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Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognized for its association with dementia. Aims: This study investigated clinical and neuropathological differences between DLB and PDD. Methods: 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. Results: CAA was more common in DLB than in PDD (P = 0.003). The severity of CAA was greater in DLB than in PDD (P = 0.009), with significantly higher CAA scores in the parietal lobe (P = 0.043), and the occipital lobe (P = 0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. Conclusions: This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD. [ABSTRACT FROM AUTHOR]

Aims: There is evidence that accumulation of α‐synuclein (α‐syn) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) results from impaired removal of α‐syn rather than its overproduction. Kallikrein‐6 (KLK6), calpain‐1 (CAPN1) and cathepsin‐D (CTSD) are among a small number of proteases that cleave α‐syn and are dysregulated in PD and DLB. Our aim in this study was to determine whether protease activity is altered in another α‐synucleinopathy, multiple system atrophy (MSA), and might thereby modulate the regional distribution of α‐syn accumulation. Methods: mRNA and protein level and/or activity of KLK6, CAPN1 and CTSD were measured and assessed in relation to α‐syn load in multiple brain regions (posterior frontal cortex, caudate nucleus, putamen, occipital cortex, pontine base and cerebellar white matter), in MSA (n = 20) and age‐matched postmortem control tissue (n = 20). Results: CTSD activity was elevated in MSA in the pontine base and cerebellar white matter. KLK6 and CAPN1 levels were elevated in MSA in the putamen and cerebellar white matter. However, the activity or level of these proteolytic enzymes did not correlate with the regional distribution of α‐syn. Conclusions: Accumulation of α‐syn in MSA is not due to reduced activity of the proteases we have studied. We suggest that their upregulation is likely to be a compensatory response to increased α‐syn in MSA. [ABSTRACT FROM AUTHOR]

Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in the tauopathies, which include Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Tau isoform composition and cellular and regional distribution as well as morphology of these inclusions vary in each disorder. Recently, several pathological missense and exon 10 splice-donor site mutations of the tau gene were iden-tified in FTDP-17. Exon 10 codes for the second of four microtubule-binding repeat domains. The splice-site mutations result in increased inclusion of exon 10 which causes a relative increase in tau isoforms containing four microtubule-binding repeat domains over those containing three repeat domains. This could be a central aetiological mechanism in FTDP-17 and, perhaps, other related tauopathies. We have investigated changes in the ratio and distribution of three-repeat and four-repeat tau in the different tauopathies as a basis of the phenotypic range of these disorders and the selective vulnerability of different subsets of neurones. In this study, we have developed two monoclonal antibodies, RD3 and RD4 that effectively distinguish these closely related tau isoforms. These new isoform-specific antibodies are useful tools for analysing tau isoform expression and distribution as well as pathological changes in the human brain. [ABSTRACT FROM AUTHOR]