A unified 3D reconstruction of microscopy and MRI in a brain showing Alzheimer's disease-related neuropathology.

Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes

Alzheimer's disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer's disease biomarkers predict Alzheimer's neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer's disease neuropathological findings. This study included 720 participants, 42-91 years of age, who were enrolled in longitudinal studies of memory and aging in the Washington University Knight Alzheimer Disease Research Center and were cognitively normal at baseline, underwent amyloid PET imaging and/or CSF collection within 1 year of baseline clinical assessment, and had subsequent clinical follow-up. Cognitive status was assessed longitudinally by Clinical Dementia Rating®. Biomarker status was assessed using predefined cut-offs for amyloid PET imaging or CSF p-tau181/amyloid-β42. Subsequently, 57 participants died and underwent neuropathologic examination. Alzheimer's disease neuropathological changes were assessed using standard criteria. We assessed the predictive value of Alzheimer's disease biomarker status on progression to cognitive impairment and for presence of Alzheimer's disease neuropathological changes. Among cognitively normal participants with positive biomarkers, 34.4% developed cognitive impairment (Clinical Dementia Rating > 0) as compared to 8.4% of those with negative biomarkers. Cox proportional hazards modelling indicated that preclinical Alzheimer's disease biomarker status, APOE ɛ4 carrier status, polygenic risk score and centred age influenced risk of developing cognitive impairment. Among autopsied participants, 90.9% of biomarker-positive participants and 8.6% of biomarker-negative participants had Alzheimer's disease neuropathological changes. Sensitivity was 87.0%, specificity 94.1%, positive predictive value 90.9% and negative predictive value 91.4% for detection of Alzheimer's disease neuropathological changes by preclinical biomarkers. Single CSF and amyloid PET baseline biomarkers were also predictive of Alzheimer's disease neuropathological changes, as well as Thal phase and Braak stage of pathology at autopsy. Biomarker-negative participants who developed cognitive impairment were more likely to exhibit non-Alzheimer's disease pathology at autopsy. The detection of preclinical Alzheimer's disease biomarkers is strongly predictive of future cognitive impairment and accurately predicts presence of Alzheimer's disease neuropathology at autopsy.

Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both. We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD). Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8-31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2-17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2-6.6; p = 0.92). There was a highly significant trend test across groups (χ(2)(1) = 19.3; p = 1.1 × 10(-5)), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB. GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.

More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2(2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2(2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2(3) = 13.87, p = 0.003). Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.

Alzheimer's disease (AD) neuropathological changes (ADNC) are characterized by amyloid plaques and neurofibrillary tangles. The role of nitric oxide synthase (NOS) in disease progression remains unclear. This study investigates the expression of neural, inducible, and endothelial NOS (nNOS, iNOS, eNOS) and 3-nitrotyrosine (3-NT) in the hippocampal subregions of individuals with ADNC and their association with cognitive abilities. Immunohistochemistry was performed on hippocampal samples from 10 individuals with ADNC and 10 age- and sex-matched controls to detect NOS enzymes, and 3-NT expression in CA1, CA2, CA3, and CA4. Logistic ordinal regressions evaluated associations of NOS and 3-NT expression with AD pathology, while linear regressions assessed relationships with cognitive abilities. Overexpression of nNOS was observed in all hippocampal subregions in ADNC participants. iNOS expression was elevated in CA1 and CA3, while eNOS showed increased levels only in CA3. 3-NT was significantly higher in CA3 of ADNC participants. nNOS expression in all hippocampal regions correlated with AD pathology and cognitive impairment. iNOS in CA3 was associated with AD pathology and cognitive scores. No associations were found for eNOS, and 3-NT in CA3 correlated with cognitive impairment. Associations of nNOS and iNOS with neuropathology and cognition suggest a role for NOS in AD pathophysiology.

This study investigates the inter-related roles of hippocampal neuronal loss (HNL), limbic-predominant age-related TAR-DNA binding protein of 43 kDa (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and Alzheimer's disease neuropathologic changes (ADNC) on cognitive decline. Participants underwent annual cognitive testing and autopsy. HNL, ADNC, LATE-NC, and other age-related pathologies were evaluated. Regression and mixed-effects models examined the association of HNL with ADNC and LATE-NC, and separately with cognitive decline. Path analyses examined the extent to which associations of LATE-NC and ADNC with cognitive decline were attributable to HNL. LATE-NC was associated with more severe HNL, but ADNC was associated only after excluding subjects with hippocampal sclerosis (HS). HNL was associated with faster decline in global cognition and episodic, semantic, and working memory. In path analyses, about 61% of the association of LATE-NC with cognitive decline was attributable to HNL, whereas for ADNC it was mostly independent of HNL. HNL has an independent contribution to cognitive decline and acts as a major step in LATE-NC-related cognitive decline. Hippocampal neuronal loss (HNL) is associated with cognitive decline. HNL is a prominent feature of limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) and less so with Alzheimer's disease neuropathologic changes (ADNC). HNL acts as a major pathway in cognitive decline for LATE-NC. Differential mechanisms in hippocampal degeneration are associated with LATE-NC versus ADNC.

This study was undertaken to assess cross-sectional and longitudinal [18 F]-flortaucipir positron emission tomography (PET) uptake in pathologically confirmed frontotemporal lobar degeneration (FTLD) and to compare FTLD to cases with high and low levels of Alzheimer disease (AD) neuropathologic changes (ADNC). One hundred forty-three participants who had completed at least one flortaucipir PET and had autopsy-confirmed FTLD (n=52) or high (n=58) or low ADNC (n=33) based on Braak neurofibrillary tangle stages 0-IV versus V-VI were included. Flortaucipir standard uptake value ratios (SUVRs) were calculated for 9 regions of interest (ROIs): an FTLD meta-ROI, midbrain, globus pallidum, an AD meta-ROI, entorhinal, inferior temporal, orbitofrontal, precentral, and medial parietal. Linear mixed effects models were used to compare mean baseline SUVRs and annual rate of change in SUVR by group. Sensitivity and specificity to distinguish FTLD from high and low ADNC were calculated. Baseline uptake in the FTLD meta-ROI, midbrain, and globus pallidus was greater in FTLD than high and low ADNC. No region showed a greater rate of flortaucipir accumulation in FTLD. Baseline uptake in the AD-related regions and orbitofrontal and precentral cortices was greater in high ADNC, and all showed greater rates of accumulation compared to FTLD. Baseline differences were superior to longitudinal rates in differentiating FTLD from high and low ADNC. A simple baseline metric of midbrain/inferior temporal ratio of flortaucipir uptake provided good to excellent differentiation between FTLD and high and low ADNC (sensitivities/specificities=94%/95% and 71%/70%). There are cross-sectional and longitudinal differences in flortaucipir uptake between FTLD and high and low ADNC. However, optimum differentiation between FTLD and ADNC was achieved with baseline uptake rather than longitudinal rates. ANN NEUROL 2022;92:1016-1029.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals. Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART). In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART. Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups. Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

Plasma TDP‐43 levels are associated with neuroimaging measures of brain structure in limbic regions

Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples

Alzheimer's disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-β (Aβ) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aβ-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles. The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT). We compared 2,884 subjects with autopsy-confirmed intermediate-high stage ADNC to 208 subjects with definite PART (Braak stage I-IV, Thal phase 0, CERAD NP score "absent") and 178 NT subjects from the National Alzheimer's Coordinating Center dataset. PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ɛ4 alleles than the PART or NT cohort, and less frequent APOE ɛ2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language. Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC.

Although neuropathological comorbidities, including Alzheimer's disease neuropathological change (AD-NC) and limbic-predominant age-related TAR DNA-binding protein 43encephalopathy neuropathological change (LATE-NC), are associated with medial temporal atrophy in patients with Lewy body disease (LBD), the diagnostic performance of magnetic resonance imaging (MRI)-derived indices remains unclear. This study aimed to investigate the diagnostic performance of MRI-derived indices representing medial temporal atrophy in differentiating between LBD with AD-NC and/or LATE-NC (mixed LBD [mLBD]) and without these comorbidities (pure LBD [pLBD]). This study included 24 and 16 patients with pathologically confirmed mLBD and pLBD, respectively. In addition to the well-known medial temporal atrophy and entorhinal cortex atrophy (ERICA) scores, the cross-sectional areas of the bilateral entorhinal cortices/parahippocampal gyri (ABEP) were segmented manually. Even incorporating various covariates such as age at MRI examination, sex, argyrophilic grain, the MRI-derived indices, especially ABEP, significantly correlated with the severity of AD-NC, and showed a trend of correlation with LATE-NC. For the differentiation between all mLBD and pLBD, the ERICA score and ABEP demonstrated higher diagnostic performance (area under the receiver-operating-characteristic curve [AUC] of 0.80 and 0.87, respectively). Additionally, the highest diagnostic performance for ABEP (AUC, 0.94; sensitivity, 100%; specificity, 88.9%; accuracy, 96%) was observed in differentiating between pLBD and mLBD with two comorbidities (AD-NC and LATE-NC). In patients with pathologically confirmed LBD, medial temporal atrophy was significantly correlated with AD-NC, and showed a trend of correlation with LATE-NC. Moreover, MRI-derived indices indicative of medial temporal atrophy were useful in diagnosing these comorbidities.

With aging populations, the incidence of brain tumors and neurodegenerative diseases is rising. Recently, Alzheimer's disease neuropathological change (ADNC) has been documented in the tumor-adjacent cortex of 50% of patients with glioblastoma, with isolated hyperphosphorylated tau (pTau) deposits already present in younger individuals. This study extends ADNC screening to younger patients with IDH-mutant glioma, focusing on pTau and amyloid beta (Abeta) deposits, microglial activation, and amyloid precursor protein (APP) expression in the context of cortical tumor cell infiltration. We included 85 patients with IDH-mutant gliomas (37 astrocytomas, median age: 39; 48 oligodendrogliomas, median age: 50) classified as CNS-WHO grades 2-3. Tumor-adjacent cortex was immunohistochemically stained for b-A4, t-AT8, NeuN, APP, Ki67, and Iba1, and cells were quantified using Matlab and QuPath script. Longitudinal samples were available for 15 patients. The median cell density in the tumor-adjacent cortex was significantly higher in glioma patients (astrocytoma: 1395/mm2, oligodendroglioma: 1492/mm2) compared to non-tumor cortex (1098/mm2, P < .0001). ADNC, including pTau (36%, N = 31/85) and Abeta (14%, N = 12/85), was observed in 38% (N = 32/85) of individuals. pTau and A beta positively correlated with age (Hazard ratio = 0.1, P = .02), tumor cell infiltration (Kendall's tau = 0.100, P = 4.7*10-4), and diffuse axonal injury (P = .018). ADNC was commonly found in the temporal cortex (53%, N = 9/17). Our study reveals an unexpectedly high prevalence of ADNC, particularly isolated pTau deposits, in the tumor-adjacent cortex of younger individuals with IDH-mutant glioma. These findings suggest tumor-driven tau accumulation, prompting further research into potential long-term cognitive effects.

BACKGROUNDMixed neuropathology is common in dementia, but the clinical implications for neuropsychiatric symptoms (NPSs) are not well characterized.METHODSIn a population‐based post mortem study, cases with Alzheimer's disease neuropathological change (ADNC) and Lewy body disease (LBD) were identified with any comorbid neuropathology (limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy neuropathological change (LATE‐NC), cerebrovascular disease, LBD, and ADNC, respectively). Post mortem interviews collected information regarding NPSs and cognition to explore associations between each co‐pathology and NPSs across the whole cohort, as well as in participants without dementia.RESULTSCo‐existing neuropathology was frequent, even among individuals without clinical dementia. In cases with ADNC, comorbid neocortical LBD pathology was associated with hallucinations, regardless of cognitive status. However, ADNC co‐pathology in LBD was linked to a greater NPS burden in the full cohort but not in individuals without dementia.DISCUSSIONLewy bodies are associated with hallucinations independent of cognitive impairment, whereas ADNC co‐pathology may contribute to NPS only when widespread and associated with cognitive dysfunction.HighlightsNeuropathological heterogeneity is high even in clinical stages without dementia.Neocortical but not limbic or brainstem LBD co‐pathology is associated with hallucinations.LBs are associated with hallucinations independent of cognitive status.ADNC co‐pathology is not associated with NPSs in LBD without dementia.LATE co‐pathology is associated with increased risk of dementia but not NPS.Vascular co‐pathology is associated with increased risk of delusions in ADNC.

Posterior hippocampal sparing in Lewy body disorders with Alzheimer's copathology: An in vivo MRI study.