Acetylcholinesterase inhibitors are approved drugs currently used for the treatment of Alzheimer's disease (AD) dementia. Basal forebrain cholinergic system (BFCS) atrophy is reported to precede both ...entorhinal cortex atrophy and memory impairment in AD, challenging the traditional model of the temporal sequence of topographical pathology associated with AD. We studied the effect of one-year Donepezil treatment on the rate of BFCS atrophy in prodromal AD patients using a double-blind, randomized, placebo-controlled trial of Donepezil (10 mg/day). Reduced annual BFCS rates of atrophy were found in the Donepezil group compared to the Placebo treated arm. Secondary analyses on BFCS subregions demonstrated the largest treatment effects in the Nucleus Basalis of Meynert (NbM) and the medial septum/diagonal band (Ch1/2). Donepezil administered at a prodromal stage of AD seems to substantially reduce the rate of atrophy of the BFCS nuclei with highest concentration of cholinergic neurons projecting to the cortex (NbM), hippocampus and entorhinal cortex (Ch1/2).
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Measuring the morphology of brain sulci has been recently proposed as a novel imaging approach in Alzheimer's disease (AD). We aimed to investigate the relevance of such an approach in AD, by ...exploring its (1) clinical relevance in comparison with traditional imaging methods, (2) relationship with amyloid deposition, (3) association with cognitive functions. Here, 51 patients (n = 32 mild cognitive impairment/mild dementia-AD, n = 19 moderate/severe dementia-AD) diagnosed according to clinical-biological criteria (CSF biomarkers and amyloid-PET) and 29 controls (with negative amyloid-PET) underwent neuropsychological and 3T-MRI examinations. Mean sulcal width (SW) and mean cortical thickness around the sulcus (CT-S) were automatically measured. We found higher SW and lower CT-S in patients with AD than in controls. These differences were more pronounced at later stages of the disease and provided the best diagnostic accuracies among the imaging markers. Correlations were not found between CT-S or SW and amyloid deposition but between specific cognitive functions and regional CT-S/SW in key associated regions. Sulcal morphology is a good supporting diagnosis tool that reflects the main cognitive impairments in AD. It could be considered as a good surrogate marker to evaluate the efficacy of new drugs.
•Examination of sulcal morphology alterations is a good diagnosis tool for Alzheimer's disease.•This imaging marker is more accurate than traditional imaging tools such as hippocampal volume.•Sulcal morphology alterations are correlated to specific cognitive impairment observed.•Sulcal morphology alterations are related to disease severity.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Behavioural variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease that is clinically characterised by progressive behavioural changes and social interpersonal dysfunctions. Its ...diagnosis remains a clinical challenge, and depression is one of the main causes of misdiagnoses due to the prevalence of apathy in bvFTD.
To evaluate the sensitivity and specificity of the Social Cognition and Emotional Assessment (SEA) and the mini-SEA for differentiating bvFTD from major depressive disorder (MDD).
Scores for the SEA and mini-SEA for 37 patients with bvFTD (divided into subgroups of 17 with early bvFTD and 20 with moderate bvFTD according to the normal range of the Mattis Dementia Rating Scale), 19 MDD patients and 30 control subjects were compared to define the discrimination power of these tools compared with other standard neuropsychological tests.
SEA and mini-SEA scores were significantly lower for both the early and moderate bvFTD groups compared with control subjects and the MDD group, and very few scores overlapped between patients in the bvFTD subgroups and patients in the MDD and control subgroups. SEA and mini-SEA scores distinguished early bvFTD from MDD with sensitivity and specificity rates above 94%.
Unlike standard executive neuropsychological tests, SEA and the mini-SEA can differentiate MDD from bvFTD in the early stages of the disease. The mini-SEA is an easy tool that can be utilised in neurological or psychiatric departments.
Purpose
We present and evaluate a new automated method based on support vector machine (SVM) classification of whole-brain anatomical magnetic resonance imaging to discriminate between patients with ...Alzheimer’s disease (AD) and elderly control subjects.
Materials and methods
We studied 16 patients with AD mean age ± standard deviation (SD) = 74.1 ± 5.2 years, mini-mental score examination (MMSE) = 23.1 ± 2.9 and 22 elderly controls (72.3 ± 5.0 years, MMSE = 28.5 ± 1.3). Three-dimensional T1-weighted MR images of each subject were automatically parcellated into regions of interest (ROIs). Based upon the characteristics of gray matter extracted from each ROI, we used an SVM algorithm to classify the subjects and statistical procedures based on bootstrap resampling to ensure the robustness of the results.
Results
We obtained 94.5% mean correct classification for AD and control subjects (mean specificity, 96.6%; mean sensitivity, 91.5%).
Conclusions
Our method has the potential in distinguishing patients with AD from elderly controls and therefore may help in the early diagnosis of AD.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Vous connaissez sans doute les déceptions issues des essais thérapeutiques par immunothérapie anti-amyloïde menés par l’industrie dans la maladie d’Alzheimer, ouvrant un débat médical et scientifique ...loin d’être clos. Les recherches et essais se poursuivent. Des résultats annoncés par les industriels comme très encourageants ont été récemment annoncés. Nous essaierons d’apporter, au cours de cette présentation, des clés de lecture sur les controverses engagées quant à leurs interprétations.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Whether theory of mind (ToM) is preserved in Alzheimer's disease (AD) remains a controversial subject. Recent studies have showed that performance on some ToM tests might be altered in AD, though to ...a lesser extent than in behavioural-variant Frontotemporal Dementia (bvFTD). It is however, unclear if this reflects a genuine impairment of ToM or a deficit secondary to the general cognitive decline observed in AD. Aiming to investigate the cognitive determinants of ToM performance in AD, a data-mining study was conducted in 29 AD patients then replicated in an independent age-matched group of 19 AD patients to perform an independent replication of the results. 44 bvFTD patients were included as a comparison group. All patients had an extensive neuropsychological examination. Hierarchical clustering analyses showed that ToM performance clustered with measures of executive functioning (EF) in AD. ToM performance was also specifically correlated with the executive component extracted from a principal component analysis. In a final step, automated linear modelling conducted to determine the predictors of ToM performance showed that 48.8% of ToM performance was significantly predicted by executive measures. Similar findings across analyses were observed in the independent group of AD patients, thereby replicating our results. Conversely, ToM impairments in bvFTD appeared independent of other cognitive impairments. These results suggest that difficulties of AD patients on ToM tests do not reflect a genuine ToM deficit, rather mediated by general (and particularly executive) cognitive decline. They also suggest that EF has a key role in mental state attribution, which support interacting models of ToM functioning. Finally, our study highlights the relevancy of data-mining statistical approaches in clinical and cognitive neurosciences.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Early markers are needed for more effective prevention of Alzheimer's disease. We previously showed that individuals with Alzheimer's disease have decreased plasma DYRK1A levels compared to controls. ...We assessed DYRK1A in the plasma of cognitively healthy elderly volunteers, individuals with either Alzheimer's disease (AD), tauopathies or Down syndrome (DS), and in lymphoblastoids from individuals with DS. DYRK1A levels were inversely correlated with brain amyloid β burden in asymptomatic elderly individuals and AD patients. Low DYRK1A levels were also detected in patients with tauopathies. Individuals with DS had higher DYRK1A levels than controls, although levels were lower in individuals with DS and with dementia. These data suggest that plasma DYRK1A levels could be used for early detection of at risk individuals of AD and for early detection of AD. We hypothesize that lack of increase of DYRK1A at middle age (40-50 years) could be a warning before the cognitive decline, reflecting increased risk for AD.
Morphological alterations of the endosomal compartment have been widely described in post-mortem brains from Alzheimer's disease (AD) patients and subjects with Down syndrome (DS) who are at high ...risk for AD. Immunostaining with antibodies against endosomal markers such as Early Endosome Antigen 1 (EEA1) revealed increased size of EEA1-positive puncta. In DS, peripheral cells such as peripheral blood mononuclear cells (PBMCs) and fibroblasts, share similar phenotype even in the absence of AD. We previously found that PBMCs from AD patients have larger EEA1-positive puncta, correlating with brain amyloid load. Here we analysed the endosomal compartment of fibroblasts from a very well characterised cohort of AD patients (IMABio3) who underwent thorough clinical, imaging and biomarkers assessments. Twenty-one subjects were included (7 AD with mild cognitive impairment (AD-MCI), 7 AD with dementia (AD-D) and 7 controls) who had amyloid-PET at baseline (PiB) and neuropsychological tests at baseline and close to skin biopsy. Fibroblasts isolated from skin biopsies were immunostained with anti-EEA1 antibody and imaged using a spinning disk microscope. Endosomal compartment ultrastructure was also analysed by electron microscopy. All fibroblast lines were genotyped and their AD risk factors identified. Our results show a trend to an increased EEA1-positive puncta volume in fibroblasts from AD-D as compared to controls (p.adj = 0.12) and reveal enhanced endosome area in fibroblasts from AD-MCI and AD-AD versus controls. Larger puncta size correlated with PiB retention in different brain areas and with worse cognitive scores at the time of biopsy as well as faster decline from baseline to the time of biopsy. Finally, we identified three genetic risk factors for AD (ABCA1, COX7C and MYO15A) that were associated with larger EEA1 puncta volume. In conclusion, the endosomal compartment in fibroblasts could be used as cellular peripheral biomarker for both amyloid deposition and cognitive decline in AD patients.
Results of Phase III studies involving a large number of Alzheimer’s disease (AD) patients treated by passive immunotherapy with humanized anti-amyloid β monoclonal antibodies have recently been ...released. These approaches failed to show a significant clinical benefit in patients with mild to moderate AD. The most considered explanation is that the patients have been treated too late. Whereas targeting patients at asymptomatic stages of the disease is a critical step in the goal of improving the efficacy of such antibody-based strategies, several other important factors should be considered in the development and clinical evaluation of anti-amyloid β immunotherapies, including the as yet poorly understood relationship of AD with the immune system and the importance of cerebral amyloid angiopathy. Better understanding the role of immune responses in AD and their impact on immunotherapy appears essential in the design of alternative or combinatorial immunotherapy approaches in AD, which may imply effectors other than antibodies and even additional antigenic targets.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant ...age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.
Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.
We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.
The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
PDF
