Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This “disease signature” approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases.

The Cortical Signature of Alzheimer's Disease: Regionally Specific Cortical Thinning Relates to Symptom Severity in Very Mild to Mild AD Dementia and is Detectable in Asymptomatic Amyloid-Positive Individuals

Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway.

Glymphatic failure as a final common pathway to dementia.

Background: Magnetic resonance diffusion tensor imaging (DTI) shows promise in the early detection of microstructural pathophysiological changes in the brain. Objectives: To measure microstructural differences in the brains of participants with amnestic mild cognitive impairment (MCI) compared with an age-matched control group using an optimised DTI technique with fully automated image analysis tools and to investigate the correlation between diffusivity measurements and neuropsychological performance scores across groups. Methods: 34 participants (17 participants with MCI, 17 healthy elderly adults) underwent magnetic resonance imaging (MRI)-based DTI. To control for the effects of anatomical variation, diffusion images of all participants were registered to standard anatomical space. Significant statistical differences in diffusivity measurements between the two groups were determined on a pixel-by-pixel basis using gaussian random field theory. Results: Significantly raised mean diffusivity measurements (p<0.001) were observed in the left and right entorhinal cortices (BA28), posterior occipital-parietal cortex (BA18 and BA19), right parietal supramarginal gyrus (BA40) and right frontal precentral gyri (BA4 and BA6) in participants with MCI. With respect to fractional anisotropy, participants with MCI had significantly reduced measurements (p<0.001) in the limbic parahippocampal subgyral white matter, right thalamus and left posterior cingulate. Pearson's correlation coefficients calculated across all participants showed significant correlations between neuropsychological assessment scores and regional measurements of mean diffusivity and fractional anisotropy. Conclusions: DTI-based diffusivity measures may offer a sensitive method of detecting subtle microstructural brain changes associated with preclinical Alzheimer's disease.

Diffusion indices on magnetic resonance imaging and neuropsychological performance in amnestic mild cognitive impairment

people aged ≥ 65 years is projected to grow, the number of incident strokes in older adults is expected to rise, presenting major challenges for clinicians and policy makers in the foreseeable future. Aging and cerebral vasculature. The complex network of the adult brain vasculature measures approximately 370 miles, receives about 20% of total cardiac output, and exchanges 20% of total blood glucose and oxygen. With aging, both cerebral microand macro-circulations undergo structural and functional alterations. Age-related microcirculatory changes are presumably mediated by endothelial dys-function and impaired cerebral autoregulation and neurovascular coupling. Whereas endothelial dysfunc-tion promotes neuro-inflammation, impaired cerebral autoregulation may lead to microvascular injury, and impaired neurovascular coupling fosters a decline in cortical function, all potential targets for future therapeutic interventions. Aging, in otherwise healthy individuals, is associated with numerous noticeable changes in human intracranial and extracranial cerebral arteries that predict the risk of future stroke. Aging and silent cerebrovascular disease. Silent cerebrovascular disease represents structural abnormalities, presumed vascular etiology, on neuroimaging not supported by clinically recognized stroke symptoms. The prevalence of silent cerebrovascular disease increases with advancing age and is recognizable as the following parenchymal lesions: 1) Silent infarcts (silent strokes), prevalence 6% and 28%, exceeds symptomatic stroke by a ratio of 10:1, 2) white matter hyperintensity or hypodensity on neuroimaging represent microvascular disease occurring in 20% to 94% older adults, and 3) cerebral microbleeds indicate silent intracerebral hemorrhages in 38% of general population aged >80 years. These conditions are age dependent and forecast increased risk of future symptomatic strokes (Figure 1). Aging and stroke risk factors. A worldwide population-based study identified 10 risk factors that collectively account for 88% of the risk of stroke in all Editorial

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Aging and ischemic stroke.

Sports-related concussions have been shown to lead to persistent subclinical anomalies of the motor and cognitive systems in young asymptomatic athletes. In advancing age, these latent alterations correlate with detectable motor and cognitive function decline. Until now, the interacting effects of concussions and the normal ageing process on white matter tract integrity remain unknown. Here we used a tract-based spatial statistical method to uncover potential white matter tissue damage in 15 retired athletes with a history of concussions, free of comorbid medical conditions. We also investigated potential associations between white matter integrity and declines in cognitive and motor functions. Compared to an age- and education-matched control group of 15 retired athletes without concussions, former athletes with concussions exhibited widespread white matter anomalies along many major association, interhemispheric, and projection tracts. Group contrasts revealed decreases in fractional anisotropy, as well as increases in mean and radial diffusivity measures in the concussed group. These differences were primarily apparent in fronto-parietal networks as well as in the frontal aspect of the corpus callosum. The white matter anomalies uncovered in concussed athletes were significantly associated with a decline in episodic memory and lateral ventricle expansion. Finally, the expected association between frontal white matter integrity and motor learning found in former non-concussed athletes was absent in concussed participants. Together, these results show that advancing age in retired athletes presenting with a history of sports-related concussions is linked to diffuse white matter abnormalities that are consistent with the effects of traumatic axonal injury and exacerbated demyelination. These changes in white matter integrity might explain the cognitive and motor function declines documented in this population.

Diffuse white matter tract abnormalities in clinically normal ageing retired athletes with a history of sports-related concussions

While it is relatively widely known that cardiovascular disease (CVD) can result in cognitive decline, it is becoming increasingly clearer that actual risk factors for CVD, such as high blood pressure, diabetes, and obesity are also associated with alterations to brain structure and cognition. The prevalence of CVD risk factors increase exponentially with age and are often overlooked as a source of cognitive changes that are otherwise thought to be part of the 'normal' aging process. Associated cognitive changes are observed even at levels of risk that would be considered subclinical by current diagnostic convention, and are often significant enough to interfere with daily functional abilities. More importantly, if not controlled, CVD risk can lead to further decline, including cerebrovacsular disease and dementia. Thus, it is critically important to consider these factors in the elderly and we recommend more routine cognitive screenings, particularly when CVD risk factors are involved.

Cardiovascular Disease Risk Factors and Cognition in the Elderly.

Improved understanding of the pattern of white matter changes in early and prodromal Alzheimer's disease (AD) states such as mild cognitive impairment (MCI) is necessary to support earlier preclinical detection of AD, and debate remains whether white matter changes in MCI are secondary to gray matter changes. We applied neuropsychologically based MCI criteria to a sample of normally aging older adults; 32 participants met criteria for MCI and 81 participants were classified as normal control (NC) subjects. Whole-head high resolution T1 and diffusion tensor imaging scans were completed. Tract-Based Spatial Statistics was applied and a priori selected regions of interest were extracted. Hippocampal volume and cortical thickness averaged across regions with known vulnerability to AD were derived. Controlling for cortical thickness, the MCI group showed decreased average fractional anisotropy (FA) and decreased FA in parietal white matter and in white matter underlying the entorhinal and posterior cingulate cortices relative to the NC group. Statistically controlling for cortical thickness, medial temporal FA was related to memory and parietal FA was related to executive functioning. These results provide further support for the potential role of white matter integrity as an early biomarker for individuals at risk for AD and highlight that changes in white matter may be independent of gray matter changes. (JINS, 2013, 19, 1–13)

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Ida L. Kellison

Papers

Cardiovascular Disease Risk Factors and Cognition in the Elderly.

Decreased White Matter Integrity in Neuropsychologically Defined Mild Cognitive Impairment Is Independent of Cortical Thinning