Patterns of tau, amyloid and synuclein pathology in ageing, Alzheimer's disease and synucleinopathies.

Alzheimer's disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and β-amyloid. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterised pathologically by α-synuclein aggregates. HP-tau and β-amyloid can also occur as copathologies in LB dementia, and a diagnosis mixedAD/DLB can be made if present in sufficient quantities.

Regional AT-8 reactive tau species correlate with intracellular Aβ levels in cases of low AD neuropathologic change.

The amyloid cascade hypothesis states that Aβ aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aβ and tau species in the revised amyloid cascade hypothesis.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories.

Deep learning from multiple experts improves identification of amyloid neuropathologies.

Pathologists can label pathologies differently, making it challenging to yield consistent assessments in the absence of one ground truth. To address this problem, we present a deep learning (DL) approach that draws on a cohort of experts, weighs each contribution, and is robust to noisy labels. We collected 100,495 annotations on 20,099 candidate amyloid beta neuropathologies (cerebral amyloid angiopathy (CAA), and cored and diffuse plaques) from three institutions, independently annotated by five experts.

Frontal white matter lesions in Alzheimer's disease are associated with both small vessel disease and AD-associated cortical pathology.

Cerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer's disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving posterior white matter disruption, and both AD-associated degenerative and vascular mechanisms contributed to anterior matter disruption.

Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia.

Introduction: The aged brain frequently exhibits multiple pathologies, rather than a single hallmark pathology (pure pathology [PurP]), ranging from low/intermediate levels of additional pathology (LowP) to mixed severe pathology (mixed SevP). We investigated the frequency of PurP, LowP, and mixed SevP, and the impact of additional LowP on cognition.

Methods: Data came from 670 cases from the Brains for Dementia research program.

Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study.

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e.

Neuropsychiatric symptoms in limbic-predominant age-related TDP-43 encephalopathy and Alzheimer's disease.

There is clinical overlap between presentations of dementia due to limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer's disease. It has been suggested that the combination of Alzheimer's disease neuropathological change (ADNC) and LATE neuropathological changes (LATE-NC) is associated with greater neuropsychiatric symptom burden, compared to either pathology alone. Longitudinal Neuropsychiatric Inventory and psychotropic medication prescription data from neuropathologically diagnosed pure ADNC (n = 78), pure LATE-NC (n = 14) and mixed ADNC/LATE-NC (n = 39) brain bank donors were analysed using analysis of variance and linear mixed effects regression models to examine the relationship between diagnostic group and neuropsychiatric symptom burden.

Neurodegenerative Diseases and Ageing.

This chapter describes the main neuropathological features of the most common age associated neurodegenerative diseases including Alzheimer's disease, Lewy body diseases, vascular dementia and the various types of frontotemporal lobar degeneration. In addition, the more recent concepts of primary age-related tauopathy and ageing-related tau astrogliopathy as well as chronic traumatic encephalopathy are briefly described. One section is dedicated to cerebral multi-morbidity as it is becoming increasingly clear that the old brain is characterised by the presence of multiple pathologies (to varying extent) rather than by one single, disease specific pathology alone.

Extravascular fibrinogen in the white matter of Alzheimer's disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer's disease.

The blood-brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood-derived fibrinogen. Dysfunction of the BBB has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and white matter lesions (WML). Furthermore, BBB dysfunction is associated with the pathogenesis of Alzheimer's disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD.

Parietal white matter lesions in Alzheimer's disease are associated with cortical neurodegenerative pathology, but not with small vessel disease.

Cerebral white matter lesions (WML) encompass axonal loss and demyelination, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, WML may also result from the activation of Wallerian degeneration as a consequence of cortical Alzheimer's disease (AD) pathology, i.e.

Quantitative neuropathology: an update on automated methodologies and implications for large scale cohorts.

A tissue microarray (TMA) has previously been developed for use in assessment of neurodegenerative diseases. We investigated the variation of pathology loads in semi-quantitative score categories and how pathology load related to disease progression. Post-mortem tissue from 146 cases were used; Alzheimer's disease (AD) (n = 36), Lewy body disease (LBD) (n = 56), mixed AD/dementia with Lewy bodies (n = 14) and controls (n = 40).

TDP-43 pathology in Alzheimer's disease, dementia with Lewy bodies and ageing.

Intracellular inclusions consisting of TAR DNA binding protein-43 (TDP-43 pathology) are present in up to 57% of Alzheimer's disease (AD) cases and follow a distinct topographical pattern of progression described in the TDP-43 in AD staging scheme. This scheme has not been applied to the assessment of TDP-43 pathology in dementia with Lewy bodies (DLB) and aged controls. We investigated TDP-43 pathology prevalence and severity in AD, DLB, mixed AD/DLB (Mx AD/DLB) and aged controls.

Cortical tau load is associated with white matter hyperintensities.

Introduction: Cerebral white matter lesions (WML), visualized as white matter hyperintensities (WMH) on T2-weighted MRI, encompass structural damage and loss of integrity of the cerebral white matter (WM) and are commonly assumed to be associated with small vessel disease (SVD). However, it has been suggested that WM damage may also be the result of degenerative axonal loss that is secondary to cortical Alzheimer's disease (AD) pathologies i.e.

Neuropathologically mixed Alzheimer's and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes.

Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-β protein (Aβ) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer's disease (AD) and neocortical Lewy body disease (LBD) but clinically presented either as dementia due to AD or LBD, the latter including dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).