Showing papers by "Serge Gauthier published in 2017"
TL;DR: The results indicate that the interpretation of 18F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain.
Abstract: 18F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of 18F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on 18F-THK5351 brain uptake using PET and autoradiography. Eight participants (five mild cognitive impairment, two Alzheimer’s disease, and one progressive supranuclear palsy) had baseline 18F-AZD4694 and 18F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second 18F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third 18F-THK5351 scan 9–28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after 18F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region. 18F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline. At baseline, 18F-THK5351 SUVs were highest in the basal ganglia (0.64 ± 0.11) and thalamus (0.62 ± 0.14). In the post-selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced 18F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9–28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on 18F-THK5351 uptake. These results indicate that the interpretation of 18F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain. In addition, the heterogeneous MAO-B availability across the cortex may limit the interpretation of 18F-THK5351 scans using reference region methods.
275 citations
TL;DR: The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria, and its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time.
Abstract: ZI is supported by the Hotchkiss Brain Institute via
the Alzheimer Society of Calgary. EES is supported
by the Katthy Taylor Chair in Vascular Dementia
and CIHR. DS is supported in part by the Department
ofVeterans Affairs.GSis supported by National
Institute of Health: AG038893 and AG041633. JC
acknowledges funding from the National Institute of
General Medical Sciences (Grant: P20GM109025)
and support from Keep Memory Alive. MEM is
supported by the Australian National Health and
Medical Research Council (NHMRC) and Australian
Research Council (ARC) Dementia Research Development
Fellowship #1102028. SG is supported by
CIHR and the Weston Brain Institute. KGL is supported
in part by NIH grant P50AG005146 for the
Johns Hopkins ADRC.
256 citations
TL;DR: P positron emission tomography evidence is provided that activation of astrocytic glutamate transport via the excitatory amino acid transporter GLT-1 triggers widespread but graded glucose uptake in the rodent brain.
Abstract: Contributions of glial cells to neuroenergetics have been the focus of extensive debate. Here we provide positron emission tomography evidence that activation of astrocytic glutamate transport via the excitatory amino acid transporter GLT-1 triggers widespread but graded glucose uptake in the rodent brain. Our results highlight the need for a reevaluation of the interpretation of [18F]FDG positron emission tomography data, whereby astrocytes would be recognized as contributing to the [18F]FDG signal.
210 citations
TL;DR: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses.
Abstract: The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-170560. The study was sponsored by TauRx Therapeutics (Singapore). We thank Lon Schneider and Howard Feldman for their contribution to the Scientific Advisory Board. We gratefully acknowledge study investigators and the generosity of study participants. Authors’ disclosures available online (http://j-alz.com/manuscript disclosures/17-0560r3).
134 citations
TL;DR: It is concluded that PET imaging with FEOBV is more sensitive than either FDG or NAV to distinguish AD patients from control subjects, and may be useful to quantify disease severity.
Abstract: 18F-fluoroethoxybenzovesamicol (FEOBV) is a new PET radiotracer that binds to the vesicular acetylcholine transporter. In both animals and healthy humans, FEOBV was found sensitive and reliable to characterize presynaptic cholinergic nerve terminals in the brain. It has been used here for we believe the first time in patients with Alzheimer's disease (AD) to quantify brain cholinergic losses. The sample included 12 participants evenly divided in healthy subjects and patients with AD, all assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) cognitive scales. Every participant underwent three consecutive PET imaging sessions with (1) the FEOBV as a tracer of the cholinergic terminals, (2) the 18F-NAV4694 (NAV) as an amyloid-beta tracer, and (3) the 18F-Fluorodeoxyglucose (FDG) as a brain metabolism agent. Standardized uptake value ratios (SUVRs) were computed for each tracer, and compared between the two groups using voxel wise t-tests. Correlations were also computed between each tracer and the cognitive scales, as well as between FEOBV and the two other radiotracers. Results showed major reductions of FEOBV uptake in multiple cortical areas that were evident in each AD subject, and in the AD group as a whole when compared to the control group. FDG and NAV were also able to distinguish the two groups, but with lower sensitivity than FEOBV. FEOBV uptake values were positively correlated with FDG in numerous cortical areas, and negatively correlated with NAV in some restricted areas. The MMSE and MoCA cognitive scales were found to correlate significantly with FEOBV and with FDG, but not with NAV. We concluded that PET imaging with FEOBV is more sensitive than either FDG or NAV to distinguish AD patients from control subjects, and may be useful to quantify disease severity. FEOBV can be used to assess cholinergic degeneration in human, and may represent an excellent biomarker for AD.
101 citations
TL;DR: In this article, a voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapapir and standardized uptake value ratios (SUVR), rather than the sum of their independent effects, was associated with a 24-month metabolic decline.
Abstract: This study was designed to test the interaction between amyloid-β and tau proteins as a determinant of metabolic decline in preclinical Alzheimer's disease (AD). We assessed 120 cognitively normal individuals with [18F]florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [18F]fluorodeoxyglucose ([18F]FDG) PET at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapir and [18F]FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [18F]florbetapir SUVR and CSF phosphorylated tau (p-tau) measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (P<0.001). In contrast, interactions using CSF amyloid-β1-42 and total tau biomarkers did not associate with metabolic decline over a time frame of 24 months. The interaction found in this study further support the framework that amyloid-β and hyperphosphorylated tau aggregates synergistically interact to cause downstream AD neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-β plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-β PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [18F]FDG as a biomarker of efficacy.
92 citations
TL;DR: A machine learning-based probabilistic method designed to assess the progression to dementia within 24 months, based on the regional information from a single amyloid positron emission tomography scan, which obtained an accuracy of 84% and an under-receiver operating characteristic curve of 0.91, outperforming the existing algorithms using the same biomarker measures and previous studies using multiple biomarkers.
85 citations
TL;DR: Accumulating evidence points to the superiority of the MoCA over the MMSE as a cognitive screening tool, but it is unknown whether a conversion table generated from AD patients would apply to patients with other dementia subtypes like vascular dementia or frontotemporal dementia.
Abstract: Background
Accumulating evidence points to the superiority of the MoCA over the MMSE as a cognitive screening tool. To facilitate the transition from the MMSE to the MoCA in clinical and research settings, authors have developed MMSE-MoCA conversion tables. However, it is unknown whether a conversion table generated from Alzheimer's disease (AD) patients would apply to patients with other dementia subtypes like vascular dementia or frontotemporal dementia. Furthermore, the reliability and accuracy of MMSE-MoCA conversion tables has not been properly evaluated.
Method
We retrospectively examined the MMSE-MoCA relationship in a large multicenter sample gathered from 3 Memory Clinics in Quebec, Canada (1492 patients). We produced an MMSE-MoCA conversion table using the equi-percentile method with log-linear smoothing. We then cross-validated our conversion table with the ADNI dataset (1202 patients) and evaluated its accuracy for future predictions.
Results
The MMSE-MoCA conversion table is consistent with previously published tables and has an intra-class correlation of 0.633 with the ADNI sample. However, we found that the MMSE-MoCA relationship is significantly modified by diagnosis (P < .01), with dementia subtypes associated with a dysexecutive syndrome showing a trend towards higher MMSE than other dementia syndromes for a given MoCA score. The large width of 95% confidence interval (CI) for a new prediction suggests questionable reliability for clinical use.
Conclusion
In this study, we validated a conversion table between MMSE and MoCA using a large multicenter sample. Our results suggest caution in interpreting the tables in heterogeneous clinical populations, as the MMSE-MoCA relationship may be different across dementia subtypes.
83 citations
TL;DR: It is proposed that amyloid β and phosphorylated tau (p‐tau) synergism accelerates biomarker abnormalities in controls, and whether this synergism is the driving force behind Alzheimer disease (AD) dementia is answered.
Abstract: Introduction Recent literature proposes that amyloid β (Aβ) and phosphorylated tau (p-tau) synergism accelerates biomarker abnormalities in controls. Yet, it remains to be answered whether this synergism is the driving force behind Alzheimer disease (AD) dementia. Methods We stratified 314 mild cognitive impairment individuals using [ 18 F]florbetapir positron emission tomography Aβ imaging and cerebrospinal fluid p-tau. Regression and voxel-based logistic regression models with interaction terms evaluated 2-year changes in cognition and clinical status as a function of baseline biomarkers. Results We found that the synergism between [ 18 F]florbetapir and p-tau, rather than their additive effects, was associated with the cognitive decline and progression to AD. Furthermore, voxel-based analysis revealed that temporal and inferior parietal were the regions where the synergism determined an increased likelihood of developing AD. Discussion Together, the present results support that progression to AD dementia is driven by the synergistic rather than a mere additive effect between Aβ and p-tau proteins.
80 citations
TL;DR: The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism.
Abstract: Objective: To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). Methods: We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET. Results: Individuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction. Conclusions: The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.
65 citations
TL;DR: Twenty two- to twenty four-week treatment with Ginkgo biloba extract EGb 761® improved BPSD (except psychotic-like features) and caregiver distress caused by such symptoms.
Abstract: BACKGROUND In randomized controlled trials, Ginkgo biloba extract EGb 761® has been found to be effective in the treatment of behavioral and psychological symptoms of dementia (BPSD). METHODS To assess the effects of EGb 761® on specific BPSD, we analyzed data from all randomized, placebo-controlled, at least 20-week, trials of EGb 761® enrolling patients with dementia (probable Alzheimer's disease (AD), probable vascular dementia or probable AD with cerebrovascular disease) who had clinically significant BPSD (Neuropsychiatric Inventory (NPI) total score at least 6). Data were pooled and joint analyses of NPI single item composite and caregiver distress scores were performed by meta-analysis with a fixed effects model. RESULTS Four trials involving 1628 patients (EGb 761®, 814; placebo, 814) were identified; treatment duration was 22 or 24 weeks; the daily dose of EGb 761® was 240 mg in all trials. Pooled analyses including data from the full analysis sets of all trials (EGb 761®, 796 patients; placebo, 802 patients) revealed significant superiority of EGb 761® over placebo in total scores and 10 single symptom scores. Regarding caregiver distress scores, EGb 761®-treated patients improved significantly more than those receiving placebo in all symptoms except delusions, hallucinations, and elation/euphoria. The benefit of EGb 761® mainly consists of improvement in symptoms present at baseline, but the incidence of some symptoms was also decreased. CONCLUSIONS Twenty two- to twenty four-week treatment with Ginkgo biloba extract EGb 761® improved BPSD (except psychotic-like features) and caregiver distress caused by such symptoms.
TL;DR: The present results demonstrate the promise of calibrated fMRI measurements as potential biomarkers in AD and use more widely available imaging infrastructure, avoids exposure to ionizing radiation, and integrates with other MRI-based measures of brain structure and function.
TL;DR: It is demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses.
Abstract: Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9-11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16-19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages.SIGNIFICANCE STATEMENT The present study proposes a "back translation" of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses.
TL;DR: Functional differences in episodic memory-related regions are present by early midlife in adults with + FH and + APOE-4 risk factors for late onset AD, compared to middle-aged controls.
TL;DR: Dementia as a whole does not appear to be a risk factor for suicide completion, but some subgroups of patients with dementia apparently have an increased risk for suicidal behavior, such as patients with psychiatric comorbidities and of younger age.
Abstract: Background: Evidence-based data on prevalence and risk factors of suicidal intentions and behavior in dementia are as scarce as the data on assisted dying. The present literature review aimed on summarizing the current knowledge and provides a critical discussion of the results. Methods: A systematic narrative literature review was performed using Medline, Cochrane Library, EMBASE, PSYNDEX, PSYCINFO, Sowiport, and Social Sciences Citation Index literature. Results: Dementia as a whole does not appear to be a risk factor for suicide completion. Nonetheless some subgroups of patients with dementia apparently have an increased risk for suicidal behavior, such as patients with psychiatric comorbidities (particularly depression) and of younger age. Furthermore, a recent diagnosis of dementia, semantic dementia, and previous suicide attempts most probably elevate the risk for suicidal intentions and behavior. The impact of other potential risk factors, such as patient's cognitive impairment profile, behavioral disturbances, social isolation, or a biomarker based presymptomatic diagnosis has not yet been investigated. Assisted dying in dementia is rare but numbers seem to increase in regions where it is legally permitted. Conclusion: Most studies that had investigated the prevalence and risk factors for suicide in dementia had significant methodological limitations. Large prospective studies need to be conducted in order to evaluate risk factors for suicide and assisted suicide in patients with dementia and persons with very early or presymptomatic diagnoses of dementia. In clinical practice, known risk factors for suicide should be assessed in a standardized way so that appropriate action can be taken when necessary.
DOI•
01 Jan 2017TL;DR: The CTAD Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures.
Abstract: At a meeting of the EU/US/Clinical Trials in Alzheimer’s Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.
TL;DR: This study highlights the need to understand more fully the mechanism behind rapid cognitive decline in patients with early signs of Alzheimer's disease.
Abstract: Introduction Rapid cognitive decline (RCD) occurs in dementia due to Alzheimer's disease (AD). Methods Literature review, consensus meetings, and a retrospective chart review of patients with probable AD were conducted. Results Literature review showed that RCD definitions varied. Mini-Mental State Examination scores P Discussion RCD is sufficiently common to interfere with randomized clinical trials. We propose a 6-month prerandomization determination of the decline rate or use of an RCD risk score to ensure balanced allocation among treatment groups.
TL;DR: The prevalence and detailed biomarkers’ characteristic of rapidly progressive Alzheimer's disease (rpAD) remain incompletely understood.
DOI•
01 Jan 2017TL;DR: Dependence levels may be considered as meaningful interim clinical milestones that reflect Alzheimer's disease-related functional deficits, although a time frame that extends beyond 18 months may be necessary to observe changes.
Abstract: BACKGROUND While functional loss forms part of the current diagnostic criteria used to identify dementia due to Alzheimer's disease, the gradual and progressive nature of the disease makes it difficult to recognize clinically relevant signposts that could be helpful in making treatment and management decisions. Having previously observed a significant relationship between stages of functional dependence (the level of assistance patients require consequent to Alzheimer's disease deficits, derived from the Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale) and cognitive severity, we investigated whether measures of functional dependence could be utilized to identify clinical milestones of Alzheimer's disease progression. OBJECTIVES To describe the patterns of change in dependence over the course of 18 months in groups stratified according to cognitive Alzheimer's disease dementia severity (determined using the Mini-Mental State Examination score) and to identify characteristics associated with patients showing worsening dependence (progressors) versus those showing no change or improvement (non-progressors). DESIGN Analysis of longitudinal data from the GERAS study. SETTING GERAS is an 18-month prospective, multicenter, naturalistic, observational cohort study reflecting the routine care of patients with Alzheimer's disease in France, Germany, and the United Kingdom. PARTICIPANTS 1495 community-living patients, aged ≥55 years, diagnosed with probable Alzheimer's disease dementia, and their caregivers. MEASUREMENTS Dependence levels, cognitive function, behavioral symptoms, caregiver burden, and cost were assessed at baseline and at 18 months. RESULTS Of 971 patients having both baseline and 18-month data, 42% (408) were progressors and 563 (58%) were non-progressors. This general pattern held for all three levels of baseline Alzheimer's disease dementia severity - mild (Mini-Mental State Examination score 21-26), moderate (15-20) or moderately severe/severe (<15) - with 40-45% of each group identified as progressors and 55-60% as non-progressors. No baseline differences were seen between progressors and non-progressors in cognitive scores or behavioral symptoms, although progressors had significantly shorter times since diagnosis and showed milder functional impairment. Baseline factors predictive of increasing dependence over 18 months included more severe cognitive impairment, living with others, and having multiple caregivers. A higher level of initial dependence was associated with less risk of dependence progression. Total societal costs of care also increased with greater dependence. CONCLUSIONS In this large cohort, 42% of Alzheimer's disease dementia patients at all levels of cognitive severity became more dependent within 18 months of observation while 58% did not progress. Dependence levels may be considered as meaningful interim clinical milestones that reflect Alzheimer's disease-related functional deficits, although a time frame that extends beyond 18 months may be necessary to observe changes if used in clinical trials or other longitudinal studies. Recognition of predictors of greater dependence offers opportunities for intervention.
TL;DR: REM sleep imaging is a valuable tool with which to identify individuals at risk of developing AD by identifying brain perfusion defects in the anterior cingulate cortex.
TL;DR: The results suggest that the age‐related impairment in recollection is linked with reduced hippocampal structural integrity.
Abstract: Dual-process theories posit that two separate processes are involved in recognition, namely recollection and familiarity. Studies investigating the neuroanatomical substrates of these two processes have frequently revealed that, while recollection is functionally linked with the hippocampus, familiarity appears to be associated with perirhinal and/or entorhinal cortices integrity. Interestingly these regions are known to be sensitive to normal and neuropathological aging processes. The objective of this study was to examine the effects of aging on recollection and familiarity performance, as well as to investigate associations with the rate of false alarms. In older individuals, we further aimed to explore relationships between these recognition variables and structural integrity of the hippocampus and the entorhinal and perirhinal cortices. Younger (N = 56) and older (N = 59) adults were tested on a computerized recollection and familiarity task. In a separate session, older adults (N = 56) underwent a structural MRI. Hippocampal, entorhinal and perihinal cortices volumes were automatically segmented and then manually corrected to ensure validity of the volumetric assessment. Regional volumes were normalized for total intracranial volume. While the overall recognition performance did not significantly differ across groups, our results reveal a decrease in recollection, together with an increase in familiarity in older adults. The increase reliance on familiarity was significantly and positively associated with the rate of false alarms. In the older adult sample, significant positive associations were found between recollection estimates and normalized hippocampal volumes. The normalized total hippocampal volume accounted for 25% of the variance in recollection performance. No correlation was found between any recognition variables and perirhinal or entorhinal cortices volumes. Overall, our results suggest that the age-related impairment in recollection is linked with reduced hippocampal structural integrity.
TL;DR: Current trial designs where drugs are simply added on to each other do not allow to adequately measure positive (synergistic) and negative interactions, and none has been demonstrated to achieve disease modification.
Abstract: There have been an increasing number of publications on new medications for Alzheimer’s disease (AD). Results from the first study in mild-to-moderate stages of AD using LMTM which inhibits the tau...
TL;DR: This follow-up report aimed to explore the neural correlates of this selective cognitive impairment in otherwise asymptomatic carriers of the APOE ε4 allele.
TL;DR: P3-436 NATURAL HISTORY of the DECLINE in InSTRUMENTAL ACTIVities of Daily Living Prior to Dementia in People with MILD COGNITIVE IMPAIRMENT.
Abstract: P3-436 NATURAL HISTORY OF THE DECLINE IN INSTRUMENTAL ACTIVITIES OF DAILY LIVING PRIOR TO DEMENTIA IN PERSONS WITH MILD COGNITIVE IMPAIRMENT Simon Cloutier, Howard Chertkow, Marie-Jeanne Kergoat, Serge Gauthier, Sylvie Belleville, Institut Universitaire de G eriatrie de Montr eal, Montreal, QC, Canada; Universit e de Montr eal, Montreal, QC, Canada; Lady Davis Institute, Montreal, QC, Canada; Jewish General Hospital, Montreal, QC, Canada; McGill University, Montreal, QC, Canada; Institut Universitaire de G eriatrie de Montr eal, Montreal, QC, Canada; Douglas Hospital Research Centre, Verdun, QC, Canada; McGill University Research Centre for Studies in Aging, Verdun, QC, Canada. Contact e-mail: simon.cloutier@umontreal.ca
TL;DR: Increased risk of AD was found in participants diagnosed with glaucoma for less than 5 years, and AMD or DR for more than 5 Years, and the findings may suggest common pathways between eye diseases and AD.
Abstract: Background: Relationships between dementia and eye conditions are poorly understood. Using data from a well-characterized prospective cohort study, we sought to determine whether glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR) are associated with increased risk of developing Alzheimer’s disease (AD). Methods: Participants aged 65 and dementia-free were recruited in a prospective, observational cohort. Self-reported smoking history, hypertension, congestive heart failure, diabetes, and history of cardiovascular or cerebrovascular disease were obtained at study visits, and APOEgenotype was obtained from consenting participants. Cognition was evaluated every two years with a screening test. Individuals with low screening test scores had neurological and neuropsychological evaluations. All data were reviewed at consensus conferences to assign participants to diagnostic categories including dementia and probable and possible AD. Eye diagnoses were obtained using ICD-9 codes. Hazard ratios (HR) of developing AD in participants with each of three ophthalmic conditions were compared to those with none of these using Cox regression. Results: A total of 3790 participants were included in the analytic sample. Over 30,627 person-years of follow-up, there were 767 incident cases of AD. In a model controlling for APOEε4 and other covariates, the HR was 1.51 (95%CI 1.13, 2.00) in participants diagnosed with glaucoma 5 years previously, but no increased risk was found among thosewho had glaucoma for > 5 years (HR 0.91, 95%CI 0.74, 1.12). The risks in participants who had AMD for 0-5 years and > 5 years were 1.24 (95%CI 0.99, 1.55) and 1.50 (95%CI 1.24, 1.81). The HR for participants diagnosed with DR for 0-5 years and >5 years were 1.57 (95%CI 0.94, 2.64) and 1.47 (95%CI 1.02, 2.12). Conclusions:Increased risk of ADwas found in participants diagnosed with glaucoma for less than 5 years, and AMD or DR for more than 5 years. Our findings may suggest common pathways between eye diseases and AD. Further studies to determine the potential of eye-based biomarkers of incipient ADmay identify people destined to develop AD.
TL;DR: LAGARDE et al. as discussed by the authors presented a review of the state of the art in the field of memory and language in the context of neuro-spine disorders, focusing on brain and spinal networks.
Abstract: Lorraine Hamelin, Julien Lagarde, Guillaume Doroth ee, MarieClaude Potier, H el ene Corne, Ludovic Fillon, Fabien Caill e, Philippe Gervais, Michel Bottlaender, Marie Sarazin, Neurology of Memory and Language, Universit e Paris Descartes, Sorbonne Paris Cit e, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France; INSERM-UPMC UMRS 938, Centre de Recherche Saint-Antoine, Paris, France; Brain and Spine Institute (ICM), UPMC/Inserm UMR-S 975, CNRS UMR 7225, Paris, France; Sorbonne Universit es, Universit e Pierre et Marie Curie (UPMC), Paris, France; CATI Project, Paris, France; CEA, Orsay, France; NeuroSpin, Institut d’Imagerie Biom edicale, Direction des Sciences du Vivant, Commissariat a l’Energie Atomique, Gif sur Yvette, France; Neurologie de la M emoire et du Langage, Universit e Paris Descartes, Sorbonne Paris Cit e, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France. Contact e-mail: J.LAGARDE@ ch-sainte-anne.fr
TL;DR: The authors showed an association between neuropsychiatric inventory (NPI scores and [18F]fluorodeoxyglucose (FDG) uptake in preclinical Alzheimer disease (AD).
Abstract: We thank Landin-Romero and Kumfor for the comments. Our regression techniques showed an association between neuropsychiatric inventory (NPI) scores and [18F]fluorodeoxyglucose (FDG) uptake in preclinical Alzheimer disease (AD).1 We did not find posterior cingulate cortex (PCC) hypermetabolism, but higher PCC-FDG uptake was found in patients with preclinical AD with higher NPI scores at baseline. We did not find hypermetabolism even when we contrasted the mean FDG uptake at the local maxima within the cluster.
TL;DR: The analysis suggests that some subfields (CA3 and CA4) are affected earlier and others (fimbria) later in the disease, so hippocampal subfield analysis may allow a better disease staging than the analysis of the entire hippocampus alone.
Abstract: Conclusions:Discrimination between disease groups could not be reliably improved by studying hippocampal subfields. However, our analysis suggests that some subfields (CA3 and CA4) are affected earlier and others (fimbria) later in the disease. Thus, hippocampal subfield analysis may allow a better disease staging than the analysis of the entire hippocampus alone, but validation with higher resolution data might be necessary. (1)Iglesias et al., Neuroimage 2015;115:117–37.
TL;DR: This is the first study to show that there are differences in the brain areas engaged during context memory encoding and retrieval in middle-aged adults with +FH and +APOE-4 risk factors for late onset AD, compared to controls.
Abstract: Episodic memory impairment is a consistent, pronounced deficit in preclinical stages of late-onset Alzheimer9s disease (AD). Individuals with risk factors for AD exhibit altered brain function several decades prior to the onset of AD-related symptoms. In the current fMRI study of spatial context memory we tested the hypothesis that middle-aged adults (MA; 40-58yrs) with a family history of late onset AD (MA+FH), or a combined +FH and apolipoprotein E e4 allele risk factors for AD (MA+FH+APOE4), will exhibit differences in encoding and retrieval-related brain activity , compared to -FH -APOE4 MA controls. We also hypothesized that the two at-risk MA groups will exhibit distinct patterns of correlation between brain activity and memory performance, compared to controls. To test these hypotheses we conducted multivariate task, and behavior, partial least squares analysis of fMRI data obtained during successful context encoding and retrieval. Our results indicate that even though there were no significant group differences in context memory performance, there were significant differences in brain activity and brain-behavior correlations involving hippocampus, left angular gyrus, cingulate, and precuneus in MA with AD risk factors, compared to controls. In addition, we observed that brain activity and brain-behavior correlations in anterior medial PFC and in ventral visual cortex differentiated the two MA risk groups from each other, and from MA controls. This is the first study to show that there are differences in the brain areas engaged during context memory encoding and retrieval in middle-aged adults with +FH and +APOE-4 risk factors for late onset AD, compared to controls.