Progressive White Matter Injury in Preclinical Dutch Cerebral Amyloid Angiopathy.

Autosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D-CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D-CAA carriers and non-carriers, we observed divergence of white matter injury measures between D-CAA carriers and non-carriers prior to the appearance of cerebral microbleeds and >14 years before the average age of first symptomatic hemorrhage. These results indicate that white matter disruption measures may be valuable cross-sectional and longitudinal biomarkers of D-CAA progression. ANN NEUROL 2022;92:358-363.

Manual segmentation qualification platform for the EADC-ADNI harmonized protocol for hippocampal segmentation project.

BACKGROUND: The use of hippocampal volumetry as a biomarker for Alzheimer's disease (AD) requires that tracers from different laboratories comply with the same segmentation method. Here we present a platform for training and qualifying new tracers to perform the manual segmentation of the hippocampus on magnetic resonance images (MRI) following the European Alzheimer's Disease Consortium and Alzheimer's Disease Neuroimaging Initiative (EADC-ADNI) Harmonized Protocol (HarP). Our objective was to demonstrate that the training process embedded in the platform leads to increased compliance and qualification with the HarP. METHOD: Thirteen new tracers' segmentations were compared with benchmark images with respect to: (a) absolute segmentation volume; (b) spatial overlap of contour with the reference using the Jaccard similarity index; and (c) spatial distance of contour with the reference. Point by point visual feedback was provided through three training phases on 10 MRI. Tracers were then tested on 10 different MRIs in the qualification phase. RESULTS: Statistical testing of training over three phases showed a significant increase of Jaccard (i.e. mean Jaccard overlap P < .001) between phases on average for all raters, demonstrating that training positively increased compliance with the HarP. Based on these results we defined qualification thresholds which all tracers were able to meet. CONCLUSIONS: This platform is an adequate infrastructure allowing standardized training and evaluation of tracers' compliance with the HarP. This is a necessary step allowing the use of hippocampal volumetry as a biomarker for AD in clinical and research centers.

Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly.

Our primary objective was to investigate a biomarker driven model for the interrelationships between vascular disease pathology, amyloid pathology, and longitudinal cognitive decline in cognitively normal elderly subjects between 70 and 90 years of age. Our secondary objective was to investigate the beneficial effect of cognitive reserve on these interrelationships. We used brain amyloid-ß load measured using Pittsburgh compound B positron emission tomography as a marker for amyloid pathology. White matter hyperintensities and brain infarcts were measured using fluid-attenuated inversion recovery magnetic resonance imaging as a marker for vascular pathology. We studied 393 cognitively normal elderly participants in the population-based Mayo Clinic Study of Aging who had a baseline 3 T fluid-attenuated inversion recovery magnetic resonance imaging assessment, Pittsburgh compound B positron emission tomography scan, baseline cognitive assessment, lifestyle measures, and at least one additional clinical follow-up. We classified subjects as being on the amyloid pathway if they had a global cortical amyloid-ß load of ≥1.5 standard uptake value ratio and those on the vascular pathway if they had a brain infarct and/or white matter hyperintensities load ≥1.11% of total intracranial volume (which corresponds to the top 25% of white matter hyperintensities in an independent non-demented sample). We used a global cognitive z-score as a measure of cognition. We found no evidence that the presence or absence of vascular pathology influenced the presence or absence of amyloid pathology and vice versa, suggesting that the two processes seem to be independent. Baseline cognitive performance was lower in older individuals, in males, those with lower education/occupation, and those on the amyloid pathway. The rate of cognitive decline was higher in older individuals (P < 0.001) and those with amyloid (P = 0.0003) or vascular (P = 0.0037) pathologies. In those subjects with both vascular and amyloid pathologies, the effect of both pathologies on cognition was additive and not synergistic. For a 79-year-old subject, the predicted annual rate of global z-score decline was -0.02 if on neither pathway, -0.07 if on the vascular pathway, -0.08 if on the amyloid pathway and -0.13 if on both pathways. The main conclusions of this study were: (i) amyloid and vascular pathologies seem to be at least partly independent processes that both affect longitudinal cognitive trajectories adversely and are major drivers of cognitive decline in the elderly; and (ii) cognitive reserve seems to offset the deleterious effect of both pathologies on the cognitive trajectories.

A quantitative postmortem MRI design sensitive to white matter hyperintensity differences and their relationship with underlying pathology.

White matter hyperintensities (WMHs) associate with both cognitive slowing and motor dysfunction in the neurologically normal elderly. A full understanding of the pathology underlying this clinicoradiologic finding is currently lacking in autopsy-confirmed normal brains. To determine the histopathologic basis of WMH seen on magnetic resonance imaging, we studied the relationship between postmortem fluid-attenuated inversion recovery (FLAIR) intensity and neuropathologic markers of WM lesions (WMLs) that correspond to WMH in cognitively normal aging brains. Samples of periventricular (n = 24), subcortical (n = 26), and normal-appearing WM (NAWM, n = 31) from 4clinically and pathologically confirmed normal cases were examined. The FLAIR intensity, vacuolation, and myelin basic protein immunoreactivity loss were significantly higher in periventricular WML versus subcortical WML; both were higher than in NAWM. The subcortical WML and NAWM had significantly less axonal loss, astrocytic burden, microglial density, and oligodendrocyte loss than those of the periventricular WML. Thus, vacuolation, myelin density, and small vessel density contribute to the rarefaction of WM, whereas axonal density, oligodendrocyte density, astroglial burden, and microglial density did not. These data suggest that the age-related loss of myelin basic protein and the decrease in small vessel density may contribute to vacuolation of WM. Vacuolation enables interstitial fluid to accumulate, which contributes to the prolonged T2 relaxation and elevated FLAIR intensity in the WM.

Functional impact of white matter hyperintensities in cognitively normal elderly subjects.

OBJECTIVE: To investigate the impact white matter hyperintensities (WMH) detected on magnetic resonance imaging have on motor dysfunction and cognitive impairment in elderly subjects without dementia. DESIGN: Cross-sectional study. SETTING: Population-based study on the incidence and prevalence of cognitive impairment in Olmsted County, Minnesota. PARTICIPANTS: A total of 148 elderly subjects (65 men) without dementia ranging in age from 73 to 91 years. MAIN OUTCOME MEASURES: We measured the percentage of the total white matter volume classified as WMH in a priori-defined brain regions (ie, frontal, temporal, parietal, occipital, periventricular, or subcortical). Motor impairment was evaluated qualitatively using the Unified Parkinson's Disease Rating Scale summary measures of motor skills and quantitatively using a digitized portable walkway system. Four cognitive domains were evaluated using z scores of memory, language, executive function, and visuospatial reasoning. RESULTS: A higher WMH proportion in all regions except the occipital lobe was associated with lower executive function z score (P value <.01). A higher WMH proportion in all regions, but most strongly for the parietal lobe, correlated with higher Unified Parkinson's Disease Rating Scale gait, posture, and postural stability sum (P value <.01). A higher WMH proportion, whether periventricular, subcortical, or lobar, correlated with reduced velocity (P value <.001). CONCLUSIONS: We conclude that executive function is the primary cognitive domain affected by WMH burden. The data suggest that WMH in the parietal lobe are chiefly responsible for reduced balance and postural support compared with the other 3 lobes and may alter integration of sensory information via parietal lobe dysfunction in the aging brain. Parietal white matter changes were not the predominant correlate with motor speed, lending evidence to a global involvement of neural networks in gait velocity.