[Show abstract][Hide abstract] ABSTRACT: This chapter questions the prevailing "implicit" assumption that molecular mechanisms and the biological phenotype of dominantly inherited early-onset alzheimer's disease (EOAD) could serve as a linear model to study the pathogenesis of sporadic late-onset alzheimer's disease (LOAD). Now there is growing evidence to suggest that such reductionism may not be warranted; these suppositions are not adequate to explain the molecular complexities of LOAD. For example, the failure of some recent amyloid-centric clinical trials, which were largely based on the extrapolations from EOAD biological phenotypes to the molecular mechanisms in the pathogenesis of LOAD, might be due to such false assumptions. The distinct difference in the biology of LOAD and EOAD is underscored by the presence of EOAD cases without evidence of familial clustering or Mendelian transmission and, conversely, the discovery and frequent reports of such clustering and transmission patterns in LOAD cases. The primary thesis of this chapter is that a radically different way of thinking is required for comprehensive explanations regarding the distinct complexities in the molecular pathogenesis of inherited and sporadic forms of Alzheimer's disease (AD). We propose using longitudinal analytical methods and the paradigm of systems biology (using transcriptomics, proteomics, metabolomics, and lipidomics) to provide us a more comprehensive insight into the lifelong origin and progression of different molecular mechanisms and neurodegeneration. Such studies should aim to clarify the role of specific pathophysiological and signaling pathways such as neuroinflammation, altered lipid metabolism, apoptosis, oxidative stress, tau hyperphosphorylation, protein misfolding, tangle formation, and amyloidogenic cascade leading to overproduction and reduced clearance of aggregating amyloid-beta (Aβ) species. A more complete understanding of the distinct difference in molecular mechanisms, signaling pathways, as well as comparability of the various forms of AD is of paramount importance. The development of knowledge and technologies for early detection and characterization of the disease across all stages will improve the predictions regarding the course of the disease, prognosis, and response to treatment. No doubt such advances will have a significant impact on the clinical management of both EOAD and LOAD patients. The approach propped here, combining longitudinal studies with the systems biology paradigm, will create a more effective and comprehensive framework for development of prevention therapies in AD.
[Show abstract][Hide abstract] ABSTRACT: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia.
The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review.
In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer’s disease and healthy controls.
IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.
Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0099-0 · 3.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Although non-drug interventions are widely used in patients with Alzheimer's disease, few large scale randomized trials involving a long-term intervention and several cognitive-oriented approaches have been carried out. ETNA3 trial compares the effect of cognitive training, reminiscence therapy, and an individualized cognitive rehabilitation program in Alzheimer's disease to usual care.
This is a multicenter (40 French clinical sites) randomized, parallel-group trial, with a two-year follow-up comparing groups receiving standardized programs of cognitive training (group sessions), reminiscence therapy (group sessions), individualized cognitive rehabilitation program (individual sessions), and usual care (reference group). Six hundred fifty-three outpatients with Alzheimer's disease were recruited. The primary efficacy outcome was the rate of survival without moderately severe to severe dementia at two years. Secondary outcomes were cognitive impairment, functional disability, behavioral disturbance, apathy, quality of life, depression, caregiver's burden, and resource utilization.
No impact on the primary efficacy measure was evidenced. For the two group interventions (i.e. cognitive training and reminiscence), none of the secondary outcomes differed from usual care. The larger effect was seen with individualized cognitive rehabilitation in which significantly lower functional disability and a six-month delay in institutionalization at two years were evidenced.
These findings challenge current management practices of Alzheimer's patients. While cognitive-oriented group therapies have gained popularity, this trial does not show improvement for the patients. The individualized cognitive rehabilitation intervention provided clinically significant results. Individual interventions should be considered to delay institutionalization in Alzheimer's disease.
International Psychogeriatrics 11/2015; DOI:10.1017/S1041610215001830 · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The relationship of executive function (EF) and theory of mind (ToM) deficits in neurodegeneration is still debated. There is contradicting evidence as to whether these cognitive processes are overlapping or distinct, which has clear clinical relevance for the evaluation of their associated clinical symptoms.
To investigate the relationship of EF and ToM deficits via a data-driven approach in a large sample of patients with behavioural variant frontotemporal dementia (bvFTD).
Data of 46 patients with bvFTD were employed in a hierarchical cluster analysis to determine the similarity of variance between different EF measures (verbal abstraction, verbal initiation, motor programming, sensitivity to interference, inhibitory control, visual abstraction, flexibility, working memory/attention) and ToM (faux pas).
Overall results showed that EF measures were clustered separately from the ToM measure. A post hoc analysis revealed a more complex picture where selected ToM subcomponents (empathy; intention) showed a relationship to specific EF measures (verbal abstraction; working memory/attention), whereas the remaining EF and ToM subcomponents were separate.
Taken together, these findings suggest that EF and ToM are distinct components; however, ToM empathy and intention subcomponents might share some functions with specific EF processes. This has important implications for guiding diagnostic assessment of these deficits in clinical conditions.
Journal of neurology, neurosurgery, and psychiatry 10/2015; DOI:10.1136/jnnp-2015-311643 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far.
[Show abstract][Hide abstract] ABSTRACT: Importance:
Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms.
To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia.
Design, setting, and participants:
A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity.
Oral avagacestat or placebo daily.
Main outcomes and measure:
Safety and tolerability of avagacestat.
Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures.
Conclusions and relevance:
Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD.
clinicaltrials.gov Identifier: NCT00890890.
[Show abstract][Hide abstract] ABSTRACT: In therapeutic trials, it is crucial to identify Alzheimer's disease (AD) at its prodromal stage. We assessed the accuracy of the free and cued selective reminding test (FCSRT) compared to other cognitive tests to predict AD dementia in subjects with subjective cognitive decline or mild cognitive impairment. Subjects from the placebo group of the GuidAge trial over 70 years old and without clinical signs of dementia at baseline who completed the 5-year follow-up free of dementia (n = 840) or developed AD dementia (n = 73) were included in our study. Among all the tests, the sum of the 3 free recall of the FCSRT (FCSRT-FR) and the sum of free and cued recall (FCSRT-TR) yielded the best results to predict AD dementia occurrence (all p values <0.05 for comparison of FCSRT-FR ROC and MMSE, CDRsb, and CVF ROCs). FCSRT-FR had an area under the ROC curve of 0.799 (95% CI 0.738-0.85) and the optimal cut-off was 20 (se 68.06% , sp 81.43% , PPV 23.90% , NPV 96,75% ). Concerning FCSRT-TR, the AUC was 0.776 and the optimal cut-off was 42 (se 62.5% , sp 82.26% , PPV 23.20% and NPV 96.24% ). This study sets the framework for implementing the FCSRT in clinical and therapeutic trials for efficient subject selection.
[Show abstract][Hide abstract] ABSTRACT: The preclinical stage of frontotemporal lobar degeneration (FTLD) is not well characterized. We conducted a brain metabolism (FDG-PET) and structural (cortical thickness) study to detect early changes in asymptomatic GRN mutation carriers (aGRN+) that were evaluated longitudinally over a 20-month period. At baseline, a left lateral temporal lobe hypometabolism was present in aGRN+ without any structural changes. Importantly, this is the first longitudinal study and, across time, the metabolism more rapidly decreased in aGRN+ in lateral temporal and frontal regions. The main structural change observed in the longitudinal study was a reduction of cortical thickness in the left lateral temporal lobe in carriers. A limit of this study is the relatively small sample (n = 16); nevertheless, it provides important results. First, it evidences that the pathological processes develop a long time before clinical onset, and that early neuroimaging changes might be detected approximately 20 years before the clinical onset of disease. Second, it suggests that metabolic changes are detectable before structural modifications and cognitive deficits. Third, both the baseline and longitudinal studies provide converging results implicating lateral temporal lobe as early involved in GRN disease. Finally, our study demonstrates that structural and metabolic changes could represent possible biomarkers to monitor the progression of disease in the presymptomatic stage toward clinical onset.
[Show abstract][Hide abstract] ABSTRACT: Most forms of Alzheimer's disease (AD) are sporadic (sAD) or inherited in a non-Mendelian fashion, and less than 1% of cases are autosomal-dominant. Forms of sAD do not exhibit familial aggregation and are characterized by complex genetic and environmental interactions. Recently, the expansion of genomic methodologies, in association with substantially larger combined cohorts, has resulted in various genome-wide association studies that have identified several novel genetic associations of AD. Currently, the most effective methods for establishing the diagnosis of AD are defined by multi-modal pathways, starting with clinical and neuropsychological assessment, cerebrospinal fluid (CSF) analysis, and brain-imaging procedures, all of which have significant cost- and access-to-care barriers. Consequently, research efforts have focused on the development and validation of non-invasive and generalizable blood-based biomarkers. Among the modalities conceptualized by the systems biology paradigm and utilized in the "exploratory biomarker discovery arena", proteome analysis has received the most attention. However, metabolomics, lipidomics, transcriptomics, and epigenomics have recently become key modalities in the search for AD biomarkers. Interestingly, biomarker changes for familial AD (fAD), in many but not all cases, seem similar to those for sAD. The integration of neurogenetics with systems biology/physiology-based strategies and high-throughput technologies for molecular profiling is expected to help identify the causes, mechanisms, and biomarkers associated with the various forms of AD. Moreover, in order to hypothesize the dynamic trajectories of biomarkers through disease stages and elucidate the mechanisms of biomarker alterations, updated and more sophisticated theoretical models have been proposed for both sAD and fAD.
[Show abstract][Hide abstract] ABSTRACT: Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures- approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcomes.
[Show abstract][Hide abstract] ABSTRACT: There is evolving evidence that individuals categorized with subjective cognitive decline (SCD) are potentially at higher risk for developing objective and progressive cognitive impairment compared to cognitively healthy individuals without apparent subjective complaints. Interestingly, SCD, during advancing preclinical Alzheimer's disease (AD), may denote very early, subtle cognitive decline that cannot be identified using established standardized tests of cognitive performance. The substantial heterogeneity of existing SCD-related research data has led the Subjective Cognitive Decline Initiative (SCD-I) to accomplish an international consensus on the definition of a conceptual research framework on SCD in preclinical AD. In the area of biological markers, the cerebrospinal fluid signature of AD has been reported to be more prevalent in subjects with SCD compared to healthy controls; moreover, there is a pronounced atrophy, as demonstrated by magnetic resonance imaging, and an increased hypometabolism, as revealed by positron emission tomography, in characteristic brain regions affected by AD. In addition, SCD individuals carrying an apolipoprotein ɛ4 allele are more likely to display AD-phenotypic alterations. The urgent requirement to detect and diagnose AD as early as possible has led to the critical examination of the diagnostic power of biological markers, neurophysiology, and neuroimaging methods for AD-related risk and clinical progression in individuals defined with SCD. Observational studies on the predictive value of SCD for developing AD may potentially be of practical value, and an evidence-based, validated, qualified, and fully operationalized concept may inform clinical diagnostic practice and guide earlier designs in future therapy trials.
[Show abstract][Hide abstract] ABSTRACT: Time-to-event analysis is frequently used in medical research to investigate potential disease-modifying treatments in neurodegenerative diseases. Potential treatment effects are generally evaluated using the logrank test, which has optimal power and sensitivity when the treatment effect (hazard ratio) is constant over time. However, there is generally no prior information as to how the hazard ratio for the event of interest actually evolves. In these cases, the logrank test is not necessarily the most appropriate to use. When the hazard ratio is expected to decrease or increase over time, alternative statistical tests such as the Fleming-Harrington test, provide a better sensitivity. An example of this comes from a large, five-year randomised, placebo-controlled prevention trial (GuidAge) in 2854 community-based subjects making spontaneous memory complaints to their family physicians, which evaluated whether treatment with EGb761® can modify the risk of developing AD. The primary outcome measure was the time to conversion from memory complaint to Alzheimer’s type dementia. Although there was no significant difference in the hazard function of conversion between the two treatment groups according to the preplanned logrank test, a significant treatment-by-time interaction for the incidence of AD was observed in a protocol-specified subgroup analysis, suggesting that the hazard ratio is not constant over time. For this reason, additional post hoc analyses were performed using the Fleming-Harrington test to evaluate whether there was a signal of a late effect of EGb761®. Applying the Fleming-Harrington test, the hazard function for conversion to dementia in the placebo group was significantly different from that in the EGb761® treatment group (p = 0.0054), suggesting a late effect of EGb761®. Since this was a post hoc analysis, no definitive conclusions can be drawn as to the effectiveness of the treatment. This post hoc analysis illustrates the interest of performing another randomised clinical trial of EGb761® explicitly testing the hypothesis of a late treatment effect, as well as of using of better adapted statistical approaches for long term preventive trials when it is expected that prevention cannot have an immediate effect but rather a delayed effect that increases over time..
The Journal of Nutrition Health and Aging 09/2015; DOI:10.1007/s12603-015-0582-0 · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of common diseases such as Alzheimer’s disease (AD) and cancer are
currently poorly understood. Inflammation is a common risk factor for cancer and AD. Recent
data, provided by our group and from others, demonstrate that increased pressure and
inflammation are synonymous. There is a continuous increase in pressure from inflammation to
fibrosis and then cancer. This in line with the numerous papers reporting high interstitial pressure
in cancer. But most authors focus on the role of pressure in the lack of delivery of chemotherapy
in the center of the tumor. Pressure may also be a key factor in carcinogenesis. Increased
pressure is responsible for oncogene activation and cytokine secretion. Accumulation of
mechanical stress plays a key role in the development of diseases of old age such as
cardiomyopathy, atherosclerosis and osteoarthritis. Growing evidence suggest also a possible
link between mechanical stress in the pathogenesis of AD. The aim of this review is to describe
environmental and endogenous mechanical factors possibly playing a pivotal role in the
mechanism of chronic inflammation, AD and cancer.
Frontiers in Oncology 08/2015; 5. DOI:10.3389/fonc.2015.00197
[Show abstract][Hide abstract] ABSTRACT: Identification of blood-based biomarkers of Alzheimer's disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C(11)]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker.