Alzheimer's disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and amyloid-β. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterized pathologically by α-synuclein aggregates. HP-tau and amyloid-β can also occur as co-pathologies in LB dementia, and a diagnosis of mixedAD/DLB can be made if present in sufficient quantities. We hypothesized that the spread of these abnormal proteins selectively affects vulnerable areas, resulting in pathologic regional covariance that differentially associates with pre-mortem clinical characteristics. Our aims were to map regional quantitative pathology (HP-tau, amyloid-β, α-synuclein) and investigate the spatial distributions from tissue microarray post-mortem samples across healthy aging, AD and LB dementia. The study involved 159 clinico-pathologically diagnosed human post-mortem brains (48 controls, 47 AD, 25 DLB, 20 mixedAD/DLB, 19 PDD). The burden of HP-tau, amyloid-β and α-synuclein was quantitatively assessed in cortical and subcortical areas. Principal components (PC) analysis was applied across all cases to determine the pattern nature of HP-tau, amyloid-β and α-synuclein. Further analyses explored the relationships of these pathological patterns with cognitive and symptom variables. Cortical (tauPC1) and temporo-limbic (tauPC2) patterns were observed for HP-tau. For amyloid-β, a cortical-subcortical pattern (amylPC1) was identified. For α-synuclein, four patterns emerged: 'posterior temporal-occipital' (synPC1), 'anterior temporal-frontal' (synPC2), 'parieto-cingulate-insula' (synPC3), and 'frontostriatal-amygdala' (synPC4). Distinct synPC scores were apparent among DLB, mixedAD/DLB and PDD, and may relate to different spreading patterns of α-synuclein pathology. In dementia, cognitive measures correlated with tauPC1,tauPC2 and amylPC1 pattern scores (P ≤ 0.02), whereas such variables did not relate to α-synuclein parameters in these or combined LB dementia cases. Mediation analysis then revealed that in the presence of amylPC1, tauPC1 had a direct effect on global cognition in dementia (n = 65, P = 0.04), while tauPC1 mediated the relationship between amylPC1 and cognition through the indirect pathway (amylPC1 → tauPC1 → global cognition) (P < 0.05). Last, in synucleinopathies, synPC1 and synPC4 pattern scores were associated with visual hallucinations and motor impairment, respectively (P = 0.02). In conclusion, distinct patterns of α-synuclein pathology were apparent in LB dementia, which could explain some of the disease heterogeneity and differing spreading patterns among these conditions. Visual hallucinations and motor severity were associated with specific α-synuclein topographies in LB dementia that may be important to the clinical phenotype and could, after necessary testing/validation, be integrated into semiquantitative routine pathological assessment.

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. Nevertheless, despite the potential for non-plaque Aβ to contribute to tau pathology, few studies have examined relative correlative strengths between total Aβ, plaque Aβ and intracellular Aβ with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer’s disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of Aβ and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total Aβ and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between Aβ plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular Aβ was measured via the Aβ specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular Aβ may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and Aβ in controls, the robust correlative relationships observed suggest a physiological association of Aβ production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular Aβ, but not extracellular Aβ plaques.

The amyloid cascade hypothesis states that Aβ and its aggregates induce pathological changes in tau, leading to formation of neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the temporo-spatial divide between plaques and NFTs. This has been addressed by the inclusion of soluble species of Aβ and tau in the revised amyloid cascade hypothesis, however, the demonstration of a correlative relationship between Aβ and tau burden in post-mortem human tissue has remained elusive. Employing frozen and fixed frontal cortex grey and associated white matter tissue from non-AD controls (Con; n=39) and Alzheimer’s diseases (AD) cases (n=21), biochemical and immunohistochemical measures of Aβ and AT-8 phosphorylated tau were assessed. Native-state dot-blot from crude tissue lysates demonstrated robust correlations between intraregional Aβ and AT-8 tau, such increases in Aβ immunoreactivity conferred increases in AT-8 immunoreactivity, both when considered across the entire cohort as well as separately in Con and AD cases. In contrast, no such association between Aβ plaques and AT-8 were reported when using immunohistochemical measurements. However, when using the non-amyloid precursor protein cross reactive MOAB-2, antibody to measure intracellular Aβ within a subset of cases, a similar correlative relationship with AT-8 tau as that observed in biochemical analysis was observed. Collectively our data suggests that accumulating intracellular Aβ may influence AT-8 pathology. Despite the markedly lower levels of phospho-tau in non-AD controls correlative relationships between AT-8 phospho-tau and Aβ as measured in both biochemical and immunohistochemical assays were more robust in non-AD controls, suggesting a physiological association of Aβ production and tau phosphorylation, at least within the frontal cortex. Such interactions between regional Aβ load and phospho-tau load may become modified with disease potentially, as a consequence of interregional tau seed propagation, and thus may diminish the linear relationship observed between Aβ and phospho-tau in non-AD controls. This study provides evidence supportive of the revised amyloid cascade hypothesis, and demonstrates an associative relationship between AT-8 tau pathology and intracellular Aβ but not extracellular Aβ plaques.

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. DL methods trained on a consensus-of-two strategy yielded 12.6-26% improvements by area under the precision recall curve (AUPRC) when compared to those that learned individualized annotations. This strategy surpassed individual-expert models, even when unfairly assessed on benchmarks favoring them. Moreover, ensembling over individual models was robust to hidden random annotators. In blind prospective tests of 52,555 subsequent expert-annotated images, the models labeled pathologies like their human counterparts (consensus model AUPRC = 0.74 cored; 0.69 CAA). This study demonstrates a means to combine multiple ground truths into a common-ground DL model that yields consistent diagnoses informed by multiple and potentially variable expert opinions.

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. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

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. In this pilot study, we used human post-mortem brain tissue to investigate the composition and aetiology of frontal WML from AD and non-demented controls to determine if frontal WML are SVD-associated and to reveal any regional differences in the pathogenesis of WML. Frontal WML tissue sections from 40 human post-mortem brains (AD, n = 19; controls, n = 21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) burden, and arteriolosclerosis as a measure of SVD. Biochemical assessment included Wallerian degeneration-associated protease calpain and the myelin-associated glycoprotein to proteolipid protein ratio as a measure of ante-mortem ischaemia. Arteriolosclerosis severity was found to be associated with and a significant predictor of frontal WML severity in both AD and non-demented controls. Interesting, frontal axonal loss was also associated with HPτ and calpain levels were associated with increasing Aβ burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may result from both increased arteriolosclerosis and AD-associated degenerative changes. These preliminary findings in combination with previously published data tentatively indicate regional differences in the aetiology of WML in AD, which should be considered in the clinical diagnosis of dementia subtypes: posterior WML maybe associated with degenerative mechanisms secondary to AD pathology, while anterior WML could be associated with both SVD-associated and degenerative mechanisms.

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., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., “absent” vs. “present”) and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff’s α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff’s α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.

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.

AbstractBackgroundUsing the UK's Brains for Dementia Research (BDR) program, we investigated the frequency of neuropathological dementia diagnosis, the proportion of pure, mixed or concomitant pathologies and the pathological substrates for cognitive impairment.MethodAll cases (n = 673) underwent standardised neuropathological assessment outlined in [1]. Cases were classed as ‘pure’, ‘mixed’ or ‘concomitant’. 473 cases had clinical dementia rating (CDR) scores: binary linear regression was employed to estimate the odds of increasing CDR score due to the presence of pathologies and multiple pathologies.Result142 cases (21.1%) were diagnosed as controls and 531 fulfilled the criteria for a neurodegenerative disease: Alzheimer’s disease (n = 221) > Lewy body disease (n = 65) > vascular dementia (n = 50). Only 23.5% were classified as ‘pure’, 63.1% as ‘concomitant’ and 13.4% as ‘mixed’. 147 (28.9%) had no cognitive impairment and 301 had dementia. Higher burdens of hyperphosphorylated‐ τ (Hpτ), amyloid‐β and α‐synuclein burden had a three‐fold increase on the risk of being demented (OR = <3.4; 95% CI 2.1, 5.5). Regarding the conversion from mild cognitive impairment to dementia, Hpτ had a two‐fold increase on risk (OR = 1.75; 95% CI 1.16, 2.6) and the presence of multiple pathologies had a nine‐fold increase on risk (OR = 8.8; 95% CI 3.19, 24.3).ConclusionThe majority of the BDR cohort contains multiple pathologies. Increasing burden of Hpτ and multiple pathologies greatly increases the odds of dementia. (1) Francis et al, (2018) DOI 10.3233/JAD‐180699.

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is present in approximately 57% of Alzheimer’s disease (AD) cases and is associated with accelerated cognitive decline and accelerated disease progression. Hyperphosphorylated tau (HP‐τ) burden in AD is associated with cognitive deficits; it is unknown if LATE‐NC is associated with HP‐τ burden. In post‐mortem AD cases, we investigated the association between LATE‐NC and early and late HP‐τ and the impact of LATE‐NC on clinical measures of cognition.Method46 AD cases underwent neuropathological assessment for LATE‐NC [1] and quantitative assessment for early conformational HP‐τ (MC‐1) and intermediate/late stage HP‐τ (AT8) in the frontal, entorhinal, temporal, parietal and occipital cortices. Cognitive decline (n=20) was calculated from longitudinal mini‐Mental State Examination (MMSE; n =37).Result29 cases (63%) exhibited LATE‐NC (AD+). No significant differences in AT8 were revealed, however, observationally, AT8 was higher in all regions of AD+ cases. MC‐1 burden was significantly lower in the entorhinal cortex (P<0.05), and observational lower in all regions in the AD+ cases. No association between MC‐1 or AT8 with LATE‐NC score were revealed. MMSE score and cognitive decline was not significantly different between AD+ and AD‐ groups (both P>0.9) and linear regression revealed no influence of LATE‐NC on cognitive scores.ConclusionAD+ cases exhibit lower burden of MC‐1 and higher burden of AT8 pathology indicating possible advanced progression of the disease compared to AD‐ cases. The presence of LATE‐NC is not associated with differences in cognitive scores in AD. (1) Nelson et al (2019) doi:10.1093/brain/awz099.

Cellular senescence, the irreversible arrest of the cell cycle, is a common occurrence in ageing. Astrocytes have been shown to demonstrate a senescent phenotype, which is increased in ageing, and in Alzheimer’s disease (AD) (as evidenced by p16INK4a expression). Recently, a causal link was established between p16INK4a expression and hyperphosphorylated tau (HPT) pathology in the MAPTP301SPS19 mouse model of tauopathy, where treatment with a senolytic agent removed senescent p16INK4a positive astrocytes, prevented aggregation of HPT, and preserved cognitive function, suggesting senescent astrocytes may play a role in HPT deposition observed in AD. However, data in human post‐mortem tissue from AD cases (inclusive of Aβ pathology) is lacking.

AbstractBackgroundCerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries and arterioles of the white matter (WM) resulting in ischemic WM damage. Few studies have compared SVD between different cohorts. Using a sclerotic index (SI) measurement, we quantitatively assessed vessel wall fibrosis in the frontal and parietal WM of human brains donated to brain banks in the UK and the USA.Method64 cases from the University of California Davis (UCD) Alzheimer’s Disease Centre Biorepository and 55 cases from the Newcastle Brain and Tissue resource (NBTR) were included. Cases were neuropathological diagnosed as controls (UCD n=18; NBTR n=25), intermediate Alzheimer’s disease (AD) neuropathologic change (UCD n=13; NBTR n=4), and definite AD (UCD n=33; NBTR n = 26). In the UCD cohort, 49 identified racially as White, 9 as Black African American, 3 as Chinese and 1 as Indian Asian. All cases from the NBTR identified racially as White. Using H&E sections, images of approximately eight arteries/arterioles from the frontal and parietal WM were captured and SI assessment performed. Mean SI score was calculated per region, per cases.ResultNo intergroup differences in age were observed and age was not associated with SI score in either cohort. In the UCD cohort, race was not associated with neuropathological diagnosis (Chi‐sq = 8.39, p>0.211) and no differences were seen in SI scores between White and Black African Americans (p>0.69). Intergroup comparisons revealed that SI scores in both WM regions were significantly higher in the overall UCD cohort compared to the overall NBTR cohort (p>0.006) and this was consistent across controls (frontal p=0.0001; parietal p=0.045), intermediate AD neuropathological change (p=0.001), and AD (frontal p=0.001) cases.ConclusionSVD‐associated vessel occlusion is more severe in the USA cohort from Sacramento compared to the UK cohort from Newcastle. This may reflect differences in cardiovascular disease and lifestyle of individuals enrolled in the two brain donation programmes.

Aims Galanin is a highly inducible neuroprotective neuropeptide and in Alzheimer’s disease (AD), a network of galaninergic fibres has been reported to hypertrophy and hyperinnervate the surviving cholinergic neurons in the basal forebrain. We aimed to determine (i) the extent of galanin hyperinnervation in patients with AD and Lewy body disease and (ii) whether galanin expression relates to the neuropathological burden and cholinergic losses. Methods Galanin immunohistochemistry was carried out in the anterior nucleus basalis of Meynert of 27 Parkinson’s disease (PD) cases without cognitive impairment (mild cognitive impairment [MCI]), 15 with PD with MCI, 42 with Parkinson’s disease dementia (PDD), 12 with Dementia with Lewy bodies (DLB), 19 with AD, 12 mixed AD/DLB and 16 controls. Galaninergic innervation of cholinergic neurons was scored semiquantitatively. For a subgroup of cases ( n = 60), cholinergic losses were determined from maximum densities of choline acetyltransferase positive (ChAT+ve) neurons and their projection fibres. Quantitative data for α‐synuclein, amyloid beta and tau pathology were obtained from tissue microarrays covering cortical/subcortical regions. Results Significant losses of cholinergic neurons and their projection fibres were observed across all diseases. Galaninergic hyperinnervation was infrequent and particularly uncommon in established AD and DLB. We found that hyperinnervation frequencies are significantly higher in the transition between PD without MCI to PDD and that higher burdens of co‐existent AD pathology impair this galaninergic response. Conclusions Our results suggest that galanin upregulation represents an intrinsic response early in Lewy body diseases but which fails with increasing burdens of AD related pathology.

AbstractBackgroundCerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries (lipohyalinosis) and arterioles (arteriolosclerosis) of the white matter (WM) resulting in ischemic WM damage. SVD is commonly assessed using a broad semi‐quantitative (SQ) criterion. We implemented sclerotic index (SI) assessment to quantitatively assess vessel wall thickness in small arteries and arterioles separately in four regions known to exhibit WM changes.MethodThe cohort consisted of 75 cases from the University of California Davis Alzheimer’s Disease Centre Biorepository, neuropathological diagnosed as controls (n=18), intermediate Alzheimer’s disease neuropathologic change (n=13), definite Alzheimer’s disease (n=33), or cerebrovascular disease (n=11). H&E sections that included frontal and parietal WM, genu, or splenium were SQ assessed for SVD and images of small arteries (150‐800μm diameter) and arterioles (40‐150μm diameter) were captured. SI assessment was performed, and mean SI scores were calculated for arteries, arterioles, and an overall total.ResultAge was not associated with any SQ or SI measure in any region (p>0.106). SI and SQ scores of both arteries and arterioles were highly correlated in all regions (rho >0.551, p<0.0001) validating the SI method. Arteriole‐SI was significantly higher than artery‐SI in both WM regions (p<0.0001) and this was consistent cross controls and disease groups (all p<0.03). Regarding the whole cohort, frontal and parietal WM total‐SI was significantly higher than artery‐SI (P<0.0001) and significantly lower than arteriole‐SI (P<0.0001). Intragroup comparisons between frontal and parietal WM revealed no differences in artery‐ or arteriole‐SI scores (overall cohort p>0.76; subgroups p>0.112), and comparisons between genu and splenium also revealed no difference in arteriole‐SI (overall cohort p>0.41; subgroups p>0.34).ConclusionSVD‐associated vessel fibrosis is uniform between the anterior and posterior WM. Separate assessment of arteries and arterioles should be considered given arteriolosclerosis results in more severe vessel occlusion and maybe clinically relevant to ischemic WM changes. A combined SVD assessment may lead to under‐ or overestimation of disease severity.

Aims Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is present in approximately 50% of Alzheimer's disease (AD) cases and is associated with accelerated cognitive decline. Studies indicate a potential synergistic relationship between LATE-NC and hyperphosphorylated tau. It is unknown if LATE-NC is an independent driver of cognitive impairment or exerts its influence through synergistic relationships with tau. This cliniconeuropathological study investigated the impact of LATE-NC on quantified measures of AD-associated pathology and its impact on clinical measures. Methods A total of 61 AD cases underwent neuropathological assessment for LATE-NC and quantitative assessment [area covered by immunoreactivity (IR)] for early conformational tau (MC-1), late-stage hyperphosphorylated tau (AT8) and amyloid-beta in the amygdala and five neocortical regions. Clinical measures included age of disease onset, final Mini-Mental State Examination (MMSE) score and rate of cognitive decline. Results LATE-NC was present in 41 AD cases (AD/LATE-NC; 67.2%). No significant differences in MC-1-IR, AT8-IR or 4G8-IR were observed in any region between AD/LATE-NC and AD without LATE-NC, indicating no accelerated aggregation or hyperphosphorylation of tau proteins in the AD/LATE-NC cases. Final MMSE was significantly lower in AD/LATE-NC cases and was significantly associated with LATE-NC score even when controlled for the presence of both MC-1-IR and AT8-IR (P = 0.009). Conclusion The presence of LATE-NC in AD is not associated with an increase in the burden of early or late tau or A beta pathology. LATE-NC is associated with a lower final MMSE score independent of tau pathology.