Tau and atrophy: domain-specific relationships with cognition.

BackgroundLate-onset Alzheimer's disease (AD) is characterized by primary memory impairment, which then progresses towards severe deficits across cognitive domains. Here, we report how performance in cognitive domains relates to patterns of tau deposition and cortical thickness.MethodsWe analyzed data from 131 amyloid-β positive participants (55 cognitively normal, 46 mild cognitive impairment, 30 AD) of the Alzheimer's Disease Neuroimaging Initiative who underwent magnetic resonance imaging (MRI), flortaucipir (FTP) positron emission tomography, and neuropsychological testing. Surface-based vertex-wise and region-of-interest analyses were conducted between FTP and cognitive test scores, and between cortical thickness and cognitive test scores.ResultsFTP and thickness were differentially related to cognitive performance in several domains. FTP-cognition associations were more widespread than thickness-cognition associations. Further, FTP-cognition patterns reflected cortical systems that underlie different aspects of cognition.ConclusionsOur findings indicate that AD-related decline in domain-specific cognitive performance reflects underlying progression of tau and atrophy into associated brain circuits. They also suggest that tau-PET may have better sensitivity to this decline than MRI-derived measures of cortical thickness

Understanding the Contributions of Alzheimer’s Disease & Cardiovascular Risks to Cerebral Small Vessel Disease Manifest as White Matter Hyperintensities on Magnetic Resonance Imaging (MRI)

Introduction: Alzheimer’s Diseases (AD) & cerebral small vessel disease associated with cardiovascular risk factors (cSVD) frequently coexist, differentially affecting both imaging and clinical features associated with aging and dementia. We hypothesized that Magnetic Resonance Imaging (MRI) can be used in novel ways to identify relative contributions of AD & cardiovascular risks to cSVD and brain atrophy, generating new biomarkers & insights into mixed disease states associated with cognitive decline and dementia. Methods: Three experiments were conducted to address the overarching hypothesis. First, we visually rated the clinical MRI of 325 participants from a community-based cross-sectional sample to elucidate the relative association of age, AD (visualized as hippocampal atrophy) and cSVD (visualized as white matter hyperintensities; WMH) with global brain atrophy in experiment 1. In experiment 2, we analyzed cross-sectional MRI scans from 62 participants from the University of Kentucky Alzheimer’s Disease Center (UKADC) with available clinical data on cardiovascular risk and cerebrospinal fluid (CSF) beta-amyloid levels as a marker of AD. Voxel wise regression was used to examine the association of white matter hyperintensities with AD and/or cardiovascular risk (hypertension). Experiment 3, examined longitudinal MRI changes in WMH volumes in 377 participants from the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI 2). Subjects were categorized into three groups based on WMH volume change, including those that demonstrated regression (n=96; 25.5%), stability (n=72; 19.1%), and progression (n=209; 55.4%) of WMH volume over time. Differences in brain atrophy measures and cognitive testing among the three group were conducted. Results: In the first experiment, logistic regression analysis demonstrated that a 1-year increase in age was associated with global brain atrophy (OR = 1.04; p = .04), medial temporal lobe atrophy (MTA; a surrogate of AD) (OR = 3.7; p \u3c .001), and WMH as surrogate of cSVD (OR = 8.80; p \u3c .001). Both MTA and WMH were strongly associated with global brain atrophy in our study population, with WMH showing the strongest relationship after adjusting for age. In the second experiment, linear regression as well as mediation and moderation analyses demonstrated significant main effects of hypertension (HTN; the strongest risk factor associated with cSVD) and CSF Aβ 1-42 (a surrogate of AD) on WMH volume, but no significant HTN×CSF Aβ 1-42 interaction. Further exploration of the independence of HTN and Aβ using a voxelwise analysis approach, demonstrated unique patterns of WM alteration associated with either hypertension or CSF Aβ 1-42, confirming that both independently contribute to WMH previously classified as cSVD. Extending this work into a longitudinal model rather than focusing on purely cross-sectional associations, we demonstrated that spontaneous WMH regression is common, and that such regression is associated with a reduced rate of global brain atrophy (p = 0.012), and improvement in memory function over time (p = 0.003). Conclusion: These data demonstrate that both AD and cSVD frequently coexist in the same brain, contributing differentially to alterations in brain structure, subcortical white matter injury, and cognitive function. These effects can be disentangled using MRI, and while we currently lack therapeutic interventions to halt or reverse AD, the dynamic WMH change evident in our data clearly suggests that the ability to reverse cSVD exists today

Radiological-pathological correlation in Alzheimer's disease : systematic review of antemortem MRI findings

Background: The standard method of ascertaining Alzheimer’s disease (AD) remains postmortem assessment of amyloid plaques and neurofibrillary degeneration. Vascular pathology, Lewy bodies, TDP-43, and hippocampal sclerosis are frequent comorbidities. There is therefore a need for biomarkers that can assess these aetiologies and provide a diagnosis in vivo. Objective: We conducted a systematic review of published radiological-pathological correlation studies to determine the relationship between antemortem magnetic resonance imaging (MRI) and neuropathological findings in AD. Methods: We explored PubMed in June-July 2015 using “Alzheimer’s disease” and combinations of radiological and pathological terms. After exclusion following screening and full-text assessment of the 552 extracted manuscripts, three others were added from their reference list. In fine, we report results based on 27 articles. Results: Independently of normal age-related brain atrophy, AD pathology is associated with whole-brain and hippocampal atrophy and ventricular expansion as observed on T1-weighted images. Moreover, cerebral amyloid angiopathy and cortical microinfarcts are also related to brain volume loss in AD. Hippocampal sclerosis and TDP-43 are respectively associated with hippocampal and medial temporal lobe atrophy. Brain volume loss correlates more strongly with tangles than with any other pathological finding. White matter hyperintensities observed on proton density, T2-weighted and FLAIR images are strongly related to vascular pathologies, but are also associated with other histological changes such as gliosis or demyelination. Discussion: Cerebral atrophy and white matter changes in the living brain reflect underlying neuropathology and may be detectable using antemortem MRI. In vivo MRI may therefore be an avenue for AD pathological staging

Whole-brain patterns of 1H-magnetic resonance spectroscopy imaging in Alzheimer's disease and dementia with Lewy bodies

Acknowledgements We thank Craig Lambert for his help in processing the MRS data. The study was funded by the Sir Jules Thorn Charitable Trust (grant ref: 05/JTA) and was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre and the Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust and Newcastle University and the NIHR Biomedical Research Centre and Biomedical Research Unit in Dementia based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge.Peer reviewedPublisher PD

The partial volume effect in the quantification of 1H magnetic resonance spectroscopy in Alzheimer's disease and aging

[Abstract] 1H-MRS variability increases due to normal aging and also as a result of atrophy in grey and white matter caused by neurodegeneration. In this work, an automatic process was developed to integrate data from spectra and high-resolution anatomical images to quantify metabolites, taking into account tissue partial volumes within the voxel of interest avoiding additional spectra acquisitions required for partial volume correction. To evaluate this method, we use a cohort of 135 subjects (47 male and 88 female, aged between 57 and 99 years) classified into 4 groups: 38 healthy participants, 20 amnesic mild cognitive impairment patients, 22 multi-domain mild cognitive impairment patients, and 55 Alzheimer's disease patients. Our findings suggest that knowing the voxel composition of white and grey matter and cerebrospinal fluid is necessary to avoid partial volume variations in a single-voxel study and to decrease part of the variability found in metabolites quantification, particularly in those studies involving elder patients and neurodegenerative diseases. The proposed method facilitates the use of 1H-MRS techniques in statistical studies in Alzheimer's disease, because it provides more accurate quantitative measurements, reduces the inter-subject variability, and improves statistical results when performing group comparisons

Interactive Effects of Physical Activity and APOE-ε4 on BOLD Semantic Memory Activation in Healthy Elders

Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer\u27s disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65–85) cognitively intact adults. A cross-sectional design was used with four groups (n = 17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous\u3eunfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline

Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy.

ObjectiveTo characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE).MethodsEleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD).ResultsAll patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls.ConclusionsMildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages