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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.
... Among early Alzheimer's disease patients, depression and apathy are the most frequently observed neuropsychiatric symptoms, although agitation also exhibits a high incidence. While aggression tends to gradually manifest as the disease progresses, apathy stands out as the most persistent and prevalent symptom among all neuropsychiatric symptoms (Lyketsos 2011). ...
... Agitation not only burdens patients themselves but also their caregivers and surrounding individuals, significantly impacting treatment costs as agitation symptoms worsen (Livingston 2020). Therefore, removing the triggers causing agitation as much as possible can help alleviate symptoms, and methods such as music therapy, massage therapy, or psychological treatments, as well as medication in severe cases, are used to alleviate agitation (Lyketsos 2011). Agitation often co-occurs with other neuropsychiatric symptoms. ...
... Depression emerges as a prevalent manifestation in Alzheimer's pathology, consequently warranting significant attention in the therapeutic approach to Alzheimer's disease (Rosenberg, 2015). The intricacies inherent in diagnosing and treating depression in Alzheimer's stem from the commonalities shared with late-life depression unrelated to Alzheimer's and symptoms of apathy, necessitating careful differentiation (Lyketsos, 2011). Furthermore, depression in Alzheimer's can exacerbate the occurrence of additional cognitive impairments or impinge upon frontal lobe functionality, yet remedying depression may concurrently ameliorate these deficits (Botto, 2022). ...
Psychosis in Alzheimer's disease (AD) is a prevalent phenomenon, marked by delusions and hallucinations, along with other neuropsychiatric symptoms such as agitation, depression, anxiety, and apathy. These neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect up to 97% of Alzheimer's patients. The presence of psychosis in AD significantly impacts patients' daily lives and places a considerable burden on caregivers. The development of AD-related psychosis (ADP) is influenced by a range of factors, including genetic predispositions and life-acquired factors. AD affects cognitive function and various brain regions, resulting in widespread brain atrophy. In addition to its neurological impact, AD can induce pathological physiological changes that serve as biomarkers for ADP. Research efforts have focused on developing pharmacological treatments for psychosis in AD, aiming to minimize side effects. Brexpiprazole has emerged as a promising medication for ADP, alongside other antipsychotics. Treatment approaches for ADP extend beyond pharmacology, incorporating methods such as sensory stimulation and digital therapeutics. This review will explore the characteristics of psychosis in Alzheimer's disease, the pathological underpinnings of ADP, and the current therapeutic landscape, highlighting emerging opportunities for managing this challenging condition.
... The prevalence of NPS in AD can vary depending on factors such as disease stage, age of onset, and genetic predispositions. While NPS typically becomes more pronounced in the later stage of AD, population-based studies have shown that these symptoms often manifest in the very early stages, including the prodromal stage, such as MCI [3][4][5][6][7]. Among NPS, depression and apathy are the most frequently observed in patients with MCI and early AD, often accompanied by verbal and physical agitation. ...
... Analysis of comorbidities in patients with AD has revealed a combination of neurological, psychiatric, and peripheral disorders [3,8,9] with significant involvement of reactive oxygen species and the anti-oxidative system, inflammation, obesity, and hypertension as determining factors [9,10], and the trajectory of comorbidity could be different from that of the aging population without AD symptoms [11]. A study based on a Spanish cohort over 6 years period reported a wide range of comorbidities in patients with AD. ...
... Additionally, the occurrence of these co-symptoms can be influenced by various factors, such as age at disease onset, level of education, and gender. Utilizing this information can help to develop personalized treatment approaches [3,8,11,13]. Furthermore, neurological comorbidities associated with AD are often not well controlled by conventional antidepressants and antipsychotics that are typically used for patients with individual disorders [3]. ...
Alzheimer’s disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer’s disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPS) associated with AD and new candidates under development for the treatment of NPS based on their therapeutic targets and mechanisms. On top of the conventional NPS studied so far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanisms of action focused on AD-related NPS rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPS in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.
... In addition to cognitive symptoms, depression and behavioral symptoms are also common in Alzheimer's disease (AD) and often surface in the disease's early stages alongside the onset of cognitive decline [3,4]. This has led to the novel concept of mild behavioral impairment (MBI), which refers to the early behavioral symptoms observed in the early stages of neurodegenerative diseases, including AD [5]. This new framework enhances our understanding of early AD symptoms and prompts us to explore whether similar pathophysiological mechanisms may be responsible for the observed cognitive and behavioral changes in the disease. ...
... Symptoms of depression are an integral part of the proposed criteria for recognition of MBI [7]. The range of depressive symptoms can be broad, including persistent sadness, feelings of isolation, loss of interest in previously enjoyed activities, disruptions in sleep, diminished energy, and fatigue [5,6]. These symptoms lead to individual distress and impair quality of life [7]. ...
... Early symptoms of AD reach beyond memory loss, including sleep disturbance, psychosis, and social isolation [10]. Depressive symptoms are also common in the early stages and depression is a strong risk factor for AD. ...
... When all the affective behavioral test are integrated in a z-score there is a significant difference in App NL−F compared to C57Bl6 mice. This is in good agreement with early depressive symptoms observed in AD patients [10] as well as results from other animals models of the disease [67]. Moreover, we confirm the lack of memory impairment at this age using the five-trials social memory test. ...
Background:
Alzheimer's disease (AD) is the most common neurodegenerative disease. Unfortunately, efficient and affordable treatments are still lacking for this neurodegenerative disorder, it is therefore urgent to identify new pharmacological targets. Astrocytes are playing a crucial role in the tuning of synaptic transmission and several studies have pointed out severe astrocyte reactivity in AD. Reactive astrocytes show altered physiology and function, suggesting they could have a role in the early pathophysiology of AD.
Objective:
We aimed to characterize early synaptic impairments in the AppNL-F knock-in mouse model of AD, especially to understand the contribution of astrocytes to early brain dysfunctions.
Methods:
The AppNL-F mouse model carries two disease-causing mutations inserted in the amyloid precursor protein gene. This strain does not start to develop amyloid-β plaques until 9 months of age. Thanks to electrophysiology, we investigated synaptic function, at both neuronal and astrocytic levels, in 6-month-old animals and correlate the synaptic activity with emotional behavior.
Results:
Electrophysiological recordings in the hippocampus revealed an overall synaptic mistuning at a pre-plaque stage of the pathology, associated to an intact social memory but a stronger depressive-like behavior. Astrocytes displayed a reactive-like morphology and a higher tonic GABA current compared to control mice. Interestingly, we here show that the synaptic impairments in hippocampal slices are partially corrected by a pre-treatment with the monoamine oxidase B blocker deprenyl or the fast-acting antidepressant ketamine (5 mg/kg).
Conclusions:
We propose that reactive astrocytes can induce synaptic mistuning early in AD, before plaques deposition, and that these changes are associated with emotional symptoms.
... This aligns with the previous studies, which emphasise the fact that patients often present with symptoms that span cognitive, behavioural, and neurological domains, further complicating diagnosis and management. [59,63,64] The lack of detailed data on investigations conducted at FNHM reflects the resource constraints typical of many sub-Saharan African healthcare settings [34]. The limited access to advanced diagnostic tools like neuroimaging and biomarker assays can lead to a reliance on clinical symptoms for diagnosis, potentially contributing to underdiagnosis or misdiagnosis of dementia subtypes. ...
... [1] Apart from memory-related symptoms, AD is accompanied by behavioral and psychological symptoms of dementia (BPSD), which include agitation, aggression, depression, anxiety and sleep disturbances. [2] The progression of these symptoms is attributed to the deterioration of nerve connections and compromised neurotransmission. This is particularly relevant to the cholinergic system, which plays a pivotal role in memory processes. ...
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as γ‐aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, using a combination of crystallography and computational methods we developed compound 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC50=0.21 μM) and GABA transporter 1 (IC50=10.96 μM) and 3 (IC50=7.76 μM), along with a favorable drug‐likeness profile. Subsequent in vivo studies revealed the effectiveness of 6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi‐target‐directed ligand 6 offers a new approach to treating cognitive deficits and BPSD in AD.
... NPS frequently accompany AD and related dementias, and it has been estimated that, throughout the course of the disease, more than 80% of individuals will exhibit at least one NPS that significantly impacts their clinical outcomes 111 . So far, various studies have examined population data to characterize NPS along the AD continuum [112][113][114] . For example, depression and apathy are often the most observed symptoms in the early stages of AD, while delusions, hallucinations, and aggression become more prevalent as the disease advances 112 . ...
The dorsolateral prefrontal cortex is central to higher cognitive functions and is particularly vulnerable to age-related decline. To advance our understanding of the molecular mechanisms underlying brain development, maturation, and aging, we constructed a detailed single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, encompassing over 1.3 million nuclei from 284 postmortem samples spanning the full human lifespan (0-97 years). This atlas reveals distinct phases of transcriptomic activity: a dynamic developmental period, stabilization during midlife, and subtle yet coordinated changes in late adulthood. Modeling non-linear age trends across the lifespan shows ten distinct trajectories of the entire transcriptome from all cell types, with notable findings in neurons and microglia, linked to neurodevelopmental disorders and Alzheimer's disease risk, respectively. Moreover, excitatory neurons exhibit a convergence of gene expression patterns across the lifespan, suggesting the emergence of a common molecular signature of aging. Pseudotime analysis tracing the progression of cellular lineages throughout life reveals key gene clusters with dynamic expression changes that reflect development, maturation, and aging, as well as their connection to brain-related diseases. We uncover significant circadian rhythm reprogramming in late adulthood, characterized by disruption of core clock gene rhythmicity and the emergence of new rhythmic patterns, particularly within microglia and oligodendrocytes. This comprehensive single-cell atlas provides a baseline for understanding the molecular transitions from development through successful aging in the human dorsolateral prefrontal cortex.
... It affects an ever-increasing number of individuals. Neurodegeneration, a decline in brain function, delusions, anxiety, inaction, and despair are some of the hallmarks of Alzheimer's disease [2][3][4]. Due to the absence of effective therapies, a proper diagnosis of AD is crucial. Imaging techniques like as PET and MRI are often used to identify cases of AD. ...
Alzheimer's disease (AD) is a neurodegenerative brain disorder that causes diminished memory and cognitive decline, and it affects millions of people throughout the world. In particular, acetylcholinesterase (AChE) inhibitors have been studied as a means of studying the cholinergic system, since low acetylcholine levels, T protein aggregation, oxidative stress, inflammatory processes, and abnormal beta-amyloid, are all related to AD. For the aim of ADMET experiments for cholinesterase inhibitors against Alzheimer's disease, a series of new acridine scaffolds were developed, docked, and predicted in this research. When compared to normal Donepezil, the proposed compound showed improved docking studies in the binding region of acetylcholinesterase enzyme when utilizing the Pyrex docking program. Compound 19 (12.3 Kcal/mol) was the most widely proposed new acridine derivative, and its inhibitory activity against AChE was mediated by two hydrogen bonding interactions. Pharmacokinetic and drug-like properties were predicted in vitro using Swiss ADME software. The pharmacokinetic characteristics of the synthetic compounds suggest that they may be effective cholinesterase inhibitors in the treatment of Alzheimer's disease.
... 2,3 Ample evidence has suggested that the presence of NPSs has been associated with cognitive decline, accelerated disease progression, reduced quality of life, and greater disability. [4][5][6] In addition, NPSs are among the most challenging and costly aspects of dementia, 7 leaving enormous burdens and limited treatment options for the public. Hence, identifying potentially early risk factors for NPSs in older adults is critical. ...
Introduction
To investigate the association between cardiometabolic multimorbidity (CMM) patterns and dementia‐related neuropsychiatric symptoms (NPSs) among multiregional and ethnic seniors.
Methods
Four Asian studies (discovery) and UK Biobank (validation) were included. CMM was defined as two or more of hypertension, hyperlipidemia, diabetes mellitus, stroke, and heart disease. The latent class analysis identified CMM patterns. Two‐step individual participant data (IPD) and Cox regressions explored associations between CMM and the presence and short‐term (1–2 years) incidence of four neuropsychiatric subsyndromes: psychosis, hyperactivity, affective, and apathy.
Results
A total of 2950 Asian and 40,424 UK participants were included. Metabolic multimorbidity (≥2 of hypertension, hyperlipidemia, and diabetes mellitus) was associated with the presence (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.00–1.81; and 1.93, 1.73–2.16; in the respective data set), and incidence (hazard ratio [HR] = 3.91, 1.53–10.01; and 6.94, 2.52–19.07) of affective subsyndrome. Cardio‐cerebrovascular multimorbidity (≥2 of hypertension, stroke, and heart disease) was not associated with any NPSs.
Discussion
Metabolic multimorbidity may exacerbate the neuropsychiatric disturbances of possible dementia.
Highlights
Four Asian multiregional and ethnic studies were included as the discovery data set, with the UK Biobank being applied as the validation data set.
Metabolic multimorbidity had a higher presence and short‐term incidence of affective syndromes.
Cardio‐cerebrovascular multimorbidity was not associated with any neuropsychiatric symptoms.
... An estimated 6.7 million Americans aged 65 and older are living with AD today, which could grow to as much as 13.8 million by 2060, barring the development of novel methods to prevent, cure or slow the disease [1]. In addition to the hallmark cognitive impairment associated with AD, studies have shown that the frequency of neuropsychiatric symptoms is also much higher in AD than in the general population, of which the most frequently observed symptoms are increased generalized apathy, anxiety and depression [2]. ...
Withania somnifera (WS), also known as ashwagandha, is a popular botanical supplement used to treat various conditions including memory loss, anxiety and depression. Previous studies from our group showed an aqueous extract of WS root (WSAq) enhances cognition and alleviates markers for depression in Drosophila. Here, we sought to confirm these effects in the 5xFAD mouse model of β-amyloid (Aβ) accumulation. Six- to seven-month-old male and female 5xFAD mice were treated with WSAq in their drinking water at 0 mg/mL, 0.5 mg/mL or 2.5 mg/mL for four weeks. In the fourth week of treatment, spatial memory, anxiety and depressive-like symptoms were evaluated. At the conclusion of behavioral testing, brain tissue was harvested, immunohistochemistry was performed, and the cortical expression of antioxidant response genes was evaluated. Both concentrations of WSAq improved spatial memory and reduced depressive and anxiety-related behavior. These improvements were accompanied by a reduction in Aβ plaque burden in the hippocampus and cortex and an attenuation of activation of microglia and astrocytes. Antioxidant response genes were upregulated in the cortex of WSAq-treated mice. Oral WSAq treatment could be beneficial as a therapeutic option in AD for improving disease pathology and behavioral symptoms. Future studies focused on dose optimization of WSAq administration and further assessment of the mechanisms by which WSAq elicits its beneficial effects will help inform the clinical potential of this promising botanical therapy.
... Additionally, the occurrence of these co-symptoms can be influenced by various factors, such as age at disease onset, level of education, and gender. Utilizing this information can help to develop personalized treatment approaches [3,4,7,9]. Furthermore, neurological comorbidities associated with AD are often not well controlled by conventional antidepressants and antipsychotics that are typically used for patients with individual disorders [4]; Ismail and Goodarzi, 2019). This highlights the urgent need for the development of new therapies that can specifically modulate NPS, indicating the presence of disease-specific mechanisms underlying NPS in AD [10]. ...
Alzheimer’s disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPSs) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer’s disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPSs) associated with AD and new candidates under development for the treatment of NPSs based on their therapeutic targets and mechanisms. On top of the conventional NPSs studied far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanism of action focused on AD-related NPS, rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPSs in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.
... Since AD has an insidious onset, it is difficult to detect and is often mistaken for a physical disease [17]. Most patients with AD repeatedly visit internal medicine outpatient clinics, such as the dermatology department, however when treatment does not provide a significant effect, then these patients are suspected of having neuropsychiatric disorders, including AD or other types of dementias [18]. This patient subsequently presented to the psychiatric department for antipsychotic treatment and received remarkable improvement. ...
BACKGROUND
Perception is frequently impaired in patients with Alzheimer’s disease (AD). Several patients exhibit visual or haptic hallucinations.
CASE SUMMARY
A 71-year-old Chinese man presented with visual and haptic hallucinations he had been experiencing for 2 weeks. The clinical manifestations were the feeling of insects crawling and biting the limbs and geison. He looked for the insects while itching and scratching, which led to skin breakage on the limbs. He was treated with topical and anti-allergic drugs in several dermatology departments without any significant improvement. After admission, the patient was administered risperidone (0.5 mg) and duloxetine (2 mg/day). One week later, the dose of risperidone was increased to 2 mg/day, and that of duloxetine was increased to 60 mg/day. After 2 weeks of treatment, the patient’s sensation of insects crawling and biting disappeared, and his mood stabilized.
CONCLUSION
This patient manifested psychiatric behavioral symptoms caused by AD brain atrophy. It was important to re-evaluate the patient’s cognitive-psychological status when the patient repeatedly went to the hospital for treatment. Follow-up attention to cognitive function and the consideration of perceptual deficits as early manifestations of AD should be considered.
... This aligns with the previous studies, which emphasise the fact that patients often present with symptoms that span cognitive, behavioural, and neurological domains, further complicating diagnosis and management. [59,63,64] The lack of detailed data on investigations conducted at FNHM reflects the resource constraints typical of many sub-Saharan African healthcare settings [34]. The limited access to advanced diagnostic tools like neuroimaging and biomarker assays can lead to a reliance on clinical symptoms for diagnosis, potentially contributing to underdiagnosis or misdiagnosis of dementia subtypes. ...
Introduction: Dementia prevalence is rising in sub-Saharan Africa due to a combination of factors, including population growth and aging. In resource-constrained settings, such as Northeastern Nigeria, dementia management is challenged by delayed diagnosis and limited specialist care. This study evaluates the burden of dementia and its management at the Federal Neuropsychiatric Hospital Maiduguri (FNHM), the only neuropsychiatric facility in Northeastern Nigeria. The study aims to provide insights into current dementia trends and practices and identify key areas for improvement.
Methods: A retrospective analysis of patient records at FNPH Maiduguri was conducted, including patients aged 60 and above diagnosed with dementia between 1999 and 2023. Data on patient demographics, dementia subtypes, comorbidities, symptoms, diagnostic investigations, and treatment modalities were analysed.
Results: The Available record from the hospital health records register showed that the total number of diagnosed cases of dementia in the FNHM is 1,216 cases with a male predominance (56%). Alzheimers disease was the most common subtype (60.5%), followed by vascular dementia (24.5%). Hypertension was the most frequently reported comorbidity (41.6%). Cognitive symptoms, particularly memory loss, were reported in all cases, while behavioural symptoms, such as agitation and hallucinations, were reported in some cases. The most commonly administered treatments included cognitive enhancers (donepezil), supplements (gingko biloba), and non-drug therapies (psychoeducation). However, 70.9% of patients were lost to follow-up, highlighting a critical gap in long-term care.
Conclusion: The increasing burden of dementia at the only neuropsychiatric facility in Northeastern Nigeria highlights the urgent need for investments and targeted interventions. Enhancing patient engagement, strengthening follow-up systems, and expanding diagnostic and treatment capacities will improve care outcomes and address the growing demands for dementia management in this underserved region.
... Neuropsychiatric symptoms (NPS), particularly depression, are common in Alzheimer disease (AD). 1,2 Recent research has linked elevated depressive symptomatology in part to AD pathophysiology, even in preclinical stages of AD (ie, before cognitive impairment), including greater core AD pathology burden, changes in functional connectivity, and cerebral metabolic dysfunction. [3][4][5][6][7][8][9][10][11] While growing evidence supports associations between emerging depressive symptoms and preclinical AD, most work has focused on cross-sectional data with large-scale measures of brain function or pathophysiology (ie, large cortical aggregates of amyloid burden or large-scale functional networks). ...
Importance
Depressive symptoms in older adults may be a harbinger of Alzheimer disease (AD), even in preclinical stages. It is unclear whether worsening depressive symptoms are manifestations of regional distributions of core AD pathology (amyloid) and whether cognitive changes affect this relationship.
Objective
To evaluate whether increasing depressive symptoms are associated with amyloid accumulation in brain regions important for emotional regulation and whether those associations vary by cognitive performance.
Design, Setting, and Participants
Participants from the Harvard Aging Brain Study, a longitudinal cohort study, underwent annual assessments of depressive symptoms and cognition alongside cortical amyloid positron emission tomography (PET) imaging at baseline and every 2 to 3 years thereafter (mean [SD] follow-up, 8.6 [2.2] years). Data collection was conducted from September 2010 to October 2022 in a convenience sample of community-dwelling older adults who were cognitively unimpaired with, at most, mild baseline depression. Data were analyzed from October 2022 to December 2023.
Main Outcomes and Measures
Depression (Geriatric Depression Scale [GDS]–30-item), cognition (Preclinical Alzheimer Cognitive Composite–5 [PACC]), and a continuous measure of cerebral amyloid (Pittsburgh compound B [PiB] PET) examined in a priori–defined regions (medial orbitofrontal cortex [mOFC], lateral orbitofrontal cortex, middle frontal cortex [MFC], superior frontal cortex, anterior cingulate cortex, isthmus cingulate cortex [IC], posterior cingulate cortex, and amygdala). Associations between longitudinal GDS scores, regional amyloid slopes, and PACC slopes were assessed using linear mixed-effects models.
Results
In this sample of 154 individuals (94 [61%] female; mean [SD] age, 72.6 [6.4] years; mean (SD) education, 15.9 [3.1] years), increasing PiB slopes in the bilateral mOFC, IC, and MFC were associated with increasing GDS scores (mOFC: β = 11.07 [95% CI, 5.26-16.87]; t = 3.74 [SE, 2.96]; P = .004; IC: β = 12.83 [95% CI, 5.68-19.98]; t = 3.51 [SE, 3.65]; P = .004; MFC: β = 9.22 [95% CI, 2.25-16.20]; t = 2.59 [SE, 3.56]; P = .03). Even with PACC slope as an additional covariate, associations remained significant in these regions.
Conclusions and Relevance
In this cohort study of cognitively unimpaired older adults with, at most, mild baseline depressive symptoms, greater depressive symptoms over time were associated with amyloid accumulation in regions associated with emotional control. Furthermore, these associations persisted in most regions independent of cognitive changes. These results shed light on the neurobiology of depressive symptoms in older individuals and underscore the importance of monitoring for elevated mood symptoms early in AD.
... These improvements in subjective well-being suggest that group reminiscence therapy may be a valuable tool for improving the quality of life of people with dementia. The emotional and social benefits of reminiscence therapy are important given the high prevalence of depression and social isolation among people with dementia [31]. Future studies should explore the integration of group reminiscence therapy into regular nursing home care routines to maintain and potentially increase these benefits. ...
The global increase in dementia cases highlights the urgent need for effective treatment and care strategies. The aim of this study was to evaluate the effects of group reminiscence therapy on cognitive function, subjective well-being, and behavioral and psychological symptoms of dementia (BPSD) in older adults with moderate to severe dementia. A pre–post comparative design was used, with 49 participants receiving eight group reminiscence therapy sessions over 4 weeks. Baseline, one-week, and one-month postintervention assessments were conducted using the Hasegawa Dementia Scale-Revised (HDS-R), the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH), and the Philadelphia Geriatric Center Morale Scale (PGC Morale Scale). The results showed no significant improvement in HDS-R scores, but significant improvements in PGC Morale Scale (p = 0.0417) and NPI-NH scores (p = 0.00226), indicating improved well-being and reduced BPSD. These findings suggest that group reminiscence therapy is effective in improving BPSD. Future research should focus on extending the duration of the intervention, including different populations, and combining group reminiscence therapy with other therapeutic approaches to fully determine its long-term benefits and mechanisms. Research on its cost-effectiveness and cultural applicability could further validate and improve the use of group reminiscence therapy in diverse care settings.
... Nevertheless, our findings cannot provide definite evidence for or against the hypothesis that when biomarker status is discordant, the underlying condition driving decline is not AD-related. The complex coincident nature of AD and non-AD comorbidities [45,46,62,63] underlines the need for further research in individuals with discordant biomarker status before one suggests the prioritization of tau over Aβ biomarkers, as a standalone biomarker strategy. It is important to consider that the clinical applicability of a biomarker depends on its characteristics and different properties are required based on its desired clinical utility [64,65]. ...
amyloid (Aβ) pathology is not always coupled with Alzheimer’s disease (AD) relevant cognitive decline. We assessed the accuracy of tau PET to identify Aβ(+) individuals who show prospective disease progression. 396 cognitively unimpaired and impaired individuals with baseline Aβ and tau PET and a follow-up of ≥ 2 years were selected from the Alzheimer’s Disease Neuroimaging Initiative dataset. The participants were dichotomously grouped based on either clinical conversion (i.e., change of diagnosis) or cognitive deterioration (fast (FDs) vs. slow decliners (SDs)) using data-driven clustering of the individual annual rates of cognitive decline. To assess cognitive decline in individuals with isolated Aβ(+) or absence of both Aβ and tau (T) pathologies, we investigated the prevalence of non-AD comorbidities and FDG PET hypometabolism patterns suggestive of AD. Baseline tau PET uptake was higher in Aβ(+)FDs than in Aβ(-)FD/SDs and Aβ(+)SDs, independently of baseline cognitive status. Baseline tau PET uptake identified MCI Aβ(+) Converters and Aβ(+)FDs with an area under the curve of 0.85 and 0.87 (composite temporal region of interest) respectively, and was linearly related to the annual rate of cognitive decline in Aβ(+) individuals. The T(+) individuals constituted largely a subgroup of those being Aβ(+) and those clustered as FDs. The most common biomarker profiles in FDs (n = 70) were Aβ(+)T(+) (n = 34, 49%) and Aβ(+)T(-) (n = 19, 27%). Baseline Aβ load was higher in Aβ(+)T(+)FDs (M = 83.03 ± 31.42CL) than in Aβ(+)T(-)FDs (M = 63.67 ± 26.75CL) (p-value = 0.038). Depression diagnosis was more prevalent in Aβ(+)T(-)FDs compared to Aβ(+)T(+)FDs (47% vs. 15%, p-value = 0.021), as were FDG PET hypometabolism pattern not suggestive of AD (86% vs. 50%, p-value = 0.039). Our findings suggest that high tau PET uptake is coupled with both Aβ pathology and accelerated cognitive decline. In cases of isolated Aβ(+), cognitive decline may be associated with changes within the AD spectrum in a multi-morbidity context, i.e., mixed AD.
... Alzheimer's disease (AD) is the sixth leading cause of death, and currently affects > 6 million people, in the United States. 1 AD is a progressive neurodegenerative disorder for which available therapeutics only minimally impact disease severity and progression. 2 Neuropsychiatric symptoms (NPS; e.g., aggression, psychosis, anxiety, apathy, depression, eating changes, agitation, sleep disturbances, repetitive behaviors) occur in 85% of AD patients, 3,4 and are associated with accelerated decline, out-of-home placement, increased costs, and greatly increased suffering of patients and families. 5-10 NPS can be a prodrome of AD 11 and related neurodegenerative disorders 12 ADSP-FUS), 35 and analyze these data to identify genetic loci and mechanistic pathways associated with NPS in AD. ...
INTRODUCTION
Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms.
METHODS
To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole‐genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP).
RESULTS
This study will generate a genomic resource for Alzheimer's disease with both harmonized whole‐genome sequencing and NPS phenotype data that will be publicly available through NIAGADS. Primary analyses will (1) identify novel genetic risk factors associated with NPS in AD, (2) characterize the shared genetic architecture of NPS in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of NPS in AD.
DISCUSSION
Expansion of the ADSP to harmonize and refine NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations.
Highlights
Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD).
There are no effective treatments targeting NPS in AD.
The current effort aims to collate, harmonize, and analyze all NPS data from the Alzheimer's Disease Sequencing Project.
Core analyses will identify underlying genetic factors and mechanistic pathways.
The harmonized genomic and phenotypic data from this initiative will be available through National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site.
... Depression is a common comorbidity in people with neurodegenerative disorders, including MCI, often exacerbating cognitive symptoms and affecting overall quality of life. According to the study conducted by Lyketsos et al., depression is one of the neuropsychiatric symptoms that most frequently appear in people diagnosed with AD or MCI [26]. Malhi and Mann [27] mentioned that one out of five individuals experiences an episode of depression during their lifetime, with clinical depression being the third cause of disease burden worldwide according to the World Health Organization (WHO). ...
Background
The increase in cases of mild cognitive impairment (MCI) underlines the urgency of finding effective methods to slow its progression. Given the limited effectiveness of current pharmacological options to prevent or treat the early stages of this deterioration, non-pharmacological alternatives are especially relevant.
Objective
To assess the effectiveness of a cognitive-motor intervention based on immersive virtual reality (VR) that simulates an activity of daily living (ADL) on cognitive functions and its impact on depression and the ability to perform such activities in patients with MCI.
Methods
Thirty-four older adults (men, women) with MCI were randomized to the experimental group (n = 17; 75.41 ± 5.76) or control (n = 17; 77.35 ± 6.75) group. Both groups received motor training, through aerobic, balance and resistance activities in group. Subsequently, the experimental group received cognitive training based on VR, while the control group received traditional cognitive training. Cognitive functions, depression, and the ability to perform activities of daily living (ADLs) were assessed using the Spanish versions of the Montreal Cognitive Assessment (MoCA-S), the Short Geriatric Depression Scale (SGDS-S), and the of Instrumental Activities of Daily Living (IADL-S) before and after 6-week intervention (a total of twelve 40-minutes sessions).
Results
Between groups comparison did not reveal significant differences in either cognitive function or geriatric depression. The intragroup effect of cognitive function and geriatric depression was significant in both groups (p < 0.001), with large effect sizes. There was no statistically significant improvement in any of the groups when evaluating their performance in ADLs (control, p = 0.28; experimental, p = 0.46) as expected. The completion rate in the experimental group was higher (82.35%) compared to the control group (70.59%). Likewise, participants in the experimental group reached a higher level of difficulty in the application and needed less time to complete the task at each level.
Conclusions
The application of a dual intervention, through motor training prior to a cognitive task based on Immersive VR was shown to be a beneficial non-pharmacological strategy to improve cognitive functions and reduce depression in patients with MCI. Similarly, the control group benefited from such dual intervention with statistically significant improvements.
Trial registration
ClinicalTrials.gov NCT06313931; https://clinicaltrials.gov/study/NCT06313931.
... In 2019, an estimated 57 million people worldwide were living with dementia, and this number will likely increase to 150 million by 2050. 1 Alzheimer disease (AD) is the most prevalent form of dementia (70% of all cases), followed by vascular dementia (VD) and dementia with Lewy Bodies (DLB) both accounting for 5% to 10%. 2 Neuropsychiatric symptoms and cognitive disorders (e.g., disorders of executive functions, information processing, and verbal memory) are frequently present in both dementia and primary psychiatric diseases. [3][4][5] Distinction between early stage dementia and other causes of cognitive disorders (such as depression or temporal lobe epilepsy) can be difficult in patients with mild cognitive impairment (MCI). This highlights the need for additional biomarkers to facilitate early patient selection for trials and potential new treatment options. ...
Purpose
Electroencephalography (EEG) is a noninvasive diagnostic tool that can be of diagnostic value in patients with cognitive disorders. In recent years, increasing emphasis has been on quantitative EEG analysis, which is not easily accessible in clinical practice. The aim of this study was to assess the diagnostic and prognostic value of visual EEG assessment to distinguish different causes of cognitive disorders.
Methods
Patients with cognitive disorders from a specialized memory clinic cohort underwent routine workup including EEG, neuropsychological testing and brain imaging. Electroencephalography parameters including posterior dominant rhythm, background activity, and response to photic stimulation (intermittent photic stimulation) were visually scored. Final diagnosis was made by an expert panel.
Results
A total of 501 patients were included and underwent full diagnostic workup. One hundred eighty-three patients had dementia (111 Alzheimer disease, 30 vascular dementia, 15 frontotemporal dementia, and 9 dementia with Lewy bodies), 66 patients were classified as mild cognitive impairment, and in 176, no neurologic diagnosis was made. Electroencephalography was abnormal in 60% to 90% of patients with mild cognitive impairment and dementia, most profoundly in dementia with Lewy bodies and Alzheimer disease, while frontotemporal dementia had normal EEG relatively often. Only 30% of those without neurologic diagnosis had EEG abnormalities, mainly a diminished intermittent photic stimulation response. Odds ratio of conversion to dementia was 6.1 [1.5–24.7] for patients with mild cognitive impairment with abnormal background activity, compared with those with normal EEG.
Conclusions
Visual EEG assessment has diagnostic and prognostic value in clinical practice to distinguish patients with memory complaints without underlying neurologic disorder from patients with mild cognitive impairment or dementia.
... Neuropsychiatric symptoms (NPS) such as apathy, depression, agitation, and sleep disturbances, are common in older people, with rates of 80% or more in patients with cognitive impairment and dementia [1]. NPS frequently occur already at preclinical or prodromal stages of Alzheimer's disease (AD) [2,3] and therefore can be seen as a risk factor for the progression to dementia [4][5][6]. NPS have been associated with lower quality of life, more frequent hospitalizations, and earlier death [7][8][9]. Early detection and evaluation of NPS is therefore important for a more accurate prognosis and more specific treatment interventions to lower disease burden and potentially improve long-term outcomes. ...
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). Different regression and ROC analyses were used to address the associations of interest.
Results
None of the three plasma biomarker was associated with NPS at baseline. Higher GFAP levels were associated with the presence of NPS at follow-up (OR = 2.8, p = .002) and both, higher NfL and higher GFAP with an increase in the NPI-Q severity score over time (β = 0.25, p = .034 and β = 0.30, p = .013, respectively). Adding NPS and the plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.72 to 0.88, p = .002) and AD pathology (AUC 0.78 to 0.87, p = .010), but not of cognitive decline (AUC 0.79 to 0.85, p = .081).
Conclusion
Plasma NfL and GFAP are both associated with future NPS and NPS severity change. Considering the presence of NPS along with blood-based AD-biomarkers may improve the prediction of clinical progression of NPS over time and inform clinical decision-making in non-demented older people.
... NPSs may occur at any point during the disease course,including very early in the disease and during prodromal phases. [2][3][4] Agitation associated with AD (AAD) is one of the most distressing NPSs for patients and care partners. Emerging evidence indicates agitation/aggressive NPSs are associated with faster AD progression and death. ...
... Compared with healthy controls and non-AD dementia, the level of PILRB in CSF was higher in AD patients [46]. We also found that plasma PILRB level was positively associated with the risk of mild cognitive disorder which is generally considered to be symptom manifest in prodromal phases of AD [51]. In addition, Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) and PILRB belong to the PILR family and are involved in the regulation of the immune system [49]. ...
Background
Alzheimer's disease (AD) is a progressive neurodegenerative disease, with a critical shortage of effective prevention and treatment options. Here, we aimed to identify proteins whose genetically regulated plasma levels were associated with AD and its related phenotypes.
Methods
An integrative proteome-wide search using Olink-based plasma proteomes (N = 45,540) from the UK Biobank Pharma Proteomics Project (UKB-PPP) and a large-scale genome-wide association study (GWAS) for AD (N case = 111,326, N control = 677,663) was employed to identify AD-associated proteins. Cohort studies for AD or mild cognitive disorder (MCD) with average follow-ups of 13.7 years, alongside cross-sectional studies for the volume of whole hippocampus (WH) and white matter hyperintensities (WMH) were performed to provide additional supports.
Results
We identified 30 AD-associated proteins through a genetic-informed proteome-wide association study (PWAS). Among these, 14 proteins (including TREM2 and GRN) have been previously reported to be associated with AD. No clear evidence has linked the remaining 16 proteins (including PILRB, FES, and HDGF) with AD. PILRB and FES were further supported by cohort studies for AD and/or MCD. A higher plasma abundance of HDGF was found to be associated with a lower volume of whole-hippocampus and an increased risk of AD, consistent with a previous study which showed a potentially risk role of HDGF for AD in both brain tissues and cerebrospinal fluid. The protein-protein interaction analysis linked PILRB with ABCA7, an AD-related protein involved in the immune system.
Conclusions
The integrative genetic-informed proteome-wide scan provides promising AD-associated proteins for further mechanistic studies.
... Clinically key features of Alzehimer's disease are complete dementia, including memory impairment, executive dysfunction, personality changes, and behavioural changes. The majority of patients also experience signs of a mental problem [42]. It causes neurotoxicity by alteration in the levels of MDA and GSH, two compounds crucial in oxidative stress, as well as by the activation of apoptotic pathways. ...
... Neuropsychiatric symptoms (NPS) are a common feature experienced by patients diagnosed with dementia and mild cognitive impairment (MCI) due to Alzheimer's disease (AD) [1,2]. NPS are associated with early pathological changes, including disruption in various neurotransmitter systems [3], and brainstem involvement may be instrumental in AD pathogenesis [4]. ...
Background
Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer’s disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear.
Objective
We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ 1-42 , p-tau 181 ), cognitive function, and NPS.
Methods
Primary models included 781 participants from the National Alzheimer’s Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR ® ) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOE ɛ4.
Results
The sample was older adults ( M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white ( n = 688, 88.1%). Higher p-tau 181 /Aβ 1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau 181 /Aβ 1-42 ratio and CDR global impairment. With dementia excluded, p-tau 181 /Aβ 1-42 ratio was no longer associated with the NPI-Q.
Conclusions
NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia.
... Alzheimer's disease (AD) is the most common cause of dementia and thus one of the most burdensome diseases globally [1]. Individuals affected by the disease exhibit a wide range of symptoms, such as memory impairment, behavioral disturbance, and psychological symptoms [2,3] or may even lack any clinical symptoms, which is called preclinical AD [4]. Recently, the importance of biomarkers measuring the deposition of β-amyloid (Aβ) plaques in the brain-a central pathological hallmark of AD-has increasingly been recognized [5,6]. ...
Accurate quantification of amyloid positron emission tomography (PET) is essential for early detection of and intervention in Alzheimer’s disease (AD) but there is still a lack of studies comparing the performance of various automated methods. This study compared the PET-only method and PET-and-MRI-based method with a pre-trained deep learning segmentation model. A large sample of 1180 participants in the Catholic Aging Brain Imaging (CABI) database was analyzed to calculate the regional standardized uptake value ratio (SUVR) using both methods. The logistic regression models were employed to assess the discriminability of amyloid-positive and negative groups through 10-fold cross-validation and area under the receiver operating characteristics (AUROC) metrics. The two methods showed a high correlation in calculating SUVRs but the PET-MRI method, incorporating MRI data for anatomical accuracy, demonstrated superior performance in predicting amyloid-positivity. The parietal, frontal, and cingulate importantly contributed to the prediction. The PET-MRI method with a pre-trained deep learning model approach provides an efficient and precise method for earlier diagnosis and intervention in the AD continuum.
Objectives
We investigated the association between neuropsychiatric symptoms (NPS) and frontotemporal atrophy (FTA) in older adults without dementia. We hypothesized that the odds of having NPS would be increased in the presence of FTA.
Methods
NACC participants ≥ 50 years old with available data on FTA were considered for eligibility. Those with a diagnosis of mild cognitive impairment (MCI) and those who were cognitively unimpaired (CU) were separately analyzed. NPS were quantified on the Neuropsychiatric Inventory Questionnaire. Binary logistic regression models estimated the association (odds ratios and 95% confidence intervals are provided) between FTA and having each of 11 NPS (psychotic symptoms were grouped together) in CU and MCI individuals.
Results
FTA data were available for 3165 participants with MCI and 4051 CU: 207 and 55 had FTA on structural MRI studies, respectively. In the MCI group, the presence of FTA was associated with higher odds of having elation [2.42(1.33–4.40), p = 0.004], aberrant motor behavior [2.43(1.61–3.69), p < 0.001], appetite disorders [2.15(1.52–3.04), p < 0.001], apathy [2.05(1.48–2.85), p < 0.001] and disinhibition [2.02(1.38–2.96), p < 0.001]. The odds of having specific NPS were not significantly elevated in CU individuals with FTA. Of note, the size and direction of the associations were indicative of a potential relationship between FTA and specific NPS (most notably elation, aberrant motor behavior, appetite disorders and anxiety); in light of the small number of CU individuals with FTA we believe this analysis was underpowered and obscured several true associations.
Conclusions
FTA was associated with higher odds of some NPS in older adults with MCI but not with normal cognition.
Screening Aβ aggregation inhibitors (AAIs) is important for Alzheimer's disease drug discovery. However, common cellular or biochemical methods are not suitable for high‐throughput natural product screening. A gold nanoparticle (GNP) screening method was employed in this study to screen marine fungal crude extracts and pure compounds for quick AAIs discovering. The anti‐Aβ aggregation activity was further inspected using transmission electron microscopic (TEM) observation and the interaction between active molecules and different Aβ species was revealed by molecular docking. The results indicated that the fungal extracts DLS2008001 (M), BM3T2 (M), DLEN2008005 (M), TBG1‐16 (P), and TBG1‐13 (P) showed activity comparable to the positive control human serum albumin at the concentration of 500 μg/mL; 10 pure compounds also displayed moderate anti‐aggregation activity, particularly nidulin, aspergillusidone G, and butyrolactone I. The inspection of anti‐Aβ aggregation effect through TEM further demonstrated that extracts TBG1‐16 (P), DLS2008001 (M), and BM3T2 (M) dramatically inhibited the formation of Aβ aggregates. Molecular docking displayed low binding energies and key interactions of nidulin, aspergillusidone G, and butyrolactone I, with nine types of Aβ peptides. These findings indicate that the GNP method is efficient in screening AAIs and reveal marine fungal natural products as valuable sources of small molecular AAIs.
Alzheimer’s Disease (AD) is physiopathologically marked by an accumulation of beta-amyloid peptide (Aβ), hyperphosphorylation of tau protein, inflammation, and oxidative stress in the brain tissue. While new drugs for AD have been approved, novel treatments are still needed. Eplingiella fruticosa (EF) has demonstrated anti-inflammatory and antioxidant properties, which may be beneficial against AD. This study aimed to evaluate the effects of EF leaf essential oil complexed with β-cyclodextrin in a sporadic AD model induced by streptozotocin (STZ). Male Wistar rats (5–6 months old) received an intracerebroventricular STZ injection (3 mg/kg) or vehicle, and were orally treated with vehicle, EF (5 mg/kg), or donepezil (5 mg/kg) for 14 days. Behavioral tests included olfactory discrimination, open field, novel object recognition, sucrose preference, and spontaneous alternation. Upon completion, rats were euthanatized, and their brains were analyzed for Aβ, tau, and IL-1β via immunohistochemistry, and for oxidative stress markers. STZ-treated rats showed memory deficits and anhedonia, accompanied by increased Aβ, tau, and IL-1β immunoreactivity in the olfactory bulb, cortex, hippocampus, and increased TBARS levels in the hippocampus. On the other hand, EF treatment improved short-term and working memory (p < 0.001), and reduced depressive-like behavior (p = 0.02). Additionally, EF treatment decreased Aβ, tau, and IL-1β immunoreactivity in the olfactory bulb, hippocampus and cortex (p < 0.05), and reduced TBARS levels (p = 0.04) and total oxidant status in the hippocampus (p = 0.03), and increased total antioxidant status in the cortex (p = 0.04). These findings suggest EF has neuroprotective effects against STZ-induced damage, indicating its potential as a novel compound for AD treatment.
Purpose: This study aimed to identify factors influencing the care burden faced by family caregivers of older adults with dementia who use dementia care centers.Methods: This study investigated the care burden, family caregiver factors, care-recipient factors including behavioral and psychological symptoms of dementia (BPSD), depression levels, dementia attitudes, and resilience. Data were collected from March 15 to September 30, 2022. In total, 234 family caregivers using dementia care centers in five districts in Seoul, Korea, participated. Data were analyzed using the t-test, analysis of variance, Pearson correlation coefficients, and multiple regression analysis with SPSS/Windows version 27.0.Results: The mean score for care burden was 22.97. The factors influencing the care burden were BPSD (ß = .41, p < .001), depression levels (ß = .26, p < .001), hours of caregiving (ß = .18, p < .001), and resilience (ß = -.12, p = .022). The explanatory power of the final model was 46.1% (F = 47.76, p < .001).Conclusion: This study provides valuable insights into the care burden faced by family caregivers. Based on these results, programs for family caregivers should be developed with consideration of BPSD in older adults with dementia. Additionally, interventions that relieve depression and strengthen the resilience of family caregivers should be prioritized. Furthermore, it is essential to extend support systems to accommodate caregivers’ time constraints.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as γ‐aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, by using a combination of crystallography and computational methods we developed 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC50 = 0.21 μM) and GABA transporter 1 (IC50 = 10.96 μM) and 3 (IC50 = 7.76 μM), along with a favorable drug‐likeness profile. Subsequent in vivo studies revealed effectiveness of 6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi‐target‐directed ligand 6 offers a new approach to treating cognitive deficits and BPSD in AD.
Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We found deficits in reward-based operant learning in AD mice, suggesting possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing in DA neurons caused by reduced activity of small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents of single patch-clamped DA neurons (Patch-seq) identified up-regulation of the SK channel modulator casein kinase 2 (CK2), which we corroborated by immunohistochemical protein analysis. Pharmacological inhibition of CK2 restored SK channel activity and normal firing patterns in 3xTg-AD mice. These findings identify a mechanism of ion channel dysregulation in VTA DA neurons that could contribute to behavioral abnormalities in AD, paving the way for novel treatment strategies.
Alzheimer's disease (AD) is rapidly becoming one of the most expensive, burdening, and deadly diseases of this century. Up to now, there is still a lack of pharmacotherapy with substantial efficacy, and physical exercise is a promising and low‐cost way to aid in delaying the process of AD. The aim of this review is to summarise the efficacy of different physical exercise approaches and doses in the management of AD, including aerobic exercise, resistance exercise and multicomponent exercise. A literature search using MeSH terms for each topic is undertaken using PubMed and the Web of Science Core Collection database, supplemented by hand searching for additional references. Retrieved articles were reviewed, synthesised, and summarised. This review shows that aerobic exercise has been almost unanimously recognised for the improvement of cognition, neuropsychiatric symptoms and activities of daily living. Resistance exercise also shows a good prospect in the above aspects and has a unique advantage in enhancing muscle strength, while multicomponent physical activity does not seen to significantly improve cognitive function. Each type of exercise has a dose effect, but for individuals with AD, the most appropriate exercise dose is still controversial.
The benzoxazole is one of the most widely exploited heterocycles in drug discovery. Natural occurring and synthetic benzoxazoles show a broad range of biological activities. Many benzoxazoles are available for treating several diseases, and, to date, a few are in clinical trials. Moreover, an ever-increasing number of benzoxazole derivatives are under investigation in the early drug discovery phase and as potential hit or lead compounds. This perspective is an attempt to thoroughly review the rational design, the structure–activity relationship, and the biological activity of the most notable benzoxazoles developed during the past 5 years (period 2019–to date) in cancers, neurological disorders, and inflammation. We also briefly overviewed each target and its role in the disease. The huge amount of work examined suggests the great potential of the scaffold and the high interest of the scientific community in novel biologically active compounds containing the benzoxazole core.
Introduction
Group‐based cognitive stimulation has shown short‐term benefits for the cognitive outcomes of people with dementia living in nursing homes (NH). However, group participation can be a barrier for people with advanced dementia, bedridden people or isolated people. The CogStim24 project seeks to develop and implement a new psychosocial intervention based on cognitively stimulating (CS) activities integrated into daily nursing care. As part of the intervention development process, this study aimed to survey NH managers' attitudes and describe currently used approaches to CS activities in German NH.
Methods
We performed a multicentre cross‐sectional study between September and December 2021 in randomly recruited NH in the German federal state of North Rhine‐Westphalia. NH representatives were asked to fill in a self‐developed online questionnaire. We analysed data descriptively, presenting means and standard deviations. For case scenario questions, we used a summative content analysis.
Results
We contacted 354 NH and 106 agreed to participate. Representatives of 64 facilities completed the survey. Almost all stated to have implemented CS activities. Cognitive exercises (98%), physical and relaxation exercises (98%) and reminiscence therapy (95%) were most often used. The majority (96%) thought that CS activities could support people with dementia in maintaining their cognitive functions and that nurses should have a key role in the implementation of CS activities. More than half believed that regular CS activities were easy to implement alongside routine nursing care.
Conclusions
Results indicate that CS activities are frequently applied in German NH. The positive attitude of NH managers regarding the implementation and effects of CS activities is an important implementation resource.
Implications for Practice
Nursing staff should be more involved in providing CS activities for people with dementia. Training, information, and implementation material must be made available for nursing staff who wish to have an active role in providing CS activities.
Background:
Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated.
Objective:
To explore the [18F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI.
Methods:
We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC).
Results:
DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC.
Conclusions:
Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations.
Dementia, an umbrella term for widespread cognitive decline that causes disability, affects 55 million people worldwide and is expected to reach 131 million by 2050. The most common types of dementia include Alzheimer’s disease (AD) and Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) as well as dementia due to Parkinson’s disease, vascular dementia (VaD), and frontotemporal dementia (FTD).
In this chapter, we present the neuropsychiatric symptoms of dementia like depression, disinhibition, and apathy, focusing particularly on Alzheimer’s disease (AD). The neurocognitive aspects of dementia will be thoroughly and comprehensively discussed in the subsequent chapters. Our emphasis lies on providing a comprehensive understanding of these symptoms, highlighting their impact on individuals at different stages of dementia. Our aim is to discuss the approach for early and accurate diagnosis of dementia, revolving particularly around Alzheimer’s disease (AD). We delve into the nuanced aspects of diagnostic procedures, providing a comprehensive understanding essential for timely identification.
Objectives
People with dementia have several unmet needs during the syndrome progression. More unmet needs are related to hospitalizations, injuries, and death. Little is known about the care needs for people living with dementia in Brazil. This study aims to translate and adapt the Johns Hopkins Dementia Care Needs Assessment (JHDCNA 2.0), a tool design to identify the dementia-related needs of people with dementia and their caregivers, to Brazilian Portuguese, and to verify psychometric properties.
Method
JHDCNA 2.0 underwent a translation, back-translation, and cultural adaptation. Preliminary psychometric testing of the Brazilian version (JHDCNA-Br 2.0) included pilot testing and experts’ assessment, analyses of reliability, evidence based on test content and relations to other variables. We conducted 140 in-home interviews to assess several sociodemographic and health aspects and to be able to complete the JHDCNA-Br 2.0.
Results
The JHDCNA-Br 2.0 is reliable and has evidence based on test content and on relations to other variables for people living with dementia and caregivers. Preliminary results suggest high prevalence of unmet needs.
Conclusion
JHDCNA-Br 2.0 is a reliable and valid tool. The availability of this tool brings new opportunities to the study of dementia care, taking into consideration cultural aspects and may help inform future approaches to dementia care delivery to support persons and families affected by these conditions.
Introdução: A depressão em idosos com Alzheimer avançado é um tema de crescente relevância devido à complexidade e ao impacto significativo dessa condição sobre a qualidade de vida dos pacientes. O Alzheimer avançado é caracterizado por uma deterioração cognitiva severa, onde o indivíduo perde progressivamente a capacidade de realizar atividades diárias e de se reconhecer no ambiente. Quando associada à depressão, essa condição pode exacerbar os sintomas do Alzheimer, como confusão, agitação e isolamento social, tornando a gestão e o tratamento mais desafiadores. Objetivo: Analisar as evidências disponíveis sobre a prevalência, os sintomas e as abordagens terapêuticas para a depressão em idosos com Alzheimer avançado, com foco nas implicações para a prática clínica e na melhoria da qualidade de vida dos pacientes. Metodologia: A metodologia foi baseada no checklist PRISMA, que orientou a seleção e a análise dos estudos incluídos. Foram pesquisadas as bases de dados PubMed, Scielo e Web of Science, utilizando os seguintes descritores: “depressão em idosos”, “Alzheimer avançado”, “transtornos afetivos”, “demência avançada” e “intervenções terapêuticas”. Os critérios de inclusão foram: artigos publicados nos últimos 10 anos, estudos focados em idosos com Alzheimer avançado e que apresentassem dados sobre a prevalência e tratamento da depressão. Foram excluídos artigos que não tratavam especificamente da interação entre depressão e Alzheimer avançado, estudos fora do escopo temporal definido e trabalhos com amostras não representativas da população alvo. Resultados: Os estudos revisados indicaram que a depressão é prevalente em idosos com Alzheimer avançado e tende a agravar os sintomas da demência, resultando em uma deterioração mais rápida da função cognitiva e da capacidade funcional. As intervenções incluíram tratamentos farmacológicos, como antidepressivos, e abordagens psicossociais, que mostraram alguma eficácia na redução dos sintomas depressivos e na melhora da qualidade de vida. Conclusão: A depressão em idosos com Alzheimer avançado é uma condição crítica que requer uma abordagem integrada para otimizar o tratamento e melhorar a qualidade de vida. A combinação de tratamentos farmacológicos e psicossociais mostrou ser promissora, embora a eficácia varie de acordo com o perfil individual do paciente.
Older adults with Alzheimer’s disease and related dementias (ADRD) had a high risk of COVID-19-related mortality. Racial and ethnic minorities were disproportionally impacted by the pandemic. The variations in disparities, including racial and ethnic disparities and disparities across communities, in COVID-19-related mortality across the different stages of the COVID-19 pandemic among the ADRD population are unknown. This observational study estimated linear probability models for community-dwelling older adults with ADRD who were diagnosed with COVID-19 in 2020 and 2021 using multiple national data (e.g., Medicare data), accounting for individual and community characteristics. Disparities in 30-day mortality were compared between 2020 and 2021. The socioeconomic disparity in COVID-19-related mortality across communities became insignificant during the later stage of the pandemic, ethnic differences in COVID-19-related mortality decreased but persisted, and racial disparity remained largely unchanged. The study provides insights into interventions to mitigate lingering disparities in health outcomes among the vulnerable population.
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.