Past antihypertensive medication use is associated with lower levels of small vessel disease and lower Aß plaque stage in the brains of older individuals.

AIMS: This study assesses the association of antihypertensive medication use on the severities of neuropathological cerebrovascular disease (CVD excluding lobar infarction) in older individuals. METHODS: Clinical and neuropathological data were retrieved for 149 autopsy cases >75 years old with or without CVD or Alzheimer's disease and no other neuropathological diagnoses. Clinical data included hypertension status, hypertension diagnosis, antihypertensive medication use, antihypertensive medication dose (where available) and clinical dementia rating (CDR). Neuropathological CVD severity was evaluated for differences with anti-hypertensive medication usage. RESULTS: Antihypertensive medication use was associated with less severe white matter small vessel disease (SVD, mainly perivascular dilatation and rarefaction), with a 5.6-14.4 times greater likelihood of less severe SVD if medicated. No significant relationship was detected between infarction (presence, type, number and size), lacunes or cerebral amyloid angiopathy and antihypertensive medication use. Only increased white matter rarefaction/oedema and not perivascular dilation was associated with Alzheimer's pathology, with a 4.3 times greater likelihood of reduced Aß progression through the brain if white matter rarefaction severity was none or mild. Antihypertensive medication use was associated with reduced Aß progression but only in those with moderate to severe white matter SVD. CONCLUSIONS: This histopathological study provides further evidence that antihypertensive medication use in older individuals is associated with white matter SVD and not with other CVD pathologies. This is mainly due to a reduction in white matter perivascular dilation and rarefaction/oedema. Even in those with moderate to severe white matter SVD, antihypertensive medication use reduced rarefaction and Aß propagation through the brain.

Quality Output Checklist and Content Assessment (QuOCCA): a new tool for assessing research quality and reproducibility.

Research must be well designed, properly conducted and clearly and transparently reported. Our independent medical research institute wanted a simple, generic tool to assess the quality of the research conducted by its researchers, with the goal of identifying areas that could be improved through targeted educational activities. Unfortunately, none was available, thus we devised our own. Here, we report development of the Quality Output Checklist and Content Assessment (QuOCCA), and its application to publications from our institute's scientists. Following consensus meetings and external review by statistical and methodological experts, 11 items were selected for the final version of the QuOCCA: research transparency (items 1-3), research design and analysis (items 4-6) and research reporting practices (items 7-11). Five pairs of raters assessed all 231 articles published in 2017 and 221 in 2018 by researchers at our institute. Overall, the results were similar between years and revealed limited engagement with several recommended practices highlighted in the QuOCCA. These results will be useful to guide educational initiatives and their effectiveness. The QuOCCA is brief and focuses on broadly applicable and relevant concepts to open, high-quality, reproducible and well-reported science. Thus, the QuOCCA could be used by other biomedical institutions and individual researchers to evaluate research publications, assess changes in research practice over time and guide the discussion about high-quality, open science. Given its generic nature, the QuOCCA may also be useful in other research disciplines.

Chronic Traumatic Encephalopathy in a Routine Neuropathology Service in Australia.

Chronic traumatic encephalopathy (CTE) is a neuropathological diagnosis defined by a unique pattern of hyperphosphorylated tau (p-tau) accumulation that begins in neocortical regions of the brain. It is associated with a range of neuropsychological symptoms, but a definitive diagnosis can only be made by postmortem brain examination. In 2018, we instituted CTE screening for all autopsy brains as part of our routine departmental protocol by performing p-tau immunohistochemistry on a restricted set of 3 neocortical blocks (frontal, temporal, and parietal). This strategy allowed us to identify 4 cases of low-stage CTE from 180 consecutive autopsies. Two of the 4 cases had a documented history of brain injury; for the remaining 2 cases, there was a long history of treatment-resistant tonic/clonic epilepsy suggesting that undocumented brain injuries may have occurred. Our experience indicates that 3-block CTE screening is useful in identifying CTE in routine practice. The results of this study further support the association between prior head injuries and CTE and demonstrate that, albeit uncommon, CTE does occur in the general population. Our findings suggest that p-tau screening should be routinely pursued in brain autopsy, particularly where there is a documented or likely history of traumatic brain injury.

Chronic Traumatic Encephalopathy as a Preventable Environmental Disease.

In this Perspective we explore the evolution of our understanding of chronic traumatic encephalopathy (CTE) and its relationship with repetitive head injury. As with many neurodegenerative conditions, there is an imperfect correspondence between neuropathology and clinical phenotype, but unlike other neurodegenerative diseases, CTE has a discrete and easily modifiable risk factor: exposure to repetitive head injury. Consequently, evaluation of the evidence regarding exposure to repetitive head injury and CTE risk should be undertaken using public or occupational health frameworks of medical knowledge. The current debate over the existence of CTE as a disease of concern is fuelled in part by immediate medico-legal considerations, and the involvement of high-profile athletes, with inevitable media interest. Moving beyond this debate has significant potential to address and reduce disease impact in the near future, and provide novel insights into mechanisms underlying abnormal protein accumulation in CTE and other neurodegenerative diseases.

A Practical Approach to Differentiate the Frontotemporal Tauopathy Subtypes.

This study proposes a practical approach, using the minimum number of brain regions and stains, to consolidate previously published neuropathological criteria into one operationalized schema to differentiate subtypes of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau). This approach uses the superior frontal and precentral cortices and hippocampus stained for phosphorylated-tau, p62 and modified Bielschowsky silver, and the midbrain stained only for modified Bielschowsky silver. Accuracy of interrater reliability was determined by 10 raters in 24 FTLD-tau cases (Pick disease = 4, corticobasal degeneration = 9, progressive supranuclear palsy = 5, globular glial tauopathy = 6) including 4 with a mutation in MAPT collected with consent by Sydney Brain Bank. All brain regions and stains assessed proved informative for accurate pathological subtyping, and many neuropathological features were identified as common across the FTLD-tau subtypes. By identifying subtype-specific neuropathological features in the sections selected, 10 independent observers assigned the cases to a FTLD-tau subtype with almost perfect agreement between raters, emphasizing the requirement for the assessment of subtype-specific features for the accurate subtyping of FTLD-tau. This study consolidates current consensus diagnostic criteria for classifying FTLD-tau subtypes with an efficient, simple and accurate approach that can be implemented in future clinicopathological studies.

Antihypertensive medications ameliorate Alzheimer's disease pathology by slowing its propagation.

INTRODUCTION: Mounting evidence supports an association between antihypertensive medication use and reduced risk of Alzheimer's disease (AD). Consensus on possible pathological mechanisms remains elusive. METHODS: Human brain tissue from a cohort followed to autopsy that included 96 cases of AD (46 medicated for hypertension) and 53 pathological controls (33 also medicated) matched for cerebrovascular disease was available from the New South Wales Brain Banks. Quantified frontal cortex amyloid beta (Aß) and tau proteins plus Alzheimer's neuropathologic change scores were analyzed. RESULTS: Univariate analyses found no difference in amounts of AD proteins in the frontal cortex between medication users, but multivariate analyses showed that antihypertensive medication use was associated with a less extensive spread of AD proteins throughout the brain. DISCUSSION: The heterogeneous nature of the antihypertensive medications is consistent with downstream beneficial effects of blood pressure lowering and/or management being associated with the reduced spreading of AD pathology observed.

Alzheimer's amyloid-ß and tau protein accumulation is associated with decreased expression of the LDL receptor-associated protein in human brain tissue.

INTRODUCTION: One of the major neuropathological features of Alzheimer's disease (AD) is the accumulation of amyloid-ß (Aß) protein in the brain. Evidence suggests that the low-density lipoprotein receptor-associated protein (RAP) binds strongly to Aß and enhances its cellular uptake and that decreased RAP expression correlates with increased Aß production in animal models of AD. METHODS: The current study examined whether RAP levels change in AD human brain tissue and whether they are related to the amount of AD pathology. RAP and NeuN levels were determined by Western blot, while low-density lipoprotein receptor-related protein 1 (LRP1), tau and Aß levels were determined by ELISA in the temporal cortex of 17 AD and 16 control cases. RESULTS: An increase in total Aß and insoluble and soluble tau protein was observed in AD brain tissue. In contrast, RAP levels were significantly decreased in AD brain tissue compared to controls. Correlation analysis revealed that levels of RAP correlated with both total Aß and soluble and insoluble tau levels. Neither LRP1 nor NeuN levels were significantly altered in AD brain tissue homogenates and did not correlate with Aß or tau protein levels. CONCLUSION: Reduction in RAP may contribute to the accumulation and aggregation of Aß in the AD brain.

Intracellular and secreted forms of clusterin are elevated early in Alzheimer's disease and associate with both Aß and tau pathology.

Clusterin (CLU) is a pleiotropic glycoprotein that exists as a secreted, neuroprotective or intracellular, neurotoxic form, both of which increase in Alzheimer's disease (AD) causing increased Aß42 deposition. No studies have assessed the association between functionally distinct alloforms of CLU and tau protein or neuronal loss, despite its intracellular toxicity. We confirm previous reports of significant increases in both intracellular CLU and secreted CLU in the brain tissue of individuals with AD (p < 0.01) and show no association with neuronal loss. The increase in CLU alloforms was most closely associated with increases in both insoluble Aß42 and tau protein (p = 0.001), supporting its role in AD pathogenesis. Further research should investigate whether altering human CLU levels may have viability as a therapeutic option for AD.

Coexisting Lewy body disease and clinical parkinsonism in frontotemporal lobar degeneration.

OBJECTIVE: To investigate the prevalence of clinically relevant multiple system atrophy (MSA) and Lewy body disease (LBD) pathologies in a large frontotemporal lobar degeneration (FTLD) cohort to determine if concomitant pathologies underlie the heterogeneity of clinical features. METHODS: All prospectively followed FTLD-tau and FTLD-TDP cases held by the Sydney Brain Bank (n = 126) were screened for coexisting MSA and LBD (Braak ≥ stage IV) pathology. Relevant clinical (including family history) and genetic associations were determined. RESULTS: MSA pathology was not identified in this series. Of the FTLD cohort, 9 cases had coexisting LBD ≥ Braak stage IV and were associated with different FTLD subtypes including Pick disease (n = 2), corticobasal degeneration (n = 2), progressive supranuclear palsy (n = 2), and TDP type A (n = 3). All FTLD-TDP cases with coexisting LBD had mutations in progranulin (n = 2) or an abnormal repeat expansion in C9orf72 (n = 1). All FTLD-tau cases with coexisting LBD were sporadic. The H1H1 MAPT haplotype was found in all cases that could be genotyped (n = 6 of 9). Seven cases presented with a predominant dementia disorder, 3 of which developed parkinsonism. Two cases presented with a movement disorder and developed dementia in their disease course. The age at symptom onset (62 ± 11 years) and disease duration (8 ± 5 years) in FTLD cases with coexisting LBD did not differ from pure FTLD or pure LBD cases in the brain bank. CONCLUSION: Coexisting LBD in FTLD comprises a small proportion of cases but has implications for clinical and neuropathologic diagnoses and the identification of biomarkers.