Lewy bodies and neuronal loss in subcortical areas and disability in non-demented older people: a population based neuropathological cohort study.

BACKGROUND: Functional disability, the loss of ability to carry out daily tasks unaided, is a major adverse outcome more common with increasing age. The potential contribution of neuropathological changes in subcortical areas of the brain associated with normal ageing may be a contributing factor to this loss of function. This study investigates the clinicopathological relationship between functional ability during life and pathological correlates identified at post mortem in an UK population of older people (66-102 years).The aim is to examine the clinicopathological correlates of functional disability in subcortical neuronal populations of non-demented elderly individuals. METHODS: 156 non-demented participants in the brain donation programme of the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) were included in this study. Neuropathological examination was based on the CERAD protocol; pathologies of interest were amyloid plaques, neurofibrillary tangles, Lewy bodies, vascular disease and neuronal loss. Self-reported functional ability was scored according to a combined activities of daily living and instrumental activities of daily living scale. RESULTS: Functional disability was equally common in men and women over 65 years, and in both sexes disability was more common at older ages. Neuronal loss in several subcortical regions elevated the risk of functional disability by three-fold (95% CI 1.3-6.6). There was evidence for a relationship between Lewy bodies in the SN and functional disability. CONCLUSION: Neuronal loss in subcortical regions is associated with functional disability in the older population. The causal relationships are not defined and require further investigation

62nd Meeting of the French Society of Neuropathology - Meeting Abstracts , December 4th. 2020

The French Society of Neuropathology was created in 1989, succeeding the French Club of Neuropathology set up in 1965. The Society organizes two scientific meetings per year

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology

Microinfarcts in an older population-representative brain donor cohort (MRC CFAS): Prevalence, relation to dementia and mobility, and implications for the evaluation of cerebral Small Vessel Disease.

INTRODUCTION: Microinfarcts, small ischaemic foci common in ageing brain, are associated with dementia and gait dysfunction. We determined their relationship with dementia, mobility and cerebrovascular disease in an older population-representative brain donor cohort. These data on microinfarcts were evaluated in relation to pathological assessments of clinically significant cerebral small vessel disease (SVD). METHODS: Microinfarcts were assessed in the MRC Cognitive Function and Ageing Study (n = 331). Nine brain areas were staged according to the number of areas affected. RESULTS: 36% of brains showed at least 1 microinfarct. Higher cortical microinfarct stage was associated with dementia at death (OR 1.41, 95% CI 1.02; 1.96, P = 0.038), whilst cortical and subcortical microinfarct stages were associated with impaired mobility (OR 1.36, 95% CI 1.05-1.74; P 0.018) and falls (OR 1.96, 95% CI 1.11-3.43; P = 0.02). Adding data on microinfarcts to a definition of SVD, based on white matter lesions (WMLs), lacunes and significant arteriosclerosis, were assessed by comparing area under ROC curve (AUC) with and without microinfarcts. SVD was significantly related to dementia status with or without inclusion of microinfarcts. Modelling potential pathological definitions of SVD to predict dementia or impaired mobility indicated optimal prediction using combined assessment of WMLs, lacunes and microinfarcts. CONCLUSION: Cortical (dementia) and subcortical microinfarcts (impaired mobility) are related to diverse clinical outcomes. Optimal pathological assessment of significant SVD in brain ageing is achieved based on WMLs, lacunes and microinfarcts and may not require subjective assessment of the extent and severity of arteriosclerosis

Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise

Corrected by: Erratum: Molecular Psychiatry (2016) 21, 1645–1645; doi:10.1038/mp.2016.57; published online 19 April 2016. Following publication of the above article, the authors noticed that the second author’s name was presented incorrectly. The author’s name should have appeared as M Fiatarone Singh. The publisher regrets the error.Physical and cognitive exercise may prevent or delay dementia in later life but the neural mechanisms underlying these therapeutic benefits are largely unknown. We examined structural and functional magnetic resonance imaging (MRI) brain changes after 6 months of progressive resistance training (PRT), computerized cognitive training (CCT) or combined intervention. A total of 100 older individuals (68 females, average age=70.1, s.d.±6.7, 55-87 years) with dementia prodrome mild cognitive impairment were recruited in the SMART (Study of Mental Activity and Resistance Training) Trial. Participants were randomly assigned into four intervention groups: PRT+CCT, PRT+SHAM CCT, CCT+SHAM PRT and double SHAM. Multimodal MRI was conducted at baseline and at 6 months of follow-up (immediately after training) to measure structural and spontaneous functional changes in the brain, with a focus on the hippocampus and posterior cingulate regions. Participants' cognitive changes were also assessed before and after training. We found that PRT but not CCT significantly improved global cognition (F(90)=4.1, P<0.05) as well as expanded gray matter in the posterior cingulate (Pcorrected <0.05), and these changes were related to each other (r=0.25, P=0.03). PRT also reversed progression of white matter hyperintensities, a biomarker of cerebrovascular disease, in several brain areas. In contrast, CCT but not PRT attenuated decline in overall memory performance (F(90)=5.7, P<0.02), mediated by enhanced functional connectivity between the hippocampus and superior frontal cortex. Our findings indicate that physical and cognitive training depend on discrete neuronal mechanisms for their therapeutic efficacy, information that may help develop targeted lifestyle-based preventative strategies.Molecular Psychiatry advance online publication, 22 March 2016; doi:10.1038/mp.2016.19.C Suo, M Fiatarone Singh, N Gates, W Wen, P Sachdev, H Brodaty, N Saigal, GC Wilson, J Meiklejohn, N Singh, BT Baune, M Baker, N Foroughi, Y Wang, Y Mavros, A Lampit, I Leung, and MJ Valenzuel

Neuropathological correlates of falling in the CC75C population-based sample of the older old.

BACKGROUND: Previous imaging studies have suggested links between brain pathologies and factors that are associated with falls such as gait, balance and daily function. Possible neuropathological correlates of older people's falls have been suggested based on brain imaging studies, but to date none have been examined in brain tissue. METHODS: Falls data collected from repeated surveys of a population-based cohort of individuals aged at least 75 years old at baseline were related to neuropathological data collected from post-mortem examination of the study's associated brain donor collection (n=212). RESULTS: Amongst people without dementia, most cerebrovascular neuropathological features examined, particularly white matter pallor, microinfarcts and microscopic atherosclerosis, were increasingly common across the subgroups categorised by no reports of falling, only one or at least two reports of falling. The overall burden of pathology was greater in those with dementia, but only microinfarcts showed a similar increase with respect to reported falling status. CONCLUSIONS: Subclinical pathologies sharing a common vascular origin are associated with increased falling amongst people with no dementia, as are microinfarcts in those with dementia. Although further research is needed to address the mechanisms of falls and their neuropathological correlates, the findings from the current study would suggest that if cerebrovascular disease prevention reduces vascular neuropathology changes this may have direct benefits in reducing falls amongst older people with or without dementia