, which included the demographic data, comorbidities, EuroQol-5 dimensions-5 levels (EQ-5D-5L), mini-mental state examination (MMSE) score, clinical dementia rating scores (CDR), behavioral and psychological symptoms of dementia, and activities of daily living (ADL) of PWDs, was then conducted from 2019 to 2020.
Results:A total of 1,313 PWDs who self-completed EQ-5D-5L were enrolled in this analysis with a mean age of 76.43 ± 12.7 years. The mean utility and visual analogue scale (VAS) scores of EQ-5D-5L were 0.10 (standard deviation, SD = 0.48) and 66.57 (SD = 20.67), respectively. Multivariate linear regression analysis showed that higher scores in ADL, instrumental ADL, and lower CDR sum scores were associated with higher EQ-5D-5L utility scores. Higher ADL scores and higher MMSE scores were associated with higher scores in an EQ-5D-5L-VAS. More depressive symptoms were related to both lower utility score and lower EQ-5D-5L-VAS score.
Conclusion:Findings highlight the importance to recognize and to treat depression to maintain HRQOL of PWDs in LTC facilities. Longitudinal studies are needed to better understand the long-term changes in HRQOL of PWDs.
... ICAD is also associated with Moca and fatigue but not with the volume of WMH and gray matter volume. NPS are common features of all types of dementia, irrespective of disease etiology and disease stage [29]. MBI may be an earlier marker of neurodegenerative disease than MCI, captured at the stage of subjective cognitive decline or before, raising the possibility that MBI represents a novel target for dementia clinical trials or prevention strategies [30]. ...
Purpose
The aim of this study was to analyze the association between Intracranial atherosclerotic stenosis (ICAS) and post-stroke mild behavioral impairment (MBI) in patients with minor stroke.
Methods
A total of 121 patients underwent high-resolution 3T magnetic resonance angiography and MBI checklist (MBI-C) assessment. We adjusted for demographic and vascular risk factors in logistic regression analysis, to determine the association of ICAS with MBI.
Results
Of the 121 patients with minor stroke in this study, 52 (42.98%) were diagnosed with ICAS. After adjusting for potential confounders, we found that patients with ICAS were more likely to develop MBI after an acute, non-disabling ischemic stroke compared to patients without ICAS (Odds Ratio:5.28; 95% Confidence Interval: 2.27-13.0)
Conclusions
Our study demonstrated a positive association between ICAS and post-stroke MBI in patients with minor stroke. Furthermore, the inverse correlation between precuneus cortical thickness and MBI scores provides a new insight into further diagnosing MBI through imaging. Our findings suggest that early detection and treatment of ICAS may help prevent the development of MBI in patients with minor stroke.
... (16) There were some factors associated with personality change in MCI, for example, dysnomia (17) , neuropsychiatric symptoms (NPS), associated with faster progression of dementia (18) , an increase in disability and poor quality of life, earlier hospital admission, and an increase burden for caretakers. (19) Personality change is also believed to be useful information in making a diagnosis of MCI, which then leads to earlier treatment and better outcome for the patients. However, there are still limited numbers of studies on this issue and some also show conflicting results. ...
... Cognitive impairment, behavioral disorders, and neuropsychiatric symptoms are common findings in AD patients (Cortes et al., 2018). A high prevalence of neuropsychiatric symptoms is observed in AD, with most exhibiting one or more symptoms ranging from mild to severe throughout the disease's progression (Lyketsos et al., 2011). The underlying causes of neuropsychiatric symptoms in AD patients include neuropathological changes in the brain, unmet psychological needs, physical illness, and pain (Cammisuli et al., 2022). ...
... Additionally, AD patients often exhibit mild language impairments and judgment deficits (Miguel et al., 2020). Neuropsychiatric symptoms, including behavioral changes, can also be observed in individuals with AD (Lyketsos et al., 2011). The pathophysiological landscape of AD is multifaceted, underpinned by various hypotheses, including the roles of (a) amyloid-β, (b) Tau pathology leading to neurofibrillary tangles, (c) mitochondrial dysfunction, and reactive oxygen species (ROS) generation, among others (Alqahtani et al., 2023). ...
Alzheimer’s disease (AD) is a complex, multifactorial disorder, influenced by a multitude of variables ranging from genetic factors, age, and head injuries to vascular diseases, infections, and various other environmental and demographic determinants. Among the environmental factors, the role of the microbiome in the genesis of neurodegenerative disorders (NDs) is gaining increased recognition. This paradigm shift is substantiated by an extensive body of scientific literature, which underscores the significant contributions of microorganisms, encompassing viruses and gut-derived bacteria, to the pathogenesis of AD. The mechanism by which microbial infection exerts its influence on AD hinges primarily on inflammation. Neuroinflammation, activated in response to microbial infections, acts as a defense mechanism for the brain but can inadvertently lead to unexpected neuropathological perturbations, ultimately contributing to NDs. Given the ongoing uncertainty surrounding the genetic factors underpinning ND, comprehensive investigations into environmental factors, particularly the microbiome and viral agents, are imperative. Recent advances in neuroscientific research have unveiled the pivotal role of non-coding RNAs (ncRNAs) in orchestrating various pathways integral to neurodegenerative pathologies. While the upstream regulators governing the pathological manifestations of microorganisms remain elusive, an in-depth exploration of the nuanced role of ncRNAs holds promise for the development of prospective therapeutic interventions. This review aims to elucidate the pivotal role of ncRNAs as master modulators in the realm of neurodegenerative conditions, with a specific focus on Alzheimer’s disease.
... In particular, the role of dopamine has been proved in a validated AD mouse model [16] and confirmed in AD patients by different imaging tools [17][18][19]. Hence, the catecholaminergic synapses constitute vulnerable functional elements during the prodromal phase of AD, likely contributing to the appearance of neuropsychiatric symptoms that appear in the early stages of AD [20]. Understanding the complex interplay between dopamine dysfunction and AD pathology remains an active and important area of research. ...
Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aβ), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aβ instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aβ associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and β-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.
... Neurodegeneration, declining brain functions, apathy, anxiety, depression and memory loss are key signs of AD. Aggression, hallucinations, and delusions grow more frequently as illness worsens (Lyketsos et al., 2011). AChE, an important biochemical enzyme from cholinesterase family, is recognized as primary pharmacological target for treating AD (Arslan et al., 2020;Cavdar et al., 2019;Poslu et al., 2023). ...
Alzheimer's disease (AD) leads to gradual memory loss including other compromised cognitive abilities. Acetylcholinesterase (AChE), an important biochemical enzyme from the cholinesterase (ChE) family, is recognized as primary pharmacological target for treating AD. Currently marketed drugs for AD treatment are primarily AChE inhibitors and coumarin derivatives comprising a wide variety of pharmacological activities have proved their efficacy towards AChE inhibition. Ensaculin (KA-672 HCl), a compound that belong to the coumarin family, is a clinical trial candidate for AD treatment. Therefore, a ligand library was prepared with 60 reported coumarin derivatives for field-based 3D-QSAR and pharmacophore modelling. The field-based 3D-QSAR model obtained at partial least square (PLS) factor 7, was the best validated model that predicted activity closer to original activity for each ligand introduced. The contour maps demonstrated spatial distribution of favourable and unfavorable steric, hydrophobic, electrostatic and H-bond donor and acceptor contours around coumarin nucleus. The best pharmacophore model, ADHRR_1 exhibited five essential pharmacophoric features of four different traits for optimum AChE inhibition. Virtual screening through ADHRR_1 accompanied with molecular docking and MM/GBSA identified 10 HITs from a 4,00,000 coumarin derivatives from PubChem database. HITs comprised docking scores ranging from −12.096 kcal/mol to −8.271 kcal/mol and compared with the reference drug Donepezil (-8.271 kcal/mol). ADME properties analysis led into detecting two leads (HIT 1 and HIT 2) among these 10 HITs. Molecular Dynamics Simulation indicated thermodynamic stability of the complex of lead compounds with AChE protein. Finally, thorough survey of the experimental results from 3D-QSAR modelling, pharmacophore modelling and molecular docking interactions led us to develop the lead formula I for future advancements in treating AD through AChE inhibitors.
Causes of behaviour that challenge in dementia are often thought to be due to reversible factors, such as a urine infection or disrupted sleep‐wake cycle. In this review, the authors consider a definition of behaviour that challenges commonly cited causes and management models. Finally, recommendations for an alternative view and subsequent approach to managing behaviour that challenges are suggested.
Objective
We aimed to examine associations between neuropsychiatric symptoms (NPS) and white matter hyperintensities (WMH) status in older adults without dementia under the hypothesis that WMH increased the odds of having NPS.
Design
Longitudinal analysis of data acquired from the National Alzheimer’s Coordinating Center Uniform Data Set.
Settings
Data were derived from 46 National Institute on Aging - funded Alzheimer’s Disease Research Centers.
Participants
NACC participants aged ≥50 years with available data on WMH severity with a diagnosis of mild cognitive impairment (MCI) or who were cognitively unimpaired (CU) were studied. Among 4617 CU participants, 376 had moderate and 54 extensive WMH. Among 3170 participants with MCI, 471 had moderate and 88 had extensive WMH.
Measurements : Using Cardiovascular Health Study (CHS) scores, WMH were coded as no to mild (CHS score: 0-4), moderate (score: 5-6) or extensive (score: 7-8). NPS were quantified on the Neuropsychiatric Inventory Questionnaire. Binary logistic regression models estimated the odds of reporting each of 12 NPS by WMH status separately for individuals with MCI or who were CU.
Results
Compared to CU individuals with no to mild WMH, the odds of having elation [9.87,(2.63-37.10)], disinhibition [4.42,(1.28-15.32)], agitation [3.51,(1.29-9.54)] or anxiety [2.74,(1.28-5.88)] were higher for the extensive WMH group, whereas the odds of having disinhibition were higher for the moderate WMH group [1.94,(1.05-3.61)]. In the MCI group, he odds of NPS did not vary by WMH status.
Conclusions
Extensive WMH were associated with higher odds of NPS in CU older adults but not in those with MCI.
The integration of artificial intelligence (AI) into the realm of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease, presents a promising avenue for revolutionizing diagnosis, treatment, and management strategies. Through AI-driven technologies such as machine learning and neuroimaging analysis, researchers can sift through vast datasets encompassing genetic, molecular, clinical, and imaging data to pinpoint disease biomarkers, predict disease progression, and tailor treatment plans according to individual patient profiles.
AI algorithms coupled with neuroimaging techniques offer the ability to detect subtle changes in brain structure and function that precede clinical symptoms, allowing for early intervention and disease-modifying treatments. Additionally, AI-powered digital biomarkers extracted from wearable devices and mobile health technologies enable real-time monitoring of disease progression and treatment response.
In drug discovery and development, AI holds promise in identifying novel drug targets, repurposing existing drugs, and designing innovative therapeutic interventions tailored to the molecular mechanisms of neurodegeneration. However, challenges such as data privacy, regulatory compliance, and interdisciplinary collaboration must be addressed to fully harness the potential of AI in neurodegenerative disease research and patient care.
Overall, AI offers unprecedented opportunities to advance our understanding of neurodegenerative diseases, accelerate therapeutic innovation, and improve patient outcomes. By embracing AI-driven technologies, we can pave the way for a new era of precision medicine and personalized care in the fight against neurodegenerative diseases.
Dementia, a complex and debilitating neurodegenerative disorder, poses a significant public health challenge worldwide. This research aims to investigate the prevalence of dementia in India, shedding light on the demographic and regional variations in this rapidly evolving landscape. Utilizing a comprehensive cross-sectional study design, data was collected from diverse urban and rural populations across the country. The study employed standardized research tools to evaluate cognitive function and diagnose dementia cases. Our findings reveal a nuanced picture of dementia prevalence in India, emphasizing the influence of socio-economic factors, lifestyle, and regional disparities. The implications of our research extend beyond epidemiological insights, offering a foundation for targeted interventions, policy development, and healthcare planning to address the growing burden of dementia in the Indian population. This paper contributes to the global discourse on dementia by presenting a detailed analysis of its prevalence in a dynamic and diverse socio-cultural context.
Neuropsychiatric symptoms (NPS), or behavioral and psychological symptoms of dementia (BPSD), affect most individuals with major or mild neurocognitive disorders (NCDs), formerly termed dementia or mild cognitive impairment, respectively, at some point during the course of the illness. The near universal prevalence of NPS in NCDs has prompted the recent inclusion of noncognitive symptoms in the core diagnostic criteria of NCDs. They are associated with a reduced quality of life and increased institutionalization, with adverse effects on both the patient and the formal and informal caregivers. Despite the prevalence of NPS, there are very few licensed medications that are proven effective and safe, partly based on the limited understanding of the underlying neurobiology of NPS. This chapter will provide a concise and up-to-date overview of noncognitive symptoms of NCDs including the nature, prevalence, assessment, and management of these behaviors.
Previous studies demonstrated a significant protective effect of elevated cerebrospinal fluid (CSF) sTREM2 levels on brain structure and cognitive decline. Nonetheless, the role of sTREM2 in the depression progression remains unclear. This study aimed to investigate the association between CSF sTREM2 levels and longitudinal trajectories of depression.
Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Study were used. CSF sTREM2 levels and depression were measured using an ELISA-based assay and the Geriatric Depression Scale (GDS-15), respectively. Linear mixed-effect models were employed to assess the relationships between CSF sTREM2 levels and GDS scores.
A total of 1,017 participants were enrolled at baseline, with a mean follow-up time of 4.65 years. Baseline CSF sTREM2 levels were negatively correlated with GDS scores (β=−0.21, P=0.022) after adjustment for age, gender, race/ethnicity, education, APOE ε4 carrier status, TREM2 rare variant carrier status, marital status, smoking, and clinical cognitive status.
Our findings suggested that a higher level of CSF sTREM2 was associated with a lower risk of depression.
BACKGROUND
Neuropsychiatric symptoms (NPS) are common in older people, may occur early in the development of dementia disorders, and have been associated with faster cognitive decline. Here, our objectives were to investigate whether plasma levels of neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), and tau phosphorylated at threonine 181 (pTau181) are associated with current NPS and predict future NPS in non-demented older people. Furthermore, we tested whether the presence of NPS combined with plasma biomarkers are useful to predict Alzheimer’s disease (AD) pathology and cognitive decline.
METHODS
One hundred and fifty-one participants with normal cognition (n=76) or mild cognitive impairment (n=75) were examined in a longitudinal brain aging study at the Memory Centers, University Hospital of Lausanne, Switzerland. Plasma levels of NfL, GFAP, and pTau181 along with CSF biomarkers of AD pathology were measured at baseline. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI-Q), along with the cognitive and functional performance at baseline and follow-up (mean: 20 months). Linear regression and ROC analyses were used to address the associations of interest.
RESULTS
Higher GFAP levels were associated with NPS at baseline (β=0.23, p=.008). Higher NfL and GFAP levels were associated with the presence of NPS at follow-up (β=0.29, p=.007 and β=0.28, p=.007, respectively) and with an increase in the NPI-Q severity score over time (β=0.23, p=.035 and β=0.27, p=.011, respectively). Adding NPS and the plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.73 to 0.84, p=.007) and AD pathology (AUC 0.79 to 0.86, p=.006), but not of cognitive decline (AUC 0.79 to 0.84, p=.068).
CONCLUSION
Plasma GFAP is associated with NPS while NfL and GFAP are both associated with future NPS and NPS severity. Considering the presence of NPS along with blood-based AD-biomarkers may improve diagnosis and prediction of clinical progression of NPS and inform clinical decision-making in non-demented older people.
Stimulation of the M 4 muscarinic acetylcholine receptor reduces striatal hyperdopaminergia, suggesting its potential as a therapeutic target for schizophrenia. Emraclidine (CVL-231) is a novel, highly selective, positive allosteric modulator (PAM) of M4 muscarinic acetylcholine receptors i.e. acts as a modulator that increases the response of these receptors. First, we aimed to further characterize the positron emission tomography (PET) imaging and quantification performance of a recently developed M 4 PAM radiotracer, [ ¹¹ C]MK-6884, in non-human primates (NHPs). Second, we applied these results to determine the receptor occupancy of CVL-231 as a function of dose. Using paired baseline-blocking PET scans, we quantified total volume of distribution, binding potential, and receptor occupancy. Both blood-based and reference region-based methods quantified M 4 receptor levels across brain regions. The 2-tissue 4-parameter kinetic model best fitted regional [ ¹¹ C]MK-6884-time activity curves. Only the caudate nucleus and putamen displayed statistically significant [ ¹¹ C]MK-6884 uptake and dose-dependent blocking by CVL-231. For binding potential and receptor occupancy quantification, the simplified reference tissue model using the grey cerebellum as a reference region was employed. CVL-231 demonstrated dose-dependent M 4 receptor occupancy in the striatum of the NHP brain and shows promise for further development in clinical trials.
Importance
Dementia affects 10% of those 65 years or older and 35% of those 90 years or older, often with profound cognitive, behavioral, and functional consequences. As the baby boomers and subsequent generations age, effective preventive and treatment strategies will assume increasing importance.
Observations
Preventive measures are aimed at modifiable risk factors, many of which have been identified. To date, no randomized clinical trial data conclusively confirm that interventions of any kind can prevent dementia. Nevertheless, addressing risk factors may have other health benefits and should be considered. Alzheimer disease can be treated with cholinesterase inhibitors, memantine, and antiamyloid immunomodulators, with the last modestly slowing cognitive and functional decline in people with mild cognitive impairment or mild dementia due to Alzheimer disease. Cholinesterase inhibitors and memantine may benefit persons with other types of dementia, including dementia with Lewy bodies, Parkinson disease dementia, vascular dementia, and dementia due to traumatic brain injury. Behavioral and psychological symptoms of dementia are best treated with nonpharmacologic management, including identifying and mitigating the underlying causes and individually tailored behavioral approaches. Psychotropic medications have minimal evidence of efficacy for treating these symptoms and are associated with increased mortality and clinically meaningful risks of falls and cognitive decline. Several emerging prevention and treatment strategies hold promise to improve dementia care in the future.
Conclusions and Relevance
Although current prevention and treatment approaches to dementia have been less than optimally successful, substantial investments in dementia research will undoubtedly provide new answers to reducing the burden of dementia worldwide.
Background:
Alzheimer's disease (AD) is the most common cause of dementia. Its initially characterized by progressive short-term memory loss followed by cross-domain cognitive decline in later stages resulting in significant functional deficits and loss of activities of daily living (ADLs) independence. Apathy and depression are frequent neuropsychiatric sequelae in AD, but their contribution to functional deficits is poorly understood.
Objective:
We aimed to quantitatively investigate if apathy and depressive symptoms predict ADLs in AD. We also wanted to fractionate apathy dimensions by factor-analyzing the apathy evaluation scale (AES) and then investigate the dimensions' relation to ADLs.
Methods:
We recruited a sample of 115 patients with probable or possible AD and assessed them for depression, apathy, and ADLs alongside other measures. We hypothesized that apathy and depressive symptoms would predict ADLs and that AES items will load into cognitive, behavioral, and affective factors that would differentially relate to ADLs.
Results:
Our results indicated that apathy symptoms predict ADLs deficits. The AES items resolved into a three-factor solution but the manner of clustering diverged from that proposed by AES authors. When these factors were regressed simultaneously, only behavioral apathy predicted global ADLs. Distinguishing basic from instrumental ADLs showed that behavioral and cognitive apathy symptoms associate with ADLs deficits while affective symptoms do not.
Conclusions:
Our results highlight the influence of apathy on ADLs in AD. This has important implications for patient care considering the high prevalence of apathy in AD and other dementing illnesses.
Background:
Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health.
Objective:
To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages.
Methods:
We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs.
Results:
Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%.
Conclusions:
Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.
Background:
Mild behavioural impairment (MBI) is an emergent and persistent neuropsychiatric symptom (NPS) in subjects aged 50 and older who are at risk for cognitive decline. We examined the prevalence of MBI across the spectrum from cognitively normal (CN), mild cognitive impairment (MCI), to dementia, and further investigated the association between the MBI domain and cognitive and functional impairment.
Method:
MBI was assessed in 2337 elderly patients in the Alzheimer's Disease Neuroimaging Initiative database (mean age, 73.04 years; 52.8% male). Among the subjects, 868 (37.1%) had normal cognition, 1066 (45.6%) had MCI, and 403 (17.2%) had mild Alzheimer's dementia (AD). MBI was evaluated in accordance with the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment diagnostic criteria for MBI, utilising the Neuropsychiatric Inventory. We compared the prevalence of the MBI domain with CN using multinominal logistic regression analysis and further quantified the magnitude of the association between MCI/AD and the MBI domains by calculating the population attributable risk (PAR). We assessed the association between the MBI domains and cognitive and functional impairment using simultaneous linear regression analysis.
Results:
The most common MBI domains in each diagnostic group were affective dysregulation followed by impulse dyscontrol, decreased motivation, social inappropriateness, and abnormal perception or thought content. The PARs for MBI domains in subjects with MCI or AD were respectively: 16.60% and 24.34% for affective dysregulation; 3.72% and 18.06% for impulse dyscontrol; 4.78% and 14.13% for decreased motivation, 1.91% and 2.29% for social inappropriateness; and 0.68% and 3.85% for abnormal perception or thought content. All MBI domains except for social inappropriateness were significantly associated with a higher 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale total score. All MBI domains were significantly associated with a higher Functional Activities Questionnaire total score.
Conclusion:
Our findings show that MBI is highly prevalent across subjects with CN, MCI, and AD and is associated with cognitive and functional decline. MBI could be a crucial clinical phenotype relevant to the risk of cognitive and functional impairment, and provides a useful dimension pertinent to diagnostic approaches.
Alzheimer's disease (AD) is an onset and incurable neurodegenerative disorder that has been linked to various genetic, environmental, and lifestyle factors. Recent research has revealed several potential targets for drug development, such as the prevention of Aβ production and removal, prevention of tau hyperphosphorylation, and keeping neurons alive. Drugs that target numerous ADrelated variables have been developed, and early results are encouraging. This review provides a concise map of the different receptor signaling pathways associated with Alzheimer's Disease, as well as insight into drug design based on these pathways. It discusses the molecular mechanisms of AD pathogenesis, such as oxidative stress, aging, Aβ turnover, thiol groups, and mitochondrial activities, and their role in the disease. It also reviews the potential drug targets, in vivo active agents, and docking studies done in AD and provides prospects for future drug development. This review intends to provide more clarity on the molecular processes that occur in Alzheimer's patient's brains, which can be of use in diagnosing and preventing the condition.
Background:
The purpose of this study was to investigate the longitudinal relationship between different levels of cognitively stimulating leisure activity (CSLA) participation and different levels of positive and negative affect among older adults with mild cognitive impairment (MCI).
Methods:
Using a repeated-measured multivariate analysis of covariance (RM-MANCOVA), this study analyzed the Health and Retirement Study (HRS) data from 2012 to 2020 (N = 5932).
Results:
The results presented the following. (a) The high CSLA group showed higher positive affect and lower negative affect than the mid and low groups. Also, the mid-CSLA group presented higher positive affect and lower negative affect than the low CSLA group. (b) Both positive and negative affect showed significant differences between years and indicated a continuously declining slope year by year without exceptions. (c) The high CSLA group not only presented higher positive affect and lower negative affect during the period but also solely showed a rebounding feature in the declining slope on both emotions.
Conclusions:
The findings of this study provide valuable support for the design and implementation of CSLA participation programs and clinical guidelines for older adults with MCI. The results highlight the importance of determining the optimal level of CSLA engagement that is required to promote emotional health and cognitive function in this population. Healthcare professionals and clinical practitioners can leverage the insights gained from this study to develop and deliver effective CSLA interventions tailored to the specific needs and capacities of older adults with MCI.
Background: The concept of Alzheimer disease (AD)—since its histological discovery by Alzheimer to the present day—has undergone substantial modifications. Methods: We conducted a classical narrative review of this field with a bibliography selection (giving preference to Medline best match). Results: The following subjects are reviewed and discussed: Alzheimer’s discovery, Kraepelin’s creation of a new disease that was a rare condition until the 1970′s, the growing interest and investment in AD as a major killer in a society with a large elderly population in the second half of the 20th century, the consolidation of the AD clinicopathological model, and the modern AD nosology based on the dominant amyloid hypothesis among many others. In the 21st century, the development of AD biomarkers has supported a novel biological definition of AD, although the proposed therapies have failed to cure this disease. The incidence of dementia/AD has shown a decrease in affluent countries (possibly due to control of risk factors), and mixed dementia has been established as the most frequent etiology in the oldest old. Conclusions: The current concept of AD lacks unanimity. Many hypotheses attempt to explain its complex physiopathology entwined with aging, and the dominant amyloid cascade has yielded poor therapeutic results. The reduction in the incidence of dementia/AD appears promising but it should be confirmed in the future. A reevaluation of the AD concept is also necessary.
Background:
Emotion and cognition are intercorrelated. Impaired emotion is common in populations with Alzheimer's disease (AD) and mild cognitive impairment (MCI), showing promises as an early detection approach.
Objective:
We aim to develop a novel automatic classification tool based on emotion features and machine learning.
Methods:
Older adults aged 60 years or over were recruited among residents in the long-term care facilities and the community. Participants included healthy control participants with normal cognition (HC, n = 26), patients with MCI (n = 23), and patients with probable AD (n = 30). Participants watched emotional film clips while multi-dimensional emotion data were collected, including mental features of Self-Assessment Manikin (SAM), physiological features of electrodermal activity (EDA), and facial expressions. Emotional features of EDA and facial expression were abstracted by using continuous decomposition analysis and EomNet, respectively. Bidirectional long short-term memory (Bi-LSTM) was used to train classification model. Hybrid fusion was used, including early feature fusion and late decision fusion. Data from 79 participants were utilized into deep machine learning analysis and hybrid fusion method.
Results:
By combining multiple emotion features, the model's performance of AUC value was highest in classification between HC and probable AD (AUC = 0.92), intermediate between MCI and probable AD (AUC = 0.88), and lowest between HC and MCI (AUC = 0.82).
Conclusions:
Our method demonstrated an excellent predictive power to differentiate HC/MCI/AD by fusion of multiple emotion features. The proposed model provides a cost-effective and automated method that can assist in detecting probable AD and MCI from normal aging.
Depression is a common and devastating neuropsychiatric symptom in the elderly and in patients with dementia. In particular, nearly 80% of patients with Alzheimer’s Disease dementia experience depression during disease development and progression. However, it is unknown whether the depression in patients with dementia shares the same molecular mechanisms as depression presenting as primary psychiatric disease or occurs and persists through alternative mechanisms. In this review, we discuss how the clinical presentation and treatment differ between depression in dementia and as a primary psychiatric disease, with a focus on major depressive disorder. Then, we hypothesize several molecular mechanisms that may be unique to depression in dementia such as neuropathological changes, inflammation, and vascular events. Finally, we discuss existing issues and future directions for investigation and treatment of depression in dementia.
Introduction
This paper focuses on the expression and role of FcγRIIb in neuroinflammation, exploring the molecular mechanisms by which FcγRIIb interacts with the bridging protein DAP12 to regulate the PI3K-AKT signaling pathway that promote neuroinflammation and aggravate neuronal injury.
Methods
LPS-induced neuroinflammation models in vivo and in vitro were constructed to explore the role and mechanism of FcγRIIb in CNS inflammation. Subsequently, FcγRIIb was knocked down or overexpressed to observe the activation of BV2 cell and the effect on PI3K-AKT pathway. Then the PI3K-AKT pathway was blocked to observe its effect on cell activation and FcγRIIb expression. We analyzed the interaction between FcγRIIb and DAP12 by Immunoprecipitation technique. Then FcγRIIb was overexpressed while knocking down DAP12 to observe its effect on PI3K-AKT pathway. Finally, BV2 cell culture supernatant was co-cultured with neuronal cell HT22 to observe its effect on neuronal apoptosis and cell activity.
Results
In vivo and in vitro, we found that FcγRIIb expression was significantly increased and activated the PI3K-AKT pathway. Contrary to the results of overexpression of FcγRIIb, knockdown of FcγRIIb resulted in a significant low level of relevant inflammatory factors and suppressed the PI3K-AKT pathway. Furthermore, LPS stimulation induced an interaction between FcγRIIb and DAP12. Knockdown of DAP12 suppressed inflammation and activation of the PI3K-AKT pathway in BV2 cells, and meantime overexpression of FcγRIIb suppressed the level of FcγRIIb-induced AKT phosphorylation. Additionally, knockdown of FcγRIIb inhibited microglia activation, which induced neuronal apoptosis.
Discussion
Altogether, our experiments indicate that FcγRIIb interacts with DAP12 to promote microglia activation by activating the PI3K-AKT pathway while leading to neuronal apoptosis and exacerbating brain tissue injury, which may provide a new target for the treatment of inflammatory diseases in the central nervous system.
Background:
The associations between neuropsychiatric symptoms (NPSs) and Alzheimer's disease (AD) have been well-studied, yet gaps remain.
Objective:
We aimed to examine the associations of four subsyndromes (hyperactivity, psychosis, affective symptoms, and apathy) of NPSs with cognition, neurodegeneration, and AD pathologies.
Methods:
Totally 1,040 non-demented elderly (48.07% males) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. We assessed the relationships between NPSs and AD neuropathologies, cognition, neurodegeneration, and clinical correlates in cross-sectional and longitudinal via multiple linear regression, linear mixed effects, and Cox proportional hazard models. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition and neurodegeneration.
Results:
We found that individuals with hyperactivity, psychosis, affective symptoms, or apathy displayed a poorer cognitive status, a lower CSF amyloid-β (Aβ) level and a higher risk of clinical conversion (p < 0.05). Hyperactivity and affective symptoms were associated with increasing cerebral Aβ deposition (p < 0.05). Except psychosis, the other three subsyndromes accompanied with faster atrophy of hippocampal volume (p < 0.05). Specific NPSs were predominantly associated with different cognitive domains decline through an 8-year follow-up (p < 0.05). Moreover, the relationships between NPSs and cognitive decline, neurodegeneration might be associated with Aβ, the mediation percentage varied from 6.05% to 17.51% (p < 0.05).
Conclusions:
NPSs could be strongly associated with AD. The influences of NPSs on cognitive impairments, neurodegeneration might be partially associated with Aβ.
Background:
There is an urgent need to identify subjects with Alzheimer's disease (AD) in the predementia phase, but validated diagnostic approaches are currently lacking. In this paper, we present the background, design and methods of a study, which aims to develop clinical criteria for predementia AD. We also present baseline characteristics of the subjects included. The study was part of the multicentre DESCRIPA project, which is being conducted within the network of the European Alzheimer's Disease Consortium.
Methods:
Clinical criteria will be based on a prospective cohort study of non-demented subjects older than 55 years and referred to a memory clinic. At baseline, a number of markers and risk factors for AD were collected, including demographic variables, measures of performance in activities of daily living, cognitive, neuroimaging and genetic markers, and serum and cerebrospinal fluid markers. Subjects will be reassessed annually for 2-3 years, and we will evaluate which combination of variables best predicts AD-type dementia at follow-up.
Results:
Between 2003 and 2005, 881 subjects were included from 20 memory clinics. Subjects were on average 70.3 years old, and had 10.4 years of education. The average score on the Mini-Mental State Examination was 27.4.
Neuropsychiatric symptoms (NPS) affect almost all patients with dementia and are a major focus of study and treatment. Accurate assessment of NPS through valid, sensitive and reliable measures is crucial. Although current NPS measures have many strengths, they also have some limitations (e.g. acquisition of data is limited to informants or caregivers as respondents, limited depth of items specific to moderate dementia). Therefore, we developed a revised version of the NPI, known as the NPI-C. The NPI-C includes expanded domains and items, and a clinician-rating methodology. This study evaluated the reliability and convergent validity of the NPI-C at ten international sites (seven languages).
Face validity for 78 new items was obtained through a Delphi panel. A total of 128 dyads (caregivers/patients) from three severity categories of dementia (mild = 58, moderate = 49, severe = 21) were interviewed separately by two trained raters using two rating methods: the original NPI interview and a clinician-rated method. Rater 1 also administered four additional, established measures: the Apathy Evaluation Scale, the Brief Psychiatric Rating Scale, the Cohen-Mansfield Agitation Index, and the Cornell Scale for Depression in Dementia. Intraclass correlations were used to determine inter-rater reliability. Pearson correlations between the four relevant NPI-C domains and their corresponding outside measures were used for convergent validity.
Inter-rater reliability was strong for most items. Convergent validity was moderate (apathy and agitation) to strong (hallucinations and delusions; agitation and aberrant vocalization; and depression) for clinician ratings in NPI-C domains.
Overall, the NPI-C shows promise as a versatile tool which can accurately measure NPS and which uses a uniform scale system to facilitate data comparisons across studies.
Sleep and wake in Alzheimer's disease (AD) are often fragmented as manifested by bouts of wakefulness at night and napping during the day. Management of sleep disturbances in AD is important because of their negative impact on both patients and caregivers. Pharmacological treatments, mainly sedative-hypnotics and antipsychotics, are often used but can be associated with significant adverse effects. Non-pharmacological treatments represent a beneficial alternative approach to the management of sleep disturbances in AD since they are associated with fewer adverse effects and their efficacy can be sustained after treatment has been completed. The aim of this article is to review non-pharmacological treatments, such as sleep hygiene, sleep restriction therapy (SRT), cognitive behavioral therapy (CBT), light therapy, and continuous positive airway pressure (CPAP), for the management of sleep/wake disturbances in AD.
Depression frequently occurs in the elderly and in patients suffering from dementia. Its cause is largely unknown, but several studies point to a possible contribution of circadian rhythm disturbances. Post-mortem studies on aging, dementia and depression show impaired functioning of the suprachiasmatic nucleus (SCN) which is thought to be involved in the increased prevalence of day-night rhythm perturbations in these conditions. Bright light enhances neuronal activity in the SCN. Bright light therapy has beneficial effects on rhythms and mood in institutionalized moderate to advanced demented elderly. In spite of the fact that this is a potentially safe and inexpensive treatment option, no previous clinical trial evaluated the use of long-term daily light therapy to prevent worsening of sleep-wake rhythms and depressive symptoms in early to moderately demented home-dwelling elderly.
This study investigates whether long-term daily bright light prevents worsening of sleep-wake rhythms and depressive symptoms in elderly people with memory complaints. Patients with early Alzheimer's Disease (AD), Mild Cognitive Impairment (MCI) and Subjective Memory Complaints (SMC), between the ages of 50 and 75, are included in a randomized double-blind placebo-controlled trial. For the duration of two years, patients are exposed to approximately 10,000 lux in the active condition or approximately 300 lux in the placebo condition, daily, for two half-hour sessions at fixed times in the morning and evening. Neuropsychological, behavioral, physiological and endocrine measures are assessed at baseline and follow-up every five to six months.
If bright light therapy attenuates the worsening of sleep-wake rhythms and depressive symptoms, it will provide a measure that is easy to implement in the homes of elderly people with memory complaints, to complement treatments with cholinesterase inhibitors, sleep medication or anti-depressants or as a stand-alone treatment.
ISRCTN29863753.
Determining the genetic architecture of late onset Alzheimer's disease remains an important research objective. One approach to the identification of novel genetic variants contributing to the disease is the classification of biologically meaningful subgroups within the larger late-onset Alzheimer's disease phenotype. The occurrence of psychotic symptoms in patients with late-onset Alzheimer's disease may identify one such group. We attempted to establish methods for the reliable assessment of psychotic symptoms in a large, geographically dispersed collection of families, multiply affected with late onset Alzheimer's disease, who were participants in the larger National Institute on Aging Late Onset Alzheimer's Disease Family Study; and to characterize the correlates and familial aggregation of psychosis within this cohort. We found that reliable assessments of psychotic symptoms during in-person or phone interviews were readily implemented. The presence of psychosis in late onset Alzheimer's disease was significantly associated with degree of cognitive impairment, and significantly, albeit modestly, correlated with the severity of other behavioural symptoms. Psychosis significantly aggregated within late onset Alzheimer's disease families suggesting that it may identify a genetically determined subgroup. Future studies should examine the linkage and association of psychosis with genetic variation within these families.
A consecutive series of 79 patients with probable Alzheimer's disease were assessed with a structured psychiatric evaluation, and diagnoses of apathy and depression were made using standardized criteria. Three-dimensional MRI scans were obtained from all patients, and images were segmented into gray matter, white matter, and CSF. White matter hyperintensities were edited on segmented images, and lobar assignments (frontal, temporal, parietal, and occipital) were made based on Talairach coordinates. Patients with apathy showed a significantly larger volume of frontal white matter hyperintensities than patients without apathy. Patients with depression had a significantly larger volume of right parietal white matter hyperintensities than patients without depression. However, neither apathy nor depression was significantly associated with lobar gray or white matter atrophy. Frontal and right parietal white matter hyperintensities are the strongest brain structural correlates of apathy and depression in Alzheimer's disease.
Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group.
Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia.
The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4).
AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up.
European Commission; Ana Aslan International Foundation.
Agitation and aggression are frequently occurring and distressing behavioral and psychological symptoms of dementia (BPSD). These symptoms are disturbing for individuals with Alzheimer disease, commonly confer risk to the patient and others, and present a major management challenge for clinicians. The most widely prescribed pharmacological treatments for these symptoms-atypical antipsychotics-have a modest but significant beneficial effect in the short-term treatment (over 6-12 weeks) of aggression but limited benefits in longer term therapy. Benefits are less well established for other symptoms of agitation. In addition, concerns are growing over the potential for serious adverse outcomes with these treatments, including stroke and death. A detailed consideration of other pharmacological and nonpharmacological approaches to agitation and aggression in patients with Alzheimer disease is, therefore, imperative. This article reviews the increasing evidence in support of psychological interventions or alternative therapies (such as aromatherapy) as a first-line management strategy for agitation, as well as the potential pharmacological alternatives to atypical antipsychotics-preliminary evidence for memantine, carbamazepine, and citalopram is encouraging.
Patients with Alzheimer's disease need assistance and supervision of their daily activities. They survive for protracted periods of time, placing an extensive burden of care on the caregiver prior to the patient's death. The present study addressed the predictive value of behavior-related burden on Alzheimer's disease caregivers.
82 patients with probable Alzheimer's (73.7 +/- 8.1 years), and their primary caregivers (59.6 +/- 14.8 years, 81.5% women), were assessed.
Cognitive impairment, neuropsychiatric symptoms, and dementia severity were assessed with Mini Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Clinical Dementia Rating (CDR), respectively. Caregivers were given Zarit's Burden Interview and Carer Activity Inventory.
Neuropsychiatric symptoms like delusions, hallucinations, restlessness, anxiety, euphoria, disinhibition, unusual motor behavior, sleep disturbances, and appetite alterations were the best caregiver burden predictors (NPI r = 0.482, p < 0.001). No correlation with cognition, disease stage, or negative neuropsychiatric symptoms (depression and apathy) was found.
Increased caregiver burden was related to increased levels of patient behavioral disturbance. Of these symptoms, hallucinations, unusual (motor) behavior, and abnormal behavior at nighttime were the most significant. No correlation with neuropsychiatric symptoms such as apathy and depression was found. This may have relevance to appropriate interventions for caregivers.
Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia, at least for some patients. Behavioral symptoms in MCI are associated with a higher risk of dementia, but their association with dementia risk in patients without MCI is unknown. Mild behavioral impairment (MBI) refers to a late-life syndrome with prominent psychiatric and related behavioral symptoms in the absence of prominent cognitive symptoms that may also be a dementia prodrome. This study sought to compare MCI and MBI patients and to estimate the risk of dementia development in these 2 groups.
Between January 2001 and January 2006, a consecutive series of 358 elderly (>or= 65 years old) patients (239 with MCI and 119 with MBI) presenting to an outpatient general hospital specialty clinic were followed for up to 5 years until conversion to dementia or censoring.
Thirty-four percent of MCI patients and over 70% of patients with MBI developed dementia (log-rank p = .011). MBI patients without cognitive symptoms were more likely to develop dementia (log-rank p < .001). MBI patients were more likely to develop frontotemporal dementia (FTD) than dementia of the Alzheimer's type (DAT).
MBI appears to be a transitional state between normal aging and dementia. MBI (specifically in those without cognitive symptoms) may confer a higher risk for dementia than MCI, and it is very likely an FTD prodrome in many cases. These findings have implications for the early detection, prevention, and treatment of patients with dementia in late life, by focusing the attention of researchers on the emergence of new behavioral symptoms.
Agitation is common in people with dementia, is distressing to patients and stressful to their carers. Drugs used to treat the condition have the potential to cause particularly severe side effects in older people with dementia and have been associated with an increased death rate. Alternatives to drug treatment for agitation should be sought. The study aimed to assess the effects of bright light therapy on agitation and sleep in people with dementia.
A single center randomized controlled trial of bright light therapy versus standard light was carried out. The study was completed prior to the mandatory registration of randomized controls on the clinical trials registry database and, owing to delays in writing up, retrospective registration was not completed.
There was limited evidence of reduction in agitation in people on active treatment, sleep was improved and a suggestion of greater efficacy in the winter months.
Bright light therapy is a potential alternative to drug treatment in people with dementia who are agitated.
Little is known about the population-based prevalence of neuropsychiatric symptoms in mild cognitive impairment (MCI).
To estimate the prevalence of neuropsychiatric symptoms in MCI and normal cognitive aging in a defined population.
Cross-sectional study derived from an ongoing population-based prospective cohort study.
The Mayo Clinic Study of Aging.
We studied a random sample of 1969 individuals without dementia from the target population of 9965 elderly persons residing in Olmsted County (Minnesota) on the prevalence date (October 1, 2004). Neuropsychiatric data were available for 319 of 329 subjects with MCI (97.0%) and 1590 of 1640 subjects with normal cognition (97.0%). Neurologic, cognitive, and neuropsychiatric data were obtained from the study participants. A classification of MCI, dementia, and normal cognitive aging was adjudicated by an expert consensus panel. Accordingly, 329 subjects were classified as having MCI and the remaining 1640 subjects were classified as having normal cognition.
Neuropsychiatric Inventory Questionnaire score.
Multivariate logistic regression analyses were conducted after adjusting for age, sex, and educational status. By considering both the odds ratio (OR) and the frequency of a symptom, the most distinguishing features between the 2 groups were apathy (OR, 4.53; 95% confidence interval [CI], 3.11-6.60; P < .001), agitation (3.60; 2.18-5.92; P < .001), anxiety (3.00; 2.01-4.48; P < .001), irritability 2.99; 2.11-4.22; P < .001), and depression (2.78; 2.06-3.76; P < .001). The OR was highest for delusion (8.12; 95% CI, 2.92-22.60; P < .001); however, it was rare in both subjects with MCI (11 of 319 [3.4%]) and those with normal cognition (6 of 1590 [0.4%]). Thus, the population attributable risk for delusion was only 2.62% compared with 14.60% for apathy.
Nonpsychotic symptoms affected approximately 50% of subjects with MCI and 25% of subjects with normal cognition. In contrast, psychotic symptoms were rare.
Symptoms consistent with dysfunction of the frontal lobes can occur following traumatic brain injury (TBI) or other types of acquired brain injury (stroke, aneurysm). These symptoms can include problems with short-term memory, attention, planning, problem solving, impulsivity, disinhibition, poor motivation, and other behavioral and cognitive deficits ("frontal lobe syndrome"). These symptoms may respond to certain drugs, such as dopaminergic agents. This case series describes results of using amantadine in 7 patients with this type of symptom profile (6 with TBI, 1 with meningitis following sinus surgery). Patients received neuropsychiatric examinations and serial neuropsychological testing. All patients showed some degree of positive response. One had side effects that resolved upon discontinuation of drug. The rationale for using dopaminergics is discussed, and pertinent literature is reviewed.
Objective: Second-generation antidepressants are commonly used to treat major depression in late-life. This systematic review and meta-analysis was undertaken to assess the evidence for efficacy of second-generation antidepressants in late-life major depression. Methods: The Cochrane Library (2006 [3]), MEDLINE (1966 to August 2006), and meeting presentations were searched for trials of second-generation antidepressants (nontricyclics) marketed in the United States. Published and unpublished placebo-controlled randomized clinical trials in outpatients 60 years and older, with nonpsychotic, unipolar major depression were selected. Clinical characteristics and outcomes were extracted. Outcomes were expressed as odds ratios (OR), risk differences, and weighted mean differences. Results: Ten unique trials (four unpublished) with 13 contrasts met selection criteria. Trials were 6-12 weeks duration, and included 2,377 patients who received active drug and 1,788 received placebo. The ORs by meta-analysis for response and remission were 1.40 (95% confidence interval [CI] 1.24-1.57, z = 5.45, N = 13, p <0.001) and 1.27 (CI 1.12-1.44, z = 3.67, N = 13, p <0.001), respectively, with significant heterogeneity for response and remission among the trials. Mean pooled response rates for antidepressant and placebo were 44.4% and 34.7%, respectively. The OR for response was significantly higher in the 10-12 week trials (OR = 1.73, CI 1.42-2.09, z = 5.51, N = 5, p <0.001) than the 6-8 week trials (OR = 1.22, CI 1.05-1.42, z = 2.60, N = 8, p = 0.01). ORs for discontinuation for any reason and for adverse events were significantly higher with drugs than with placebo. Conclusions: Antidepressants are more effective than placebo in elderly depressed subjects although effects are modest and vary. Identification of the characteristics of responders and nonresponders will be crucial to improving treatment outcomes.
Low-dose methylphenidate was prescribed in an attempt to reverse the anorexia secondary to the gradual onset of apathetic behavior in three severely demented, long-term institutionalized geriatric patients. The anorexia was alleviated quickly in each case without appreciable side effects, and the benefit lasted for a prolonged period after cessation of the psychostimulant.
Copyright (C) 1993 American Association for Geriatric Psychiatry
Objective
We investigated the frequency and inter-relationship of neuropsychiatric disturbances in a population sample of persons suffering from Alzheimer's disease (AD).Method
Screening 5,092 elderly residents (90% of the population aged 65 and older) of Cache County, Utah, for dementia, we identified 198 persons with AD using a comprehensive neuropsychiatric examination protocol. This examination included the Neuropsychiatric Inventory (NPI), a widely used measure of dementia-associated neuropsychiatric disturbances.ResultsOverall, 60% of individuals with AD reported one or more neuropsychiatric symptoms. A latent class analysis revealed that these participants could be classified into three groups (classes) based on their neuropsychiatric symptom profile. The largest class included cases with no neuropsychiatric symptoms (40%) or with a mono-symptomatic disturbance (19%). A second class (28%) exhibited a predominantly affective syndrome, while a third class (13%) had a psychotic syndrome.Conclusion
Data from this first US population-based study of AD-associated neuropsychiatric disturbances suggest that a significant majority of persons with AD suffer from one or more neuropsychiatric disturbance. Based on phenomenological study, the spectrum of neuropsychiatric symptoms in AD can be empirically classified into three groups: an affective syndrome, a psychotic syndrome and other neuropsychiatric disturbance. The biologic and predictive validity of this classification merits further investigation. Copyright © 2001 John Wiley & Sons, Ltd.
Background:
Agitation and aggression are common neuropsychiatric symptoms of Alzheimer's disease (AD) with a negative impact on caregivers.
Objective:
The aim of the study was to determine whether changes in agitation and aggression would follow memantine treatment and, if so, be associated with changes in nursing burden in institutionalized patients with moderate to severe AD.
Study design:
This was a 3-month open-label trial of memantine.
Setting:
The setting was two long-term care facilities.
Patients:
Thirty-one institutionalized patients with moderate to severe AD and significant behavioural and psychiatric symptoms were included in the study.
Intervention:
Memantine was titrated to a target dose of 10 mg twice daily.
Main outcome measure:
Effectiveness was assessed by the change in the Neuropsychiatric Inventory-Nursing Home (NPI-NH) agitation/aggression subscale and Clinical Global Impression of Change (CGI-C) scale using the intent-to-treat population. To establish caregiver impact, the effect on nursing burden was measured by the Modified Nursing Care Assessment Scale (primary outcome). As a secondary analysis, the caregiver distress subscale of the NPI-NH was examined, as well as changes in as required (pro re nata [prn]) psychotropic medication use.
Results:
Twenty-four patients completed the study. A significant decrease in agitation and aggression (F-test with 3 and 90 degrees of freedom [F(3,90)] = 3.721, p = 0.014) was demonstrated following memantine, with 48% of patients improving (either much improved or minimally improved) on the CGI-C scale. In addition, nursing burden (t-test with 30 degrees of freedom [t(30)] = 3.02, p = 0.005), caregiver distress (F(3,90) = 4.125, p = 0.009) and the use of prn psychotropics decreased following memantine treatment (Z = -1.99, p = 0.046). Fourteen patients experienced at least one adverse event during memantine treatment. The most common adverse event associated with treatment was somnolence (n = 5).
Conclusion:
The results of this study suggest that the decreased agitated and aggressive behaviour in institutionalized patients with moderate to severe AD following treatment with memantine was accompanied by improvements in nursing burden and decreased psychotropic use. These findings should be confirmed in a larger, controlled trial.
The increasing prevalence of dementia will precipitate a significant burden in terms of the costs of caring for people with dementia over the next 30 years; sleep disturbances in dementia are an important factor contributing to this burden.
We reviewed sleep disturbances in people with dementia and their carers and describe the various diagnostic, assessment and treatment strategies available to physicians in the management of this clinically significant problem.
Sleep disturbances in people with dementia and their carers (i) are highly prevalent; (ii) impact significantly on quality of life of both people with dementia and their carers; (iii) increase the rate of cognitive decline; and (iv) accelerate the breakdown of community-based care. The training of physicians in the assessment and treatment of sleep disturbances in dementia and caregiving is scant despite a wide range of assessment strategies and treatment approaches, which comprise both pharmacological (including hypnotic/sedative medications) and non-pharmacological approaches (including: environmental; psychobehavioral; exercise and activity; and multi-component interventions). Specific diagnostic criteria for sleep disturbances in people with dementia and their carers remain lacking despite established criteria for general insomnia. Further to this, proposed changes to diagnostic criteria for DSM-V do not include a specific focus for the diagnosis and management of sleep disturbances in people with dementia or their carers.
This review suggests that the improved training of physicians to meet the needs of these vulnerable groups of older people is a priority, especially in the context of a rapidly increasing demand for accurate, early diagnosis and efficient management of sleep disturbance in these groups.
Apathy has been reported as the most prevalent behavioural symptom experienced in Alzheimer's disease (AD), associated with greater functional decline and caregiver distress. The aim of the current study was to investigate structural correlates of apathy in AD using magnetic resonance imaging (MRI) regional volume and regional cortical thickness measures.
Semi-structured interviews were conducted with 111 AD patients and their caregivers as part of the European multi-centre study AddNeuroMed. Apathy was measured using the apathy domain of the Neuropsychiatric Inventory (NPI). All AD patients were scanned using a 1.5T MRI scanner and the images analysed using an automated analysis pipeline.
We found apathy to be the most prevalent neuropsychiatric symptom occurring in 57% of patients. Apathetic patients had significantly greater cortical thinning in left caudal anterior cingulate cortex (ACC) and left lateral orbitofrontal cortex (OFC), as well as left superior and ventrolateral frontal regions, than those without apathy symptoms.
Apathy is mediated by frontocortical structures but this is specific to the left hemisphere at least for patients in the mild to moderate stages of AD.
Insomnia is a common problem among older adults. In particular, older adults experience insomnia coupled with early morning awakenings due to an interaction between age-related changes in circadian rhythm timing coupled with behavior changes that contribute to sustained poor sleep. Cognitive-behavioral therapy for insomnia (CBT-I), at times coupled with circadian interventions (e.g., timed light exposure), are likely to be most successful in optimizing sleep quality. In delivering CBT-I to older adults, modifications are sometimes necessary to accommodate for medical problems, lifestyle, social factors, and patient preferences. Addition of circadian interventions can ameliorate the negative effects of inappropriately timed sleep as well. These treatment methods can be highly effective and benefits can be long-standing. A case example is used to illustrate these points.
Mild cognitive impairment (MCI) is a syndrome thought to be a prodrome of dementia for some patients. One subtype, amnestic MCI (aMCI), may be specifically predispose patients to develop Alzheimer's dementia (AD). Since dementia has been associated with a range of neuropsychiatric symptoms (NPS), we sought to examine the prevalence of NPS in MCI and its subtypes.
One thousand seven hundred seventy-nine participants in the National Alzheimer's Coordinating Center (NACC) with MCI were included in this study. All participants were evaluated systematically with a thorough cognitive battery, clinical interview, and consensus diagnoses, and subtyped as: (1) amnestic (aMCI) (single- or multiple-domain) versus non-amnestic (non-aMCI); (2) executive dysfunction-MCI (exMCI) (single- or multiple-domain) versus no executive dysfunction-MCI (non-exMCI); (3) both aMCI and exMCI; and (4) neither aMCI nor exMCI. Additionally, aMCI versus non-aMCI and exMCI versus non-exMCI dichotomies were explored. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS).
1379 participants (77.5%) met criteria for aMCI and 616 (34.6%) for exMCI. No differences were observed in the prevalence of NPS between aMCI versus non-aMCI. However, exMCI was associated with greater severity of depression, anxiety, agitation, disinhibition, irritability, and sleep problems, although these differences do not persist after adjustment for multiple comparisons.
While there were few associations between aMCI and NPS, the presence of executive dysfunction in MCI was associated with greater severity of symptoms and specifically with depression (evidenced by GDS score) and anxiety. These findings may have implications for MCI prognosis and need to be explored in longitudinal studies.
To test the effects of an intervention that helps families manage distressing behaviors in family members with dementia.
Two-group randomized trial.
In home.
Two hundred seventy-two caregivers and people with dementia.
Up to 11 home and telephone contacts over 16 weeks by health professionals who identified potential triggers of patient behaviors, including communication and environmental factors and patient undiagnosed medical conditions (by obtaining blood and urine samples) and trained caregivers in strategies to modify triggers and reduce their upset. Between 16 and 24 weeks, three telephone contacts reinforced strategy use.
Primary outcomes were frequency of targeted problem behavior and caregiver upset with and confidence managing it at 16 weeks. Secondary outcomes were caregiver well-being and management skills at 16 and 24 weeks and caregiver perceived benefits. Prevalence of medical conditions for intervention patients were also examined.
At 16 weeks, 67.5% of intervention caregivers reported improvement in targeted problem behavior, compared with 45.8% of caregivers in a no-treatment control group (P=.002), and reduced upset with (P=.03) and enhanced confidence managing (P=.01) the behavior. Additionally, intervention caregivers reported less upset with all problem behaviors (P=.001), less negative communication (P=.02), less burden (P=.05), and better well-being (P=.001) than controls. Fewer intervention caregivers had depressive symptoms (53.0%) than control group caregivers (67.8%, P=.02). Similar caregiver outcomes occurred at 24 weeks. Intervention caregivers perceived more study benefits (P<.05), including ability to keep family members home, than controls. Blood and urine samples of intervention patients with dementia showed that 40 (34.1%) had undiagnosed illnesses requiring physician follow-up.
Targeting behaviors upsetting to caregivers and modifying potential triggers improves symptomatology in people with dementia and caregiver well-being and skills.
Alzheimer's disease (AD) is characterized by a number of serious and debilitating behavioral and psychological symptoms of dementia (BPSD). The most common of these BPSD is apathy, which represents a major source of morbidity and premature institutionalization in the AD population. Many studies have identified discrete changes to the dopaminergic (DAergic) system in patients with AD. The DAergic system is closely related to the brain reward system (BRS) and some studies have suggested that dysfunction in the DAergic system may account for symptoms of apathy in the AD population.
Changes to the dopamine (DA) system in AD will be reviewed, and evidence supporting the involvement of the DAergic system in the development of apathy will be examined. Additionally, some pharmacological interventions with DA activity have been identified. The utility of these treatments in the AD population will be reviewed, with a focus on apathy as an outcome.
Evidence presented in this review suggests that DA dysfunction in discrete brain areas is an important correlate of apathy in AD and that the DAergic system may be a rational target for pharmacological treatment of apathy.
Depression is common in patients with Parkinson's disease, but evidence on the efficacy of antidepressants in this population is lacking. Because depression in patients with Parkinson's disease might be related to dopaminergic dysfunction, we aimed to assess the efficacy of the dopamine agonist pramipexole for treatment of depressive symptoms in patients with Parkinson's disease.
We did a 12-week randomised, double-blind, placebo-controlled (1:1 ratio) trial of pramipexole (0.125-1.0 mg three times per day) compared with placebo in patients with mild-to-moderate Parkinson's disease. Patients from 76 centres in 12 European countries and South Africa were included if they were on stable antiparkinsonian therapy without motor fluctuations and had depressive symptoms (15-item geriatric depression scale score > or =5 and unified Parkinson's disease rating scale [UPDRS] part 1 depression item score > or =2). Patients were randomly assigned by centre in blocks of four by use of a randomisation number generating system. Clinical monitors, the principal investigator, and patients were masked to treatment allocation. The primary endpoint was change in Beck depression inventory (BDI) score and all treated patients who had at least one post-baseline efficacy assessment were included in the primary analysis. We also did a pre-specified path analysis with regression models to assess the relation between BDI and UPDRS part 3 (motor score) changes. This trial is registered with ClinicalTrials.gov, number NCT00297778, and EudraCT, number 2005-003788-22.
Between March, 2006, and February, 2008, we enrolled 323 patients. Of 296 patients randomly assigned to pramipexole or placebo, 287 were included in the primary analysis: 139 in the pramipexole group and 148 in the placebo group. BDI scores decreased by an adjusted mean 5.9 (SE 0.5) points in the pramipexole group and 4.0 (0.5) points in the placebo group (difference 1.9, 95% CI 0.5-3.4; p=0.01, ANCOVA). The UPDRS motor score decreased by an adjusted mean 4.4 (0.6) points in the pramipexole group and 2.2 (0.5) points in the placebo group (difference 2.2, 95% CI 0.7-3.7; p=0.003, ANCOVA). Path analysis showed the direct effect of pramipexole on depressive symptoms accounted for 80% of total treatment effect (p=0.04). Adverse events were reported in 105 of 144 patients in the pramipexole group and 101 of 152 in the placebo group. Adverse events in the pramipexole group were consistent with the known safety profile of the drug.
Pramipexole improved depressive symptoms in patients with Parkinson's disease, mainly through a direct antidepressant effect. This effect should be considered in the clinical management of patients with Parkinson's disease.
To examine the temporal association between depressive symptoms and cognitive functioning and estimate the effect measure modification of the apolipoprotein E (APOE) epsilon4 allele on this relationship.
Prospective cohort study.
General community.
Population-based sample of 598 cognitively intact older adults aged 60 and older, with re-assessments after 3 (N=479) and 6 years (N=412).
Depressive symptoms (Symptom Checklist) and neurocognitive functioning (memory, Visual Verbal Learning Test; attention, Stroop Color-Word Test; processing speed, Letter Digit Substitution Test; general cognition, Mini-Mental State Examination). Longitudinal associations were assessed using linear mixed models. The risk for cognitive impairment, no dementia (CIND) was examined using logistic regression.
Adjusting for age, sex, education, and baseline cognition, the rate of change in memory z-scores was 0.00, -0.11, -0.20, and -0.37 for those in the lowest (reference group), second, third, and highest depressive symptom quartiles at baseline, respectively (P<.001 for highest vs lowest quartile). The odds ratios for developing CIND with amnestic features were 1.00, 0.87, 0.69, and 2.98 for the four severity groups (P=.05 for highest vs lowest quartile). Associations were strongest for those with persistent depressive symptoms, defined as high depressive symptoms at baseline and at least one follow-up visit. Results were similar for processing speed and global cognitive function but were not as strong for attention. No APOE interaction was observed.
Depression and APOE act independently to increase the risk for cognitive decline and may provide targets for prevention and early treatment.
Depression and antidepressant use are common in Alzheimer disease (AD), but the effect of antidepressant treatment for depression on longer term outcomes is unknown. The authors report the Week-24 outcomes of patients who participated in a 12-week efficacy study of sertraline for depression of AD.
One hundred thirty-one participants (sertraline = 67, placebo = 64) with mild-moderate AD and depression participated in the study. Patients who showed improvement on the modified Alzheimer's Disease Cooperative Study Clinical Global Impression-Change (mADCS-CGIC) after 12 weeks of randomized treatment with sertraline or placebo continued double-blinded treatment for an additional 12 weeks. Depression response and remission at 24 weeks were based on mADCS-CGIC score and change in Cornell Scale for Depression in Dementia (CSDD) score. Secondary outcome measures included time to remission, nonmood neuropsychiatric symptoms, global cognition, function, and quality of life.
One hundred seventeen (89.3%) participants completed all study assessments and 74 (56.5%; sertraline = 38, placebo = 36) completed all 24 weeks on randomized treatment. By 24 weeks, there were no between-group differences in depression response (sertraline = 44.8%, placebo = 35.9%; odds ratio [95% CI] = 1.23 [0.64-2.35]), change in CSDD score (median difference = 0.6 [95% CI: -2.26 to 3.46], chi2 [df = 2] = 1.03), remission rates (sertraline = 32.8%, placebo = 21.8%; odds ratio [95% CI] = 1.61 [0.70-3.68]), or secondary outcomes. Common selective serotonin reuptake inhibitor-associated adverse events, specifically diarrhea, dizziness, and dry mouth, and pulmonary serious adverse events were more frequent in sertraline-randomized patients than in placebo subjects.
Sertraline treatment is not associated with delayed improvement between 12 and 24 weeks of treatment and may not be indicated for the treatment of depression of AD.
Apathy is the most common behavioral problem in persons with dementia of the Alzheimer type (DAT). Treatment of apathy in DAT is not systematically studied. The purpose of this study was to evaluate the response of apathy to methylphenidate treatment and to examine whether functional status improved.
The authors conducted a 12-week open-labeled study with immediate release formulation of methylphenidate. Twenty-three patients with DAT scoring >40 on the Apathy Evaluation Scale (AES) were recruited. Repeated measures analysis of variance and correlation analysis were performed.
None of the patients dropped out of the study because of adverse events. Significant improvement in apathy was noted during 12 weeks. Significant improvement was also noted in depression, Mini-Mental State Examination score, and functional status. There was no correlation between changes in the AES and depression scores.
Methylphenidate was well tolerated in these patients with DAT. Apathy improved with the use of methylphenidate.
In and of itself, late-onset Alzheimer's disease (AD) can be a devastating illness. However, a sub-group of AD patients develop psychosis as the disease progresses. These patients have an added burden of greater cognitive impairment, higher rates of institutionalization, and higher mortality than AD patients without psychosis. While the etiopathogenesis such as psychosis in AD (AD+P) is not known, mounting evidence accrued over the past ten years indicates that AD+P represents a distinct phenotype with a genetic basis. Elucidating the genetic mechanism of AD+P is crucial if better pharmaceutical treatments are to be developed for these patients. The goal of this review is to summarize what is currently known regarding the genetic basis of psychosis in AD. Specific attention is given to familial aggregation and heritability, linkage to chromosomal loci, and associations of candidate genes of APOE and the monoamine neurotransmitter system.
Depression is common in Alzheimer disease (AD), and antidepressants are commonly used for its treatment, however, evidence for antidepressant efficacy in this population is lacking. The authors conducted a multicenter, randomized, placebo-controlled trial titled "Depression in Alzheimer's Disease-2" to assess the efficacy and tolerability of sertraline for depression in AD.
One hundred thirty-one participants from five U.S. medical centers with mild-to-moderate AD (Mini-Mental State Examination scores 10-26) and depression of AD were randomized to double-blinded treatment with sertraline (N = 67) or placebo (N = 64), with a target dosage of 100 mg daily. Efficacy was assessed using logistic regressions and mixed effects models in an intention-to-treat analysis with imputation of missing data. Principal outcome measures were modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC), change in Cornell Scale for Depression in Dementia (CSDD) scores, and remission defined by both mADCS-CGIC score <or=2 and CSDD score <or=6.
mADCS-CGIC ratings (odd ratio [OR = 1.01], 95% confidence interval [CI]: 0.52-1.97, p = 0.98), CSDD scores (median difference at 12 weeks 1.2, 95% CI: 1.65-4.05, p = 0.41), and remission at 12 weeks of follow-up (OR = 2.06, 95% CI: 0.84-5.04, p = 0.11) did not differ between sertraline (N = 67) and placebo (N = 64). Sertraline-treated patients experienced more adverse events, most notably gastrointestinal and respiratory, than placebo-treated patients.
Sertraline did not demonstrate efficacy for the treatment depression symptoms in patients with AD. In addition, its use was associated with an increased incidence of adverse events. Thus, selective serotonin reuptake inhibitors may be of limited value for treating depression in patients with AD.
The theta/gamma and alpha3/alpha2 ratio were investigated as early markers for prognosticating of progression to dementia. 76 subjects with mild cognitive impairment (MCI) underwent EEG recording, MRI scans and neuropsychological (NPS) tests. After 3 years of follow-up, three subgroups were characterized as converters to Alzheimer's disease (AD, N=18), converters to non-AD dementia (N=14) and non-converters (N=44). The theta/gamma and alpha3/alpha2 ratio, performance on cognitive tests and hippocampal volume, as evaluated at the time of initial MCI diagnosis, were studied in the three groups. As expected, MCI to AD converters had the smallest mean hippocampal volume and poorest performance on verbal learning tests, whereas MCI to non-AD converters had poorest cognitive performance in non-verbal learning tests, abstract thinking, and letter fluency. Increased theta/gamma ratio was associated with conversion to both AD and non-AD dementia; increased alpha3/alpha2 ratio was only associated with conversion to AD. Theta/gamma and alpha3/alpha2 ratio could be promising prognostic markers in MCI patients. In particular, the increase of high alpha frequency seems to be associated with conversion in AD. EEG markers allow a mean correct percentage of correct classification up to 88.3%. Future prospective studies are needed to evaluate the sensitivity and specificity of these measures for predicting an AD outcome.
The authors attempted to understand the role of two serotonin system genes, HTR2A and SLC6A4, on psychosis associated with Alzheimer dementia (AD).
Relevant published studies were assessed, and their data were meta-analyzed to determine pooled odds ratios (ORs) that were assessed for heterogeneity. Additional robustness checks were performed to assess for publication bias and any undue influence from a single study. Finally, the number of studies required to invalidate positive findings was determined.
The C allele of HTR2A emerged as a significant risk factor for psychosis, with an allelic OR of 2.191 that increased to 5.143 for the homozygous CC genotype. The SLC6A4 polymorphism was not reliably associated with either psychosis or delusions.
The strong and robust positive association that was noted between the C allele of HTR2A and psychosis suggests that the HTR2A T102C polymorphism is a significant risk factor for psychosis of AD.
Cerebral white-matter changes (WMCs) are frequently found in dementia and have been proposed to be related to vascular factors and a certain symptomatological profile. However, few studies have included both vascular factors and a broad spectrum of cognitive, neurological and psychiatric symptoms, easily detectable by the physician in the everyday clinical work. The objective was to study the relationships between WMCs on MRI/CT and neuropsychiatric symptoms and vascular factors in patients with cognitive impairment.
One hundred and seventy-six patients with Alzheimer's disease, vascular dementia, mixed dementia, and mild cognitive impairment were included. All patients underwent a standardized examination including medical history, clinical examinations, laboratory tests and brain imaging (CT or MRI). The identification and severity degree of WMCs was assessed blindly to clinical findings, using a semi-quantitative scale. For statistical analyses, patients were grouped based on absence or presence of WMCs. Significant variables in bivariate analyses were included as predictors in stepwise multiple logistic regression analyses.
Bivariate analyses showed significant associations between WMCs and age, gender, blood pressure, hypertension, ischaemic heart disease and TIA/RIND. Furthermore, there were significant associations between WMCs and apathy, mental slowness, disinhibition, gait disturbance and focal neurologic symptoms. The multivariate logistic model revealed apathy, mental slowness and age as the most consistent predicting factors for WMCs, together with MRI as a radiological method for the detection of WMCs.
The findings indicate that WMCs in patients with dementia are associated with a dysexecutive-related behavioural symptom profile, vascular factors related to small and large vessel diseases and age.
Monoamine dysfunction, particularly of the serotonin system, has been the dominant hypothesis guiding research and treatment development in affective disorders. The majority of research has been performed in midlife depressed adults. The importance of understanding the neurobiology of depression in older adults is underscored by increased rates of mortality and completed suicide and an increased risk of Alzheimer's dementia. To evaluate the dynamic response of the serotonin system, the acute effects of citalopram infusion on cerebral glucose metabolism was measured in depressed older adults and control subjects. The hypothesis was tested that smaller decreases in metabolism would be observed in cortical and limbic regions in depressed older adults relative to control subjects.
Sixteen depressed older adults and 13 control subjects underwent two resting positron emission tomography (PET) studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose after placebo and citalopram infusions.
In control subjects compared with depressed older adults, greater citalopram-induced decreases in cerebral metabolism were observed in the right anterior cingulate, middle temporal (bilaterally), left precuneus, and left parahippocampal gyri. Greater decreases in the depressed older adults than control subjects were observed in left superior and left middle frontal gyri and increases in left inferior parietal lobule, left cuneus, left thalamus, and right putamen.
In depressed older adults relative to control subjects, the cerebral metabolic response to citalopram is blunted in cortico-cortical and cortico-limbic pathways and increased in the left hemisphere (greater decrease interiorly and increases posteriorly). These findings suggest both blunted and compensatory cerebral metabolic responses to citalopram in depressed older adults.
Dysfunction within corticostriatal dopaminergic neurocircuitry has been implicated in neuropsychiatric symptoms associated with Alzheimer disease (AD). This study aimed to test the hypothesis that the symptom domains delusions and apathy would be associated with striatal dopamine (D2) receptor function in AD.
In vivo dopamine (D2/D3) receptor availability was determined with [(11)C]raclopride (RAC) PET in 23 patients with mild and moderate probable AD. Behavioral symptoms were measured using the Neuropsychiatric Inventory and the Apathy Inventory. Imaging data were analyzed using a region-of-interest approach. The potential confounding effects of age, sex, and disease stage were explored using a linear mixed model. Correlational and independent samples comparisons were used to examine the relationship between behavioral and binding potential (BP(ND)) measures.
Mean [(11)C]RAC BP(ND) was higher in patients with delusions (n = 7; 5 men) than in patients without delusions (n = 16; 6 men) (p = 0.006). When women were excluded from the analysis, [(11)C]RAC BP(ND) was higher in men with delusions than in men without delusions (p = 0.05). Apathy measures showed no association with [(11)C]RAC BP(ND).
Striatal dopamine (D2/D3) receptor availability is increased in Alzheimer disease patients with delusions, to an extent comparable to that observed in drug-naive patients with schizophrenia. Whether this represents up-regulation of dopamine (D2) or possibly dopamine (D3) receptors and how this relates to responsivity of the striatal dopaminergic system merit further exploration.
There is wide acknowledgement that apathy is an important behavioural syndrome in Alzheimer’s disease and in various neuropsychiatric disorders. In light of recent research and the renewed interest in the correlates and impacts of apathy, and in its treatments, it is important to develop criteria for apathy that will be widely accepted, have clear operational steps, and that will be easily applied in practice and research settings. Meeting these needs is the focus of the task force work reported here.
The task force includes members of the Association Française de Psychiatrie Biologique, the European Psychiatric Association, the European Alzheimer’s Disease Consortium and experts from Europe, Australia and North America. An advanced draft was discussed at the consensus meeting (during the EPA conference in April 7th 2008) and a final agreement reached concerning operational definitions and hierarchy of the criteria.
Apathy is defined as a disorder of motivation that persists over time and should meet the following requirements. Firstly, the core feature of apathy, diminished motivation, must be present for at least four weeks; secondly two of the three dimensions of apathy (reduced goal-directed behaviour, goal-directed cognitive activity, and emotions) must also be present; thirdly there should be identifiable functional impairments attributable to the apathy. Finally, exclusion criteria are specified to exclude symptoms and states that mimic apathy.
Patients with Alzheimer dementia often display both agitated behavior and poor sleep. Given that the disease is often associated with low endogenous levels of melatonin, exogenous melatonin administration may lead to improvements in sleep and agitation.
Randomized, placebo-controlled study.
Nursing homes in San Diego, CA, metropolitan area.
Subjects were patients with probable Alzheimer disease.
Melatonin (8.5 mg immediate release and 1.5 mg sustained release) (N = 24) or placebo (N = 17) administered at 10:00 P.M. for 10 consecutive nights. The protocol consisted of baseline (3 days), treatment (10 days), and posttreatment (5 days) phases.
Sleep was measured continuously using actigraphy. Agitation was rated using both the Agitated Behavior Rating Scale and the Cohen-Mansfield Agitation Inventory. Treatment effects were examined both across the 24-hr day and separately by nursing shift.
There were no significant effects of melatonin, compared with placebo, on sleep, circadian rhythms, or agitation.
: This study failed to find a beneficial effect of exogenous melatonin, consistent with a number of other studies. The lack of efficacy may be related to the absence of a true treatment effect or to the superphysiologic dose of melatonin used.
Neuropsychiatric symptoms (NPS) are common in patients with mild cognitive impairment (MCI). Little is known, however, about how NPS vary by MCI subtype (i.e. amnestic, single domain non-memory, and multiple domain). In addition, it is unclear whether NPS increase risk of progression to dementia. We investigated the distribution of NPS across MCI subtypes and determined whether NPS increase risk of progression to dementia.
Participants were 521 patients diagnosed with MCI at the Alzheimer's Research Centers of California between 1988 and 1999. At baseline, patients were classified into MCI subtypes and were assessed for NPS.
The mean number of NPS was 2.3 (range 0-9.6; 74% had > or =1 NPS). Patients with > or =4 NPS had more medical comorbidities and greater functional impairment (p < or = 0.0001 for both). Patients with > or =4 NPS were more likely than patients with 0-3 NPS to have amnestic MCI (81% vs 71%, respectively, p = 0.03), and patients with amnestic MCI were more likely than those with other subtypes to exhibit depressive symptoms. Patients with > or =4 NPS had nearly 2.5 times the odds of developing dementia at follow-up than patients with 0-3 NPS (adjusted OR = 2.44, 95% CI 1.07, 5.55).
NPS are common in MCI patients. Those with an elevated number of NPS may be more likely to have the amnestic subtype of MCI, and depression may be more common in amnestic MCI than in other subtypes. An elevated number of NPS may increase risk of progression to dementia for patients with MCI.
Data from 12-week placebo-controlled trials have led to mounting concerns about increased mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotics; however, there are no mortality data from long-term placebo-controlled trials. We aimed to assess whether continued treatment with antipsychotics in people with AD is associated with an increased risk of mortality.
Between October, 2001, and December, 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomised, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrollment of the last participant (range 24-54 months). Causes of death were obtained from death certificates. Analysis was by intention to treat (ITT) and modified intention to treat (mITT). This trial is registered with the Cochrane Central Registry of Controlled Trials/National Research Register, number ISRCTN33368770.
165 patients were randomised (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78%) started treatment (64 continued with their treatment and 64 received placebo). There was a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI 58-80%) in the continue treatment group versus 77% (64-85%) in the placebo group for the mITT population. Kaplan-Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0.03; ITT p=0.02). The hazard ratio for the mITT group was 0.58 (95% CI 0.35 to 0.95) and 0.58 (0.36 to 0.92) for the ITT population. The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival 46%vs 71%; 36-month survival 30%vs 59%).
There is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication; these results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in these patients.
UK Alzheimer's Research Trust.
Parkinson disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Depression affects up to 50% of these patients and is associated with a variety of poor outcomes for patients and their families. Despite this, there are few evidence-based data to guide clinical care.
An NIH-funded, randomized, controlled trial of paroxetine CR, nortriptyline, and placebo in 52 patients with PD and depression. The primary outcomes were the change in the Hamilton Depression Rating Scale (HAM-D) and the percentage of depression responders at 8 weeks.
Nortriptyline was superior to placebo for the change in HAM-D (p < 0.002); paroxetine CR was not. There was a trend for superiority of nortriptyline over paroxetine CR at 8 weeks (p < 0.079). Response rates favored nortriptyline (p = 0.024): nortriptyline 53%, paroxetine CR 11%, placebo 24%. In planned contrasts of response rates, nortriptyline was superior to paroxetine CR (p = 0.034). Nortriptyline was also superior to placebo in many of the secondary outcomes, including sleep, anxiety, and social functioning, while paroxetine CR was not. Both active drug treatments were well tolerated.
Though relatively modest in size, this is the largest placebo-controlled trial done to date in patients with Parkinson disease (PD) and depression. Nortriptyline was efficacious in the treatment of depression and paroxetine CR was not. When compared directly, nortriptyline produced significantly more responders than did paroxetine CR. The trial suggests that depression in patients with PD is responsive to treatment and raises questions about the relative efficacy of dual reuptake inhibitors and selective serotonin reuptake inhibitors.
Biogenic amine neurotransmitters and metabolites as well as choline acetyltransferase activity were quantified in eight brain regions from 37 demented patients, with or without major depression, and 10 controls with no history of dementia or depression. The middle frontal and temporal cortex, prosubiculum and entorhinal cortex of the hippocampus, substantia nigra, thalamus, amygdala, and caudate were examined. Demented patients with major depression exhibited a 10-fold to 20-fold reduction in the level of norepinephrine in the cortex, along with relative preservation of choline acetyltransferase activity in subcortical regions, compared with demented patients who were not depressed. Serotonin levels were reduced in all eight brain regions, but the reduction did not reach statistical significance in any region examined. A para-doxical increase in dopamine levels was observed in the entorhinal cortex of depressed, demented patients, although no consistent pattern of change in the level of this neurotransmitter emerged across brain regions. Our results indicate that the development of major depression in primary dementia is associated with a profile of concurrent neurochemical changes that is largely consistent with existing neurochemical hypotheses of idiopathic affective disorders, and qualitatively distinct from that associated with primary dementia.
Cognitive and noncognitive psychiatric symptoms were systematically evaluated in 21 patients with Alzheimer's disease by using the Neurobehavioral Rating Scale. Regional cerebral metabolic activity was measured in each patient by [18F]fluorodeoxyglucose PET. Significant correlations emerged between global cortical metabolic activity and the Agitation/Disinhibition factor score, Cognition factor score, and total score. Relationships between noncognitive symptoms and metabolic activity were regionally specific, with significant correlations between Agitation/Disinhibition factor score and metabolism in the frontal and temporal lobes, between Psychosis factor score and metabolism in the frontal lobe, and between Anxiety/Depression factor score and metabolism in the parietal lobe. These results suggest that psychiatric symptoms are fundamental expressions of the cortical dysfunction of Alzheimer's disease.
We investigated the range of behavioral abnormalities in patients with Alzheimer's disease (AD) compared with normal age-matched control subjects. The range of behavioral disturbances manifested and the relationship between specific abnormalities with the level of cognitive impairment have not been established. Fifty consecutive outpatients with mild (n = 17), moderate (n = 20), and severe (n = 13) AD and 40 age-matched normal controls were evaluated for behavioral abnormalities occurring in the month preceding the interview. The caregivers of the patients and the spouses of the control subjects were interviewed with the Neuropsychiatric Inventory (NPI). The frequency and severity of the following 10 behaviors were assessed: delusions, hallucinations, agitation, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability, and aberrant motor behavior. Correlations among these 10 behaviors and their relationship with cognitive impairment were also investigated. Eighty-eight percent of AD patients had measurable behavioral changes. All 10 behaviors were significantly increased in the AD patients compared with normal subjects. The most common behavior was apathy, which was exhibited by 72% of patients, followed by agitation (60%), anxiety (48%), irritability (42%), dysphoria and aberrant motor behavior (both 38%), disinhibition (36%), delusions (22%), and hallucinations (10%). Agitation, dysphoria, apathy, and aberrant motor behavior were significantly correlated with cognitive impairment.
NEUROLOGY 1996;46: 130-135
Caring for people with dementia is stressful,1 and depression occurs in 30-50% of carers.2 Few data are available, however, about the course of depression or variables associated with the length of episodes, such as age, closeness of relationship, and non-cognitive symptoms among patients. We followed up a group of carers over a year to assess the length and determinants of depression.
We recruited 124 patients with dementia as defined by DSMIIIR from consecutive referrals to psychiatric services in Birmingham (99) and a memory clinic in Bristol (25); 90% of those approached agreed to participate. One hundred and nine had informal carers, of whom 85 were followed up for one year.
Carers were interviewed initially and every month with the geriatric mental state schedule and the …
This pilot study evaluated response of negative symptoms (NS) to methylphenidate in patients with dementia and relationships between NS, depression, and cognitive deficits in these patients. Consecutively admitted patients with NS and dementia--12 with dementia of Alzheimer's type and 15 with vascular dementia--were rated on severity of NS (SANS and PANSS-N scales), depressive symptoms (Ham-D), and cognitive impairment (MMSE) before and after treatment with methylphenidate. NS decreased significantly, and cognitive scores increased. A decrease in depression scores was nonsignificant after all variance attributable to NS was removed. NS, depression, and cognitive scores were not significantly intercorrelated. Results were similar for Alzheimer's and vascular dementia patients. Negative symptoms in dementia patients appear responsive to methylphenidate treatment. This effect may underlie putative changes in symptoms of depression observed by other researchers.
The Neuropsychiatric Inventory (NPI) was developed to assess psychopathology in dementia patients. It evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. The severity and frequency of each neuropsychiatric symptom are rated on the basis of scripted questions administered to the patient's caregiver. The NPI also assesses the amount of caregiver distress engendered by each of the neuropsychiatric disorders. A total NPI score and a total caregiver distress score are calculated, in addition to the scores for the individual symptom domains. Content validity, concurrent validity, inter-rater reliability, and test-retest reliability of the NPI are established. Different neurologic disorders have characteristic neuropsychiatric manifestations and distinctive NPI profiles. The NPI is sensitive to treatment effects and has demonstrated the amelioration of behavioral symptoms in Alzheimer's disease by cholinergic agents. The NPI is a useful instrument for characterizing the psychopathology of dementia syndromes, investigating the neurobiology of brain disorders with neuropsychiatric manifestations, distinguishing among different dementia syndromes, and assessing the efficacy of treatment.