Effects of Amyloid Status and Age on Longitudinal Regional Brain Atrophy in Elderly Healthy Controls (original) (raw)
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Brain, 2007
Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation.We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating 51, n ¼ 20) and presymptomatic (clinical dementia rating ¼ 0, n ¼15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n ¼12), mean whole brain white-matter FA (P ¼ 0.045), FA of the columns of the fornix (P ¼ 0.012), area of the perforant pathways bilaterally (right side: P ¼ 0.028, left side: P ¼ 0.027) and left orbitofrontal lobe (P ¼ 0.024) were decreased relative to that of non-carriers (n ¼ 8).We also found that FA in the columns of the fornix (P ¼ 0.008) and left orbitofrontal lobe white matter (P ¼ 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean whitematter FA and left frontal lobe white-matter FA. In a linear regression analysis, white-matter volume (P ¼ 0.002), hippocampal volume (P ¼ 0.023) and mutation status (P ¼ 0.032) significantly predicted fornix FA.We conclude that FA is decreased in the white matter in preclinical and even presymptomatic FAD mutation carriers, particularly in the late-myelinating tracts connecting limbic structures. Decreased FA in of the columns of the fornix is particularly robust in early FAD and may provide a biomarker for early disease in sporadic Alzheimer's disease. by guest on September 3, 2016 http://brain.oxfordjournals.org/ Downloaded from Abbreviations: APP ¼ amyloid precursor protein; CDR ¼ clinical dementia rating; DTI ¼ diffusion tensor imaging; DWI ¼ diffusion-weighted imaging; FAD ¼ familial Alzheimer's disease; MCI ¼ mild cognitive impairment , 130, 1767^1776 J. M. Ringman et al. by guest on September 3, 2016 http://brain.oxfordjournals.org/ Downloaded from DTI in preclinical and presymptomatic carriers of FAD mutation Brain (2007), 130, 1767^1776
Frontiers in aging neuroscience, 2018
The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to mutation carriers. This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Atlas-based volumetry was performed in 13 affected FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Compared to sporadic patients, mutation...
Cortical atrophy in patients with cerebral amyloid angiopathy: a case-control study
The Lancet Neurology, 2016
Background Loss of cortical grey matter is a diagnostic marker of many neurodegenerative diseases, and is a key mediator of cognitive impairment. We postulated that cerebral amyloid angiopathy (CAA), characterised by cortical vascular amyloid deposits, is associated with cortical tissue loss independent of parenchymal Alzheimer's disease pathology. We tested this hypothesis in patients with hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D), a monogenetic disease with minimal or no concomitant Alzheimer's disease pathology, as well as in patients with sporadic CAA and healthy and Alzheimer's disease controls. Methods In this observational case-control study, we included six groups of participants: patients diagnosed with HCHWA-D using genetic testing; healthy controls age-matched to the HCHWA-D group; patients with probable sporadic CAA without dementia; two independent cohorts of healthy controls age-matched to the CAA group; and patients with Alzheimer's disease age-matched to the CAA group. De-identifi ed (but unmasked) demographic, clinical, radiological, and genetic data were collected at Massachusetts General Hospital (Boston, MA, USA), at Leiden University (Leiden, Netherlands), and at sites contributing to Alzheimer's Disease Neuroimaging Initiative (ADNI). The primary outcome measure was cortical thickness. The correlations between cortical thickness and structural lesions, and blood-oxygen-level-dependent time-to-peak (BOLD-TTP; a physiological measure of vascular dysfunction) were analysed to understand the potential mechanistic link between vascular amyloid and cortical thickness. The radiological variables of interest were quantifi ed using previously validated computer-assisted tools, and all results were visually reviewed to ensure their accuracy. Results Between March 15, 2006, and Dec 1, 2014, we recruited 369 individuals (26 patients with HCHWA-D and 28 agematched, healthy controls; 63 patients with sporadic CAA without dementia; two healthy control cohorts with 63 and 126 individuals; and 63 patients with Alzheimer's disease). The 26 patients with HCHWA-D had thinner cortices (2•31 mm [SD 0•18]) than the 28 healthy controls (mean diff erence-0•112 mm, 95% CI-0•190 to-0•034, p=0•006). The 63 patients with sporadic CAA without dementia had thinner cortices (2•17 mm [SD 0•11]) than the two healthy control cohorts (n=63, mean diff erence-0•14 mm, 95% CI-0•17 to-0•10, p<0•0001; and n=126,-0•10,-0•13 to-0•06, p<0•0001). All diff erences remained independent in multivariable analyses. The 63 patients with Alzheimer's disease displayed more severe atrophy than the patients with sporadic CAA (2•1 mm [SD 0•14], diff erence 0•07 mm, 95% CI 0•11 to 0•02, p=0•005). We found strong associations between cortical thickness and vascular dysfunction in the patients with HCHWA-D (ρ=-0•58, p=0•003) or sporadic CAA (r=-0•4, p=0•015), but not in controls. Vascular dysfunction was identifi ed as a mediator of the eff ect of hereditary CAA on cortical atrophy, accounting for 63% of the total eff ect. Interpretation The appearance of cortical thinning in patients with HCHWA-D indicates that vascular amyloid is an independent contributor to cortical atrophy. These results were reproduced in patients with the more common sporadic CAA. Our fi ndings also suggest that CAA-related cortical atrophy is at least partly mediated by vascular dysfunction. Our results also support the view that small vessel diseases such as CAA can cause cortical atrophy even in the absence of Alzheimer's disease, a conclusion that can help radiologists, neurologists, and other clinicians who diagnose these common geriatric conditions. Funding National Institutes of Health.
Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease
NeuroImage: Clinical, 2020
Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the youngeronset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (n ADRC = 381; n DIAN = 145), preclinical (n ADRC = 153; n DIAN = 76), and cognitively impaired (n ADRC = 54; n DIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11 C-Pittsburgh compound B or 18 F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.
Dementia and geriatric cognitive disorders extra, 2014
Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuoperceptual dysfunction and praxis declines. This syndrome is related to a number of underlying diseases, including, in most cases, Alzheimer's disease (AD). The aim of this study was to compare the amyloid load with (18)F-AV45 positron emission tomography (PET) between PCA and AD subjects. We performed (18)F-AV45 PET, cerebrospinal fluid (CSF) biomarker analysis and a neuropsychological assessment in 11 PCA patients and 12 AD patients. The global and regional (18)F-AV45 uptake was similar in the PCA and AD groups. No significant correlation was observed between global (18)F-AV45 uptake and CSF biomarkers or between regional (18)F-AV45 uptake and cognitive and affective symptoms. This (18)F-AV45 PET amyloid imaging study showed no specific regional pattern of cortical (18)F-AV45 binding in PCA patients. These results confirm that a distinct clinical phenotype in amnestic AD and PCA is not related t...
Journal of Cerebral Blood Flow & Metabolism, 2014
White matter hyperintensities (WMHs) and lacunes are magnetic resonance imaging hallmarks of cerebral small-vessel disease, which increase the risk of stroke, cognitive, and mobility impairment. Although most studies of cerebral small-vessel disease have focused on white matter abnormalities, the gray matter (GM) is also affected, as evidenced by frequently observed lacunes in subcortical GM. Diffusion tensor imaging (DTI) is sensitive to subtle neurodegenerative changes in deep GM structures. We explored the relationship between baseline DTI characteristics of the thalamus, caudate, and putamen, and the volume and subsequent accrual of WMHs over a 4-year period in 56 community-dwelling older (≤75 years) individuals. Baseline thalamic fractional anisotropy (FA) was an independent predictor of WMH accrual. WMH accrual also correlated with baseline lacune count and baseline WMH volume, the latter showing the strongest predictive power, explaining 27.3% of the variance. The addition of...
Neuropathologic basis of age-associated brain atrophy
2013
Importance: While brain volume changes are used as surrogate markers for Alzheimer disease neuropathology in clinical studies, the extent to which these changes are due to pathologic features of Alzheimer disease in the aging brain is not well established. This study aims to clarify the neuropathologic correlates of longitudinal brain atrophy.