Skills and Expertise
Research Items (73)
Vascular risk factors (e.g. hypertension, dyslipidemia and diabetes) are well known risk factors for Alzheimer’ disease. These vascular risk factors lead to vascular brain injuries, which also increase the likelihood of dementia. The advent of amyloid PET imaging has helped establish that vascular risk factors also lead to Alzheimer’s disease via pathways that are independent from vascular brain injuries, at least, when vascular brain injuries are measured as white matter lesions and infarcts. While vascular brain injuries (white matter lesions and infarcts) do not seem to influence amyloid pathology, some evidence from amyloid imaging suggests that increased vascular risk is related to increased amyloid burden. Furthermore, while vascular brain injuries and amyloid have an additive and independent impact on brain integrity, vascular risk factors might potentiate the impact of amyloid on cortical thickness on brain regions vulnerable to Alzheimer’s disease. New research should further explore and confirm, or refute, possible interactions between amyloid and vascular risk factors on brain integrity and cognition. Neuroimaging tools used to assess vascular brain integrity should also be expanded. Measuring cortical blood flow or damage to the capillary system might, for instance, give insight about how vascular risk factors can be associated to amyloid burden and impact. These findings also stress the need for monitoring vascular risk factors in midlife as a strategy for Alzheimer’s disease prevention.
- May 2015
Amyloid-β, a hallmark of Alzheimer's disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-β positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-β deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-β positron emission tomography signal. Next, we tested the sensitivity and specificity of the derived thresholds in 50 individuals who underwent Pittsburgh compound-B positron emission tomography during life and brain autopsy (mean time positron emission tomography to autopsy 3.1 ± 1.8 years). Amyloid at autopsy was classified using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, unadjusted for age. The analytic approaches yielded low thresholds (standard uptake value ratiolow = 1.21, distribution volume ratiolow = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratiohigh = 1.40, distribution volume ratiohigh = 1.20) that are more conservative in defining Pittsburgh compound-B positron emission tomography positivity. In voxel-wise contrasts, elevated Pittsburgh compound-B retention was first noted in the medial frontal cortex, then the precuneus, lateral frontal and parietal lobes, and finally the lateral temporal lobe. When compared to post-mortem amyloid burden, low proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratiolow 81.0%, standard uptake value ratiolow 83.3%; distribution volume ratiohigh 61.9%, standard uptake value ratiohigh 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratiolow 95.8%; standard uptake value ratiolow, distribution volume ratiohigh and standard uptake value ratiohigh 100.0%). A receiver operator characteristic analysis identified optimal distribution volume ratio (1.06) and standard uptake value ratio (1.20) thresholds that were nearly identical to the a priori distribution volume ratiolow and standard uptake value ratiolow. In summary, we found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratiohigh and standard uptake value ratiohigh) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not compromising specificity. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: email@example.com.
Objective: The objective of this study was to define whether vascular risk factors interact with β-amyloid (Aβ) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD). Methods: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aβ was assessed using [(11)C]Pittsburgh compound B-PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index. Results: Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aβ. These frontotemporal regions are also affected in individuals with Aβ deposition, but the latter show additional thinning in parietal cortices. Aβ and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aβ has its greatest effect. In this way, the negative effect of Aβ in posterior regions is increased by the presence of vascular risk. Conclusion: Aβ and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD.
- Jan 2014
To investigate the associations among β-amyloid (Aβ), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease. In 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Aβ deposition using [(11)C] Pittsburgh compound B-PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index. Increased Aβ was associated with cortical thinning, notably in frontoparietal regions. This relationship was strongest in persons with high Aβ deposition. Increased Aβ was also associated with lower episodic memory performance. Cortical thickness was found to mediate the relationship between Aβ and memory performance. While age had a marginal effect on these associations, the relationship between Aβ and cortical thickness was eliminated after controlling for vascular risk except when examined in only Pittsburgh compound B-positive subjects, in whom Aβ remained associated with thinner cortex in precuneus and occipital lobe. In addition, only the precuneus was found to mediate the relationship between Aβ and memory after controlling for vascular risk. These results suggest strong links among Aβ, cortical thickness, and memory. They highlight that, in individuals without dementia, vascular risk also contributes to cortical thickness and influences the relationships among Aβ, cortical thickness, and memory.
- Oct 2018
Previous positron emission tomography (PET) studies have quantified filamentous tau pathology using regions‐of‐interest (ROIs) based on observations of the topographical distribution of neurofibrillary tangles in post‐mortem tissue. However, such approaches may not take full advantage of information contained in neuroimaging data. The present study employs an unsupervised data‐driven method to identify spatial patterns of tau‐PET distribution, and to compare these patterns to previously published “pathology‐driven” ROIs. Tau‐PET patterns were identified from a discovery sample comprised of 123 normal controls and patients with mild cognitive impairment or Alzheimer's disease (AD) dementia from the Swedish BioFINDER cohort, who underwent [18F]AV1451 PET scanning. Associations with cognition were tested in a separate sample of 90 individuals from ADNI. BioFINDER [18F]AV1451 images were entered into a robust voxelwise stable clustering algorithm, which resulted in five clusters. Mean [18F]AV1451 uptake in the data‐driven clusters, and in 35 previously published pathology‐driven ROIs, was extracted from ADNI [18F]AV1451 scans. We performed linear models comparing [18F]AV1451 signal across all 40 ROIs to tests of global cognition and episodic memory, adjusting for age, sex, and education. Two data‐driven ROIs consistently demonstrated the strongest or near‐strongest effect sizes across all cognitive tests. Inputting all regions plus demographics into a feature selection routine resulted in selection of two ROIs (one data‐driven, one pathology‐driven) and education, which together explained 28% of the variance of a global cognitive composite score. Our findings suggest that [18F]AV1451‐PET data naturally clusters into spatial patterns that are biologically meaningful and that may offer advantages as clinical tools.
Objective: To investigate relationships between tau-PET binding and in vivo Alzheimer’s disease (AD) markers in adults at increased risk of sporadic AD. Methods: One-hundred-nineteen cognitively normal older adults with a family history of sporadic AD (PREVENT-AD cohort, mean age=67±5) underwent tau-PET ([18F]AV-1451), Aβ-PET ([18F]NAV4694) and cognitive evaluation (Repeated Battery for Assessment of Neuropsychological Status; RBANS). CSF phosphorylated (p)-tau levels were available for 59 participants. We first investigated regional tau standardized uptake value ratios (SUVR) differences between Aβ-positive and Aβ-negative individuals using linear regressions. In regions with significantly elevated tau, we used linear regressions to assess whether regional tau SUVRs are related to CSF p-tau and cognitive performance. Finally, we repeated the analyses while removing individuals with high levels of tau to assess if early increase in AV-1451 tau-PET signal is clinically meaningful. Results: Aβ-positive subjects had higher tau SUVRs than Aβ-negative ones in 14 brain regions (p<0.01) that are typically affected by AD-related tau pathology according to post-mortem studies. Increased tau SUVRs in a subset of limbic and temporal regions were associated with increased CSF p-tau (p<0.05), as well as lower delayed memory, language, visuospatial/constructional, and total RBANS scores. When tau-positive subjects were removed from analyses, results remained similar for Aβ and p-tau, but the effect of cognition was lost. Conclusions: Early tau-PET binding in AD-typical regions is associated with established AD markers. Except for the association with cognition, these findings were still present when removing the tau-positive individuals from analyses, supporting the idea that very early elevation in tau-PET signal is meaningful.
Alzheimer's disease is preceded by a lengthy 'preclinical' stage spanning many years, during which subtle brain changes occur in the absence of overt cognitive symptoms. Predicting when the onset of disease symptoms will occur is an unsolved challenge in individuals with sporadic Alzheimer's disease. In individuals with autosomal dominant genetic Alzheimer's disease, the age of symptom onset is similar across generations, allowing the prediction of individual onset times with some accuracy. We extend this concept to persons with a parental history of sporadic Alzheimer's disease to test whether an individual's symptom onset age can be informed by the onset age of their affected parent, and whether this estimated onset age can be predicted using only MRI. Structural and functional MRIs were acquired from 255 ageing cognitively healthy subjects with a parental history of sporadic Alzheimer's disease from the PREVENT-AD cohort. Years to estimated symptom onset was calculated as participant age minus age of parental symptom onset. Grey matter volume was extracted from T1-weighted images and whole-brain resting state functional connectivity was evaluated using degree count. Both modalities were summarized using a 444-region cortical-subcortical atlas. The entire sample was divided into training (n = 138) and testing (n = 68) sets. Within the training set, individuals closer to or beyond their parent's symptom onset demonstrated reduced grey matter volume and altered functional connectivity, specifically in regions known to be vulnerable in Alzheimer's disease. Machine learning was used to identify a weighted set of imaging features trained to predict years to estimated symptom onset. This feature set alone significantly predicted years to estimated symptom onset in the unseen testing data. This model, using only neuroimaging features, significantly outperformed a similar model instead trained with cognitive, genetic, imaging and demographic features used in a traditional clinical setting. We next tested if these brain properties could be generalized to predict time to clinical progression in a subgroup of 26 individuals from the Alzheimer's Disease Neuroimaging Initiative, who eventually converted either to mild cognitive impairment or to Alzheimer's dementia. The feature set trained on years to estimated symptom onset in the PREVENT-AD predicted variance in time to clinical conversion in this separate longitudinal dataset. Adjusting for participant age did not impact any of the results. These findings demonstrate that years to estimated symptom onset or similar measures can be predicted from brain features and may help estimate presymptomatic disease progression in at-risk individuals.
- Feb 2018
Importance Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms. Objective To assess whether a sporadic parental estimated years to symptom onset calculation could be used to identify information about amyloid-β (Aβ) levels in asymptomatic individuals with a parental history of AD dementia. Design, Setting, and Participants This cohort study analyzed Aβ1-42 in cerebrospinal fluid (CSF) specimens from 101 cognitively normal individuals who had a lumbar puncture as part of the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort from September 1, 2011, through November 30, 2016 (374 participants were enrolled in the cohort during this period). The study estimated each participant’s proximity to his/her parent’s symptom onset by subtracting the index relative’s onset age from his/her current age. The association between proximity to parental symptom onset and Aβ levels was then assessed using apolipoprotein E ε4 (APOE4) status and sex as interactive terms. These analyses were performed again in 2 independent cohorts using CSF and Pittsburgh compound B carbon 11–labeled positron emission tomography (PIB-PET) Aβ biomarkers: the Adult Children Study (ACS) and the Wisconsin Registry for Alzheimer Prevention (WRAP) cohorts. Main Outcomes and Measures The association between proximity to parental symptom onset and Aβ burden in asymptomatic individuals with a parental history of sporadic AD. Results The present analysis included a subset of 101 PREVENT-AD individuals (mean [SD] age, 61.8 [5.1] years; 30 [29.7%] male), 128 ACS participants (112 participants underwent CSF measurement: mean [SD] age, 63.4 [5.1] years; 31 [27.7%] male; and 107 underwent PIB-PET: mean [SD] age, 64.6 [5.3] years; 27 [25.2%] male), and 135 WRAP participants (85 participants underwent CSF measurement: mean [SD] age, 59.9 [6.0] years; 27 [31.8%] male; and 135 underwent PIB-PET: mean [SD] age, 59.6 [6.1] years; 43 [31.9%] male). In the PREVENT-AD cohort, individuals approaching their parent’s onset age had lower CSF Aβ1-42 levels (range, 402-1597; B = −9.09, P = .04). This association was stronger in APOE4 carriers (B = −17.9, P = .03) and women (B = −19.8, P = .02). In the ACS cohort, the main association was replicated using PIB-PET data, and the sex interaction was replicated using CSF and PIB-PET data. In the WRAP cohort, the results were not replicated using cross-sectional data, but the main association and the APOE interaction were replicated using PIB-PET longitudinal data. Conclusions and Relevance These results suggest that proximity to parental symptom onset may help estimate Aβ biomarker changes in women or APOE4 carrier asymptomatic individuals with a parental history of sporadic AD.
Background: Both subjective cognitive decline (SCD) and a family history of Alzheimer's disease (AD) portend risk of brain abnormalities and progression to dementia. Posterior default mode network (pDMN) connectivity is altered early in the course of AD. It is unclear whether SCD predicts similar outcomes in cognitively normal individuals with a family history of AD. Methods: We studied 124 asymptomatic individuals with a family history of AD (age 64 ± 5 years). Participants were categorized as having SCD if they reported that their memory was becoming worse (SCD+). We used extensive neuropsychological assessment to investigate five different cognitive domain performances at baseline (n = 124) and 1 year later (n = 59). We assessed interconnectivity among three a priori defined ROIs: pDMN, anterior ventral DMN, medial temporal memory system (MTMS), and the connectivity of each with the rest of brain. Results: Sixty-eight (55%) participants reported SCD. Baseline cognitive performance was comparable between groups (all false discovery rate-adjusted p values > .05). At follow-up, immediate and delayed memory improved across groups, but the improvement in immediate memory was reduced in SCD+ compared with SCD- (all false discovery rate-adjusted p values < .05). When compared with SCD-, SCD+ subjects showed increased pDMN-MTMS connectivity (false discovery rate-adjusted p < .05). Higher connectivity between the MTMS and the rest of the brain was associated with better baseline immediate memory, attention, and global cognition, whereas higher MTMS and pDMN-MTMS connectivity were associated with lower immediate memory over time (all false discovery rate-adjusted p values < .05). Conclusions: SCD in cognitively normal individuals is associated with diminished immediate memory practice effects and a brain connectivity pattern that mirrors early AD-related connectivity failure.
- Oct 2017
Sleep spindles promote the consolidation of motor skill memory in young adults. Older adults, however, exhibit impoverished sleep-dependent motor memory consolidation. The underlying pathophysiological mechanism(s) explaining why motor memory consolidation in older adults fails to benefit from sleep remains unclear. Here, we demonstrate that male and female older adults show impoverished overnight motor skill memory consolidation relative to young adults, with the extent of impairment being associated with the degree of reduced frontal fast sleep spindle density. The magnitude of the loss of frontal fast sleep spindles in older adults was predicted by the degree of reduced white matter integrity throughout multiple white matter tracts known to connect subcortical and cortical brain regions. We further demonstrate that the structural integrity of selective white matter fiber tracts, specifically within right posterior corona radiata, right tapetum, and bilateral corpus callosum, statistically moderates whether sleep spindles promoted overnight consolidation of motor skill memory. Therefore, white matter integrity within tracts known to connect cortical sensorimotor control regions dictates the functional influence of sleep spindles on motor skill memory consolidation in the elderly. The deterioration of white matter fiber tracts associated with human brain aging thus appears to be one pathophysiological mechanism influencing subcortical–cortical propagation of sleep spindles and their related memory benefits.
- Jan 2017
Objective: To comprehensively assess neurobiological effects of the protective APOE2 allele in the aged brain using a cross-sectional multimodal neuroimaging approach. Methods: Multimodal neuroimaging data were obtained from a total of 572 older individuals without dementia (cognitively normal and mild cognitive impairment) enrolled in the Alzheimer's Disease Neuroimaging Initiative and included assessments of regional amyloid load with AV45-PET, glucose metabolism with fluorodeoxyglucose-PET, and gray matter volume with structural MRI. Imaging indexes of APOE2 carriers were contrasted to risk-neutral APOE3 homozygotes, and analyses were controlled for age, sex, education, and clinical diagnosis. Additional models examined genotype-specific effects of age on the imaging markers. Results: In region-of-interest-based analyses, APOE2 carriers had significantly less precuneal amyloid pathology and did not show the typical age-related increase in amyloid load, although the age × genotype interaction was only trend-level significant. In contrast, parietal metabolism and hippocampal volume did not differ between APOE2 and APOE3 genotypes, and both groups showed comparable negative effects of age on these markers. The amyloid specificity of APOE2-related brain changes was corroborated in 2 complementary analyses: spatially unbiased voxel-wise analyses showing widespread reductions in amyloid deposition but no differences in gray matter volume or metabolism and an analysis of CSF-based biomarkers showing a significant effect on amyloid but not on tau pathology. Conclusions: Regarding the range of Alzheimer disease biomarkers considered in the present study, the APOE2 allele appears to have a relatively selective effect on reduced accumulation of amyloid pathology in the aged brain.
Imaging-pathological correlation studies show that in vivo amyloid-β (Aβ) positron emission tomography (PET) strongly predicts the presence of significant Aβ pathology at autopsy. We sought to determine whether regional PiB-PET uptake would improve sensitivity for amyloid detection in comparison with global measures (experiment 1), and to estimate the relative contributions of different Aβ aggregates to in vivo PET signal (experiment 2). In experiment 1, 54 subjects with [¹¹C] PiB-PET during life and postmortem neuropathologic examination (85.2% with dementia, interval from PET to autopsy 3.1±1.9 years) were included. We assessed Thal amyloid phase (N=36) and CERAD score (N=54) versus both global and regional PiB SUVRs. In experiment 2 (N=42), PiB SUVR and post-mortem amyloid β burden was analyzed in five customized regions of interest matching regions sampled at autopsy. We assessed the relative contribution of neuritic plaques (NPs), diffuse plaques (DPs) and cerebral amyloid angiopathy (CAA) to regional PIB SUVR using multi-linear regression. In experiment 1, there were no differences in Area Under the Curve for amyloid phase≥A2 and CERAD score≥C2 between global and highest regional PiB SUVR (p=0.186 and 0.230). In experiment 2, when NPs, DPs, and/or CAA were included in the same model, moderate to severe NPs were independently correlated with PiB SUVR in all regions except for the inferior temporal and calcarine ROI (β=0.414–0.804, p<0.05), whereas DPs were independently correlated with PiB SUVR in the angular gyrus ROI (β=0.446, p=0.010). CAA was also associated with PiB SUVR in the inferior temporal and calcarine ROI (β=0.222–0.355, p<0.05). In conclusion, global PiB-PET SUVR performed as well as regional values for amyloid detection in our cohort. The substrate-specific binding of PiB might differ among the brain specific regions.
- Aug 2016
Suspected non-Alzheimer pathophysiology (SNAP) is a biomarker-based concept suggested as a complement to the new National Institute on Aging–Alzheimer Association (NIA-AA) research criteria of preclinical Alzheimer disease (AD).¹ The NIA-AA classifies individuals with preclinical AD into 1 of the following 3 stages: biomarker evidence of β-amyloid (Aβ) but no brain injury (stage 1), biomarker evidence of Aβ and brain injury (stage 2), and biomarker evidence of Aβ and brain injury, with subtle cognitive changes (stage 3). The term SNAP was introduced to capture cognitively normal individuals with evidence of AD-like brain injury in the absence of amyloidosis. As the name suggests, this group was initially hypothesized to have a non-AD pathophysiological process such as vascular disease or other types of neurodegenerative diseases.
- Apr 2016
Recent literature has examined baseline hippocampal volume and extent of brain amyloidosis to test potential synergistic effects on worsening cognition and extent of brain atrophy. Use of hippocampal volume in prior studies was based on the notion that limbic circuit degeneration is an early manifestation of the Alzheimer's Disease (AD) pathophysiology. To clarify these interactions early in the AD process, we tested the effects of amyloid and baseline normalized hippocampal volume on longitudinal brain atrophy rates in a group of cognitively normal individuals. Results showed that the combination of elevated β-amyloid and baseline hippocampal atrophy is associated with increased rates specific to the limbic circuit and splenium. Importantly, this atrophy pattern emerged from a voxelwise analysis, corroborated by regression models over region of interests in native space. The results are broadly consistent with previous studies of the effects of amyloid and baseline hippocampal atrophy in normals, while pointing to accelerated atrophy of AD-vulnerable regions detectable at the preclinical stage.
. Apolipoprotein (Apo) E plays a key role in the handling of lipoprotein particles with ApoE2 and ApoE4 frequently having opposite effects compared to ApoE3. Some individuals simultaneously carry both E2 and E4 alleles. The impact of the ApoE2/4 genotype on lipid concentrations and its consequences on health remain poorly documented. Objective . This study compared the lipid profile between ApoE2/4 carriers and other ApoE genotypes in relation to the waist circumference. Methods . Cholesterol, triglyceride (TG), and ApoB concentrations were measured among 2,680 Caucasians. Multivariate logistic regression models were used to estimate the contribution of ApoE2/4 to various dyslipidemic profiles associated with abdominal obesity. Results . In presence of abdominal obesity, the lipid profile was as deteriorated in ApoE2/4 carriers as in carriers of other ApoE genotypes. There was a more pronounced effect on TG-rich lipoproteins, particularly in ApoE2/2 (a feature of type III dysbetalipoproteinemia), and non-high-density lipoprotein (HDL) cholesterol in ApoE4/4. Compared to ApoE2/2, ApoE2/4 carriers presented lower very-low-density lipoprotein (VLDL) cholesterol concentrations and VLDL-cholesterol/TG ratios, with or without obesity, and higher low-density lipoprotein (LDL) cholesterol concentrations. Conclusion . In presence of abdominal obesity, the influence of the ApoE2 allele could be less pronounced than that of ApoE4 among ApoE2/4 individuals.
The amyloid hypothesis proposes a serial model of causality whereby beta-amyloid (Aβ) initiates a cascade of negative events such as neurofibrillary tangle formation leading to neurodegeneration, and eventually clinical onset of Alzheimer’s disease (AD). While this hypothesis was mainly founded on genetic forms of AD observations, increasing results coming from Aβ imaging suggests that the reality for late-onset AD is more complex. Clearly, the disease develops in an older brain, where age-associated comorbid factors are more prevalent and therefore have a more significant influence on disease expression. Furthermore, it is well established that around one-third of cognitively normal older adults have abnormal Aβ accumulation in their brain (Aizenstein et al., 2008), indicating that Aβ alone might not be sufficient to lead to the clinical expression of late-onset AD. Most of the late-onset AD cases might therefore be the consequence of multi-factorial pathologies (Chetelat, 2013).
Carriers of the apolipoprotein E (APOE) 4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of-amyloid (A) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating A pathology, which could be particularly beneficial in APOE 4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE 4 allele in relation to brain A burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE 4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical A deposition, quantified using [ 11 C] Pittsburgh-compound-B (PIB)-PET. As expected, the 4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in 4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of A.
Personalized medicine uses various individual characteristics to guide medical decisions. Apolipoprotein (ApoE), the most studied polymorphism in humans, has been associated with several diseases. The purpose of this review is to elucidate the potential role of ApoE polymorphisms in personalized medicine, with a specific focus on neurodegenerative diseases, by giving an overview of its influence on disease risk assessment, diagnosis, prognosis, and therapy. This review is not a systematic inventory of the literature, but rather a summary and discussion of novel, influential and promising works in the field of ApoE research that could be valuable for personalized medicine. Empirical evidence suggests that ApoE genotype informs pre-symptomatic risk for a wide variety of diseases, is valuable for the diagnosis of type III dysbetalipoproteinemia, increases risk of dementia in neurodegenerative diseases, and is associated with a poor prognosis following acute brain damage. ApoE status appears to influence the efficacy of certain drugs, outcome of clinical trials, and might also give insight into disease prevention. Assessing ApoE genotype might therefore help to guide medical decisions in clinical practice.
Carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of β-amyloid (Aβ) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Aβ pathology, which could be particularly beneficial in APOE ε4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE ε4 allele in relation to brain Aβ burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 ± 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE ε4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Aβ deposition, quantified using [(11)C] Pittsburgh-compound-B (PIB)-PET. As expected, the ε4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in ε4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Aβ.
Importance Criteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns.Objective To examine relationships between Aβ and non-Aβ factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aβ deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions.Design, Setting, and Participants Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort.Intervention Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning.Main Outcomes and Measures For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aβ deposition (quantified using carbon 11–labeled Pittsburgh compound B positron emission tomography).Results Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention.Conclusions and Relevance Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aβ burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD.
The objective of this work was to assess the predictive accuracy of targeted neuroimaging and neuropsychological measures for the detection of incipient dementia in individuals with mild cognitive impairment (MCI), and to examine the potential benefit of combining both classes of measures. Baseline MRI measures included hippocampal volume, cortical thickness, and white matter hyperintensities. Neuropsychological assessment focused on different aspects of episodic memory (i.e., familiarity, free recall, and associative memory) and executive control functions (i.e., working memory, switching, and planning). Global and regional cortical thinning was observed in MCI patients who progress to dementia compared to those who remained stable, whereas no differences were found between groups for baseline hippocampal volume and white matter hyperintensities. The strongest neuroimaging predictors were baseline cortical thickness in the right anterior cingulate and middle frontal gyri. For cognitive predictors, we found that deficits in both free recall and recognition episodic memory tasks were highly suggestive of progression to dementia. Cortical thinning in the right anterior cingulate gyrus, combined to controlled and familiarity-based retrieval deficits, achieved a classification accuracy of 87.5%, a specificity of 90.9%, and a sensitivity of 83.3%. This predictive model including both classes of measures provided more accurate predictions than those based on neuroimaging or cognitive measures alone. Overall, our findings suggest that detecting preclinical Alzheimer's disease is probably best accomplished by combining complementary information from targeted neuroimaging and cognitive classifiers, and highlight the importance of taking into account both structural and functional changes associated with the disease.
The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0-0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Aβ deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue.
- May 2013
On the other hand, the prevalence of OSA in patients with COPD has been estimated at 10%, which is similar to that found in an equivalent general population⁴ and considerably less than the frequency of MCI observed in our study.¹ OSA is usually diagnosed based on polysomnographic recording and the presence of excessive daytime sleepiness. In our study, polysomnographic recording was not available to control for OSA. However, based on the Epworth Sleepiness Scale (ESS), patients with COPD did not differ from control subjects in the severity of daytime sleepiness symptoms (P = .45).¹ Although patients with COPD and MCI had a slightly higher ESS total score (8.42) compared with patients with COPD without MCI (6.28), the difference did not reach significance (P = .62).¹ Furthermore, no significant difference was found in the proportion of subjects with excessive daytime sleepiness (ESS ≥10) between patients with COPD and control subjects (20% vs 18%; χ² test =0.02; P = .90) or between patients with COPD with and without MCI (29% vs 15%; Fischer exact test, P = .41). Therefore, although we could not determine the proportion of subjects with objectively confirmed OSA in our sample, our results on the ESS suggest that daytime sleepiness, which is a central symptom in OSA diagnosis, is probably not a major factor explaining the high frequency of MCI in the COPD cohort.
Both cognitive aging and β-amyloid (Aβ) deposition, a pathological hallmark of Alzheimer's disease, are associated with structural and cognitive changes in cognitively normal older people. To examine independent effects of age and Aβ deposition on cognition and brain structure in aging, 83 cognitively normal older adults underwent structural magnetic resonance imaging scans and neuropsychological tests and were classified as negative (PIB-) or positive (PIB+) for Aβ deposition using the radiotracer Pittsburgh compound B (PIB). Weighted composite discriminant scores represented subjects' cognition. Older adults showed age-related gray matter (GM) atrophy across the whole brain regardless of Aβ deposition. Amyloid burden within PIB+ subjects, however, was associated with GM atrophy in the frontal, parietal, and temporal cortices. Associations between cognition and volume in PIB- subjects were primarily seen throughout frontal regions and the striatum, while, in PIB+ subjects, these associations were seen in orbital-frontal and hippocampal regions. Furthermore, in PIB- subjects, cognition was related to putaminal volume, but not to hippocampus, while, in PIB+ subjects, cognition was related to hippocampal volume, but not to putamen. These findings highlight differential age and Aβ effects on brain structure, indicating effects of age and Aβ that operate somewhat independently to affect frontostriatal and medial temporal brain systems.
Background: Cognitive impairment is a frequent feature of COPD. However, the proportion of patients with COPD with mild cognitive impairment (MCI) is still unknown, and no screening test has been validated to date for detecting MCI in this population. The goal of this study was to determine the frequency and subtypes of MCI in patients with COPD and to assess the validity of two cognitive screening tests, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), in detecting MCI in patients with COPD. Methods: Forty-five patients with moderate to severe COPD and 50 healthy control subjects underwent a comprehensive neuropsychologic assessment using standard MCI criteria. Receiver operating characteristic curves were obtained to assess the validity of the MMSE and the MoCA to detect MCI in patients with COPD. Results: MCI was found in 36% of patients with COPD compared with 12% of healthy subjects. Patients with COPD with MCI had mainly the nonamnestic MCI single domain subtype with predominant attention and executive dysfunctions. The optimal MoCA screening cutoff was 26 (≤ 25 indicates impairment, with 81% sensitivity, 72% specificity, and 76% correctly diagnosed). No MMSE cutoff had acceptable validity. Conclusions: In this preliminary study, a substantial proportion of patients with COPD were found to have MCI, a known risk factor for dementia. Longitudinal follow-up on these patients is needed to determine the risk of developing more severe cognitive and functional impairments. Moreover, the MoCA is superior to the MMSE in detecting MCI in patients with COPD.
- Nov 2011
The main goal of this study was to assess vulnerability to proactive interference and memory binding capacity, the ability to combine different information into a single coherent memory event, in persons with mild cognitive impairment (MCI). We also examined whether hippocampal atrophy and vascular burden were differentially related to these memory capacities in MCI. We further assessed whether memory performance and brain changes differ as a function of later development (or not) of dementia and whether they can predict progression to dementia. The study included 77 participants, 49 meeting the criteria for MCI and 28 healthy older adults. Results showed binding deficits and greater vulnerability to proactive interference in persons with MCI compared with healthy older adults. Hippocampal volume was associated with binding capacity, whereas vascular burden was associated with resistance to interference in persons with MCI. Follow-up analyses indicated that binding deficits predict progression from MCI to dementia. In conclusion, binding deficits and vulnerability to proactive interference are present in persons with MCI and are associated with different brain markers. However, only binding deficits predict progression to dementia.
- May 2011
The present study manipulated the nature of orientation provided at encoding in an intentional word memory task. Performance on the memory task was then compared between 23 elderly persons with amnestic mild cognitive impairment (aMCI), 13 patients with probable Alzheimer's disease (AD), and 23 healthy elderly persons. When tested following shallow (reading orientation) encoding, free-recall performance was impaired in AD compared to aMCI and healthy older adults. When tested following deep (categorical semantic orientation) encoding, both AD and aMCI groups were impaired relative to healthy older adults. The latter result was related to larger memory improvement due to semantic orientation in healthy controls than in aMCI and AD participants. Overall, these findings indicate that the encoding put up by aMCI and healthy elderly persons is comparably efficient in situations where shallow supportive cues are provided at encoding, but that healthy controls benefit more than aMCI and AD in situations where supportive cues are strong.
Mild cognitive impairment (MCI) is frequent in Parkinson's disease (PD) and idiopathic REM sleep behavior disorder (iRBD). However, only a few studies have evaluated the validity of brief cognitive measures to detect MCI in PD or iRBD using standard diagnostic criteria for MCI. Our aim was to evaluate the validity of the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (DRS-2) to detect MCI in PD and iRBD. Forty PD patients and 34 iRBD patients were studied. Receiver operating characteristic curves were created for both tests to assess their effectiveness in identifying MCI in PD and iRBD. In PD, a normality cutoff of 138 on the DRS-2 yielded the best balance between sensitivity (72%) and specificity (86%) with a correct classification of 80%. In iRBD, the optimal normality cutoff was 141 on the DRS-2, with a sensitivity of 90%, a specificity of 71% and a correct classification of 82%. No cutoff for the MMSE was found to have acceptable sensitivity or specificity. The DRS-2 has satisfactory validity to detect MCI in PD or iRBD. The MMSE proved to be invalid as a screening test for MCI in both populations.
The severity of brain lesions is not a perfect predictor of the severity of cognitive deficits in age-related brain disorders, an observation which has led to the cognitive reserve hypothesis. According to this hypothesis, cognitive reserve modulates the relationship between cerebral lesions and their clinical manifestations by limiting the negative impact of cerebral lesions on cognition. Thus, individuals with high cognitive reserve could sustain a greater amount of neuropathological lesions before they reach the criteria for dementia. The goal of this review is to present and discuss the notion of cognitive reserve, a hypothesis that brings a novel perspective to the complexity of normal and pathological cognitive aging. The present article describes the neuronal mechanisms proposed to underlie cognitive reserve and the factors that increase and decrease reserve. In addition, influent studies that have measured the cognitive reserve hypothesis in clinical populations are presented.
Vascular burden, cognition and aging There is increasing evidence for an overlap between the different forms of dementia, in particular dementia of the Alzheimer type and vascular dementia. For example, it is now well established that vascular risk factors are associated with more important cognitive decline in older adults and that they increase their risk of developing not only vascular dementia but Alzheimer’s disease as well. Little is known regarding the relation between vascular burden and cognition in persons meeting criteria for mild cognitive impairment. The goal of this article is to present and summarize studies that have examined those issues. Cognitive functions in persons with mild cognitive impairment will be examined as a function of their vascular burden expressed clinically by measuring the number of vascular diseases and risk factors and, expressed neuro-radiologically by measuring the presence and severity of subcortical white matter changes with structural magnetic resonance. We will overview data examining the effect of vascular burden on executive functions, episodic memory and on neuropsychiatric symptoms. This article will also propose a new approach where patients are not distinguished as a function of clinical criteria but rather, as a function of their brain anomalies measured with in vivo brain imaging techniques. Preliminary findings in support of this approach will be presented.
To investigate the impact of vascular burden (assessed by the number of vascular risk factors and diseases) on the cognition of persons with amnestic mild cognitive impairment (aMCI). This study included 145 participants; 68 meeting criteria for amnesic single-domain or multiple-domain MCI and 77 matched controls. Four cognitive domains were assessed: executive functions, processing speed, episodic memory and general cognitive functioning. A larger vascular burden among aMCI is correlated with lower performance in the executive domain. In addition, persons with aMCI with high vascular burden were more frequently of the multiple domain subtype, whereas persons with no vascular burden were more frequently of the single domain subtype. Our findings suggest that the combined effect of multiple vascular risk factors and diseases increases the amount of executive impairment in persons with aMCI. Vascular burden may play an important role in the heterogeneity of aMCI by impairing cognitive functions other than memory.