Acta Neuropathologica最新文献

Vasculitic myopathy (VM) represents a nonspecific manifestation of various vasculitic syndromes that presents with myalgia, leg tenderness, and muscle weakness. Most cases of VM develop in the context of polyarteritis nodosa (PAN), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, or rheumatoid vasculitis, or manifest as single organ vasculitis. Muscle inflammation in VM is poorly understood, and most studies essentially report the presence of vasculitic changes demonstrated by microscopic analysis of skeletal muscle tissue. However, no detailed characterization or in-depth analyses have been performed so far. We studied the clinicopathologic phenotype of 12 patients and analyzed the gene expression profiles of 36 patients with VM in the context of negative ANCA test results. ANCA-negative VM typically presents with myalgia involving the lower extremities, accompanied by cutaneous manifestations, constitutional symptoms, and marked systemic inflammation. Half of the patients (6/12; 50.0%) met the classification criteria for ‘classic PAN’. Serum creatine kinase (CK) activity was normal in most cases (10/12; 83.3%). The presence of skeletal muscle vasculitis was confirmed by histopathology in 9/12 (75.0%) cases. Specifically, ANCA-negative VM predominantly affected small arteries and was consistently associated with small vessel involvement of the epimysial fascia (9/10; 90.0%), which was termed ‘vasculitic fasciitis’ (VF). Signs of necrotizing vasculitis were occasionally noted (3/9; 33.3%). Mild endomysial fibrosis and muscle fiber necrosis could be compatible with a rather acute disease onset and may account for normal or slightly elevated levels of serum CK activity, respectively. Additionally, nonspecific myopathic changes such as capillary vessel mural thickening and variations of muscle fiber size were detected in all analyzed muscle biopsy specimens. Immunohistochemical studies revealed perifocal sarcolemmal upregulation of major histocompatibility complex class I in the majority of cases (10/11; 90.9%). RNA sequencing of muscle biopsies from 36 ANCA-negative VM patients, compared to 37 healthy controls and 649 samples from other inflammatory myopathies, revealed that ANCA-negative VM is characterized by a dominant interferon-gamma-driven immune response, broad cytokine activation including tumor necrosis factor-related genes, and selective upregulation of angiogenesis- and endothelium-associated transcripts. Our histomorphologic analysis highlights a distinct histopathological pattern of VF that is characteristic for muscle involvement in ANCA-negative vasculitis. Furthermore, we provide evidence for a specific molecular signature that gives new insights into the pathogenesis and treatment of ANCA-negative VM.

To advance the nosology of pathologic Parkinson’s disease (PD), we examined the associations of Lewy bodies (LBs), nigral neuronal loss (NNL), and co-pathologies with cognitive decline and progression of parkinsonian signs in older decedents without clinical PD during life. Nineteen cognitive tests and 26 Unified Parkinson’s Disease Rating Scale items were measured annually. We measured both elements of pathologic PD, i.e., LBs and NNL, and eight other Alzheimer’s disease and related dementias (ADRD) co-pathologies in 1717 brains. A semiquantitative scale (0–3) was used to assess NNL. Pathologic PD was based on the presence of LBs plus moderate or severe NNL. Possible pathologic PD was based on LBs alone or LBs with mild NNL. A series of bivariate linear mixed effect models jointly quantified cognitive decline and progressive parkinsonian signs in each decedent. Almost 30% of decedents without a diagnosis of clinical PD showed elements of pathologic PD [pathologic PD (8%); possible pathologic PD (19%)]. On average, pathologic PD accounted for 4.9% of the variance of cognitive decline and 9.4% of the variance of progression of parkinsonian signs controlling for ADRD pathologies. Adding another term for possible pathologic PD accounted for an additional 1.8% variance of cognitive decline but did not account for additional variance of progressive parkinsonian signs. Co-pathologies accounted for an additional 19% of cognitive decline and 7% of progressive parkinsonism. Thirty-three percent of the association of LBs with cognitive decline was attributable to NNL. In contrast, more than 70% of its association with progressive parkinsonism was attributable to NNL. Subclinical pathologic PD in older adults is heterogeneous. The associations of LBs with cognition and parkinsonism may vary with the severity of NNL and together with its co-pathologies account for a minority of late-life progressive parkinsonism and cognitive decline. Synucleinopathies in older adults without clinical PD may be underestimated.

The etiology of cerebrovascular pathology is heterogeneous. Independent or synergistic role of this pathology relative to Alzheimer’s disease (AD) pathology is necessary to clarify distinct neurodegenerative pathways. We evaluated the interplay of various cerebrovascular markers postmortem and their in vivo neuroimaging, clinical and neuropathologic correlates using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). In 109 individuals, postmortem cerebrovascular pathology (atherosclerosis of the circle of Willis, cerebral amyloid angiopathy [CAA], arteriolosclerosis, white matter rarefaction, old infarcts, microinfarcts, hemorrhages, other ischemic/vascular changes) was characterized. Additionally, we assessed in vivo neuroimaging (cortical thickness, subcortical volume, white matter lesion burden, glucose standardized uptake value ratio, fractional anisotropy of white matter tracts, cerebral blood flow), cognitive, and neuropathologic measures (atrophy, AD pathology and copathologies including Lewy body, TDP-43, hippocampal sclerosis). The study sample had mean (standard deviation) age of 82.9 (7.2) years and included 29 women (27%) and 84 (77%) with intermediate/high AD neuropathologic change. Arteriolosclerosis and CAA emerged as dominant cerebrovascular markers using multiple correspondence analysis. More severe arteriolosclerosis was explained by higher white matter lesion burden and greater postmortem hippocampal atrophy (β = 143.2, 95% CI 63.9 to 230.1, p = 0.0003), but not AD pathology. More severe CAA was explained by fractional anisotropy (β = − 20, 95% CI − 41.5 to -3.1, p = 0.02) adjusted for AD pathology and reduced integrity of superior cerebellar peduncle, posterior thalamic radiation, and sagittal stratum tracts (rho < − 0.6, false discovery rate corrected p < 0.05). More severe CAA was also explained by cortical atrophy and AD pathology (β = 0.6, 95% CI 0.2 to 1.2, p = 0.007), and associated with poorer memory (β = − 0.2, 95% CI − 0.3 to -0.09, p = 0.0009). Results demonstrate two dominant cerebrovascular pathways. An arteriolosclerosis-driven pathway is unspecific to AD pathology, whereas a CAA-driven pathway is specific to AD pathology. Cerebrovascular pathology is associated with AD pathology in an etiology-dependent manner which may influence eligibility for treatment or treatment-emergent adverse events in disease-modifying therapies for AD.

Alzheimer’s disease (AD) includes a defining hallmark that correlates most closely to cognitive decline, namely misfolded tau protein. However, the “upstream” etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain, proteoforms, and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequelae. We uncovered tau citrullination on multiple epitopes caused by peptidyl arginine deiminase (PAD) enzymes. PAD-induced citrullination irreversibly converts arginine residues to citrulline, producing a net loss of positive charge, elimination of pi–pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimer’s disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule-binding repeats domain (MBR), and C-terminal domain (C-term) on full-length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tau in vitro, several animal models of tauopathies, and Alzheimer’s disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher pathological tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.

Nucleolar disturbances have long been implicated in neurodegenerative diseases but, to date, aggregation and immobilization of proteins into nucleolar bodies have only been reported in vitro and in cell models, and only for amyloid β (Aβ). In model systems, these bodies have been shown to coordinate local nuclear protein synthesis with potential to seed diagnostic neuropathologies. Here we confirm the presence of nucleolar aggregates of amyloid nature in postmortem brain tissue from controls and patients with neurodegenerative pathologies and demonstrate the nucleolar sequestration of fibrillation-prone proteins associated with neurodegenerative diseases (Aβ, tau, α-synuclein, TDP-43, and FUS, but not prion or peptide repeats). We identified nucleolar bodies ranging from multiple small foci to a centralized, large amyloid aggresome, that appear to represent progressive stages of protein immobilization from liquid-like foci to the formation of nucleolar aggresomes. Neurons with nucleolar aggresomes were more vulnerable to neurodegeneration, decreasing in number with increasing duration of disease. Nucleolar aggresomes with phosphorylated tau correlated with increasing amounts of neuropathology, while phosphorylated TDP-43 in nucleolar aggresomes distinguished cases with limbic-predominant age-related TDP-43 encephalopathy. Nucleolar aggresomes containing α-synuclein occurred in a large proportion of aged controls with limited neuronal loss (potentially asserting neuroprotection). Other fibrillation-prone proteins were either absent (prion and peptide repeats) or found less commonly in nucleolar aggresomes (Aβ and FUS), and amyloidogenic nuclear proteins not screened in this study may also occur in nucleolar aggresomes. Our data do not support the concept that proteins in aggresomes seed diagnostic neuropathologies as there were no associations between their presence in nucleoli aggresomes and their cytoplasmic or extracellular accumulation. Assessment of neurons with and without phosphorylated tau or α-synuclein aggresomes showed that phosphorylated tau ameliorated the increased DNA levels found in AD. Collectively, our observations establish that nucleolar sequestration of amyloidogenic proteins is a common molecular mechanism in the brain, representing a novel contribution to the understanding of nucleolar protein aggregation in the context of neuroprotection and neurodegeneration during brain aging.

The kinase–ligase pair PINK1–PRKN initiates mitophagy by recognizing and selectively tagging worn-out and dysfunctional mitochondria with phosphorylated ubiquitin (pS65-Ub) to facilitate their elimination via autophagy. In human autopsy brains, the number of pS65-Ub positive cells increases with age but is also associated with Lewy body (LB), neurofibrillary tangles (NFT), and senile plaque (SP) burden. Through a recent genome-wide association study, we identified two genetic modifiers of pS65-Ub levels, APOE4 and ZMIZ1 rs6480922. While LB, NFT, and SP pathologies often coexist in Lewy body dementia (LBD), it is unclear how genetic factors and comorbid neuropathologies interact to impact mitophagy in vulnerable brain regions. We therefore measured levels of the age and disease marker pS65-Ub in the hippocampus and amygdala of 371 LBD cases. Significant and independent associations with pS65-Ub levels were observed for each of the three pathologies LB, NFT, and SP in both regions, and the presence of APOE4 significantly strengthened the association between NFT and pS65-Ub in the hippocampus. While no interaction between LB and SP pathologies was observed regarding association with pS65-Ub, a significant interaction between LB and NFT pathologies on pS65-Ub accumulation was found in the amygdala, which was primarily observed in carriers of the minor allele of ZMIZ1 rs6480922. In summary, our study revealed complex interactions between LB pathology, NFT pathology, and genetic mitophagy modifiers in LBD brains, highlighting potential convergent molecular mechanisms underlying α-synuclein- and tau-associated mitophagy alterations.

CSF Aβ reflects Alzheimer’s disease neuropathologic change (ADNC), while CSF p-tau offers an indirect indication of tangle pathology. However, interpretation can be challenging when cognitive impairment is present alongside Aβ positivity (Α +) but p-tau negativity (T −). We examined neuropathologic differences between CSF A + T − and A + T + profiles, defined by CSF Aβ42 and p-tau181 levels, hypothesizing that cognitively impaired older adults with a CSF A + T − profile would exhibit a greater co-pathology burden, suggesting alternative contributing disease processes. We identified 77 ADNI participants with available CSF biomarkers and neuropathologic assessments (median age = 79.8 years; IQR = 74.7–84.5). Depending on the presence–alone or in combination–of ADNC intermediate/high and non-ADNC pathologies (e.g., Lewy bodies (LB), argyrophilic grain disease (AGD), limbic-predominant age-related TDP-43 encephalopathy-neuropathologic change (LATE-NC)), individuals were classified as ADNC dominant, mixed ADNC, or non-ADNC dominant. The two CSF A + profiles were similar in demographics, frequency of cognitive impairment, longitudinal cognitive performance, clinical comorbidities, CSF Aβ42 levels, CSF α-synuclein positivity rates, and Aβ PET burden. ADNC intermediate/high was significantly more frequent in the CSF A + T + profile than in the CSF A + T − profile (100% vs. 78%, p value = 0.008). The most common co-pathologies contributing to cognitive impairment in the CSF A + T − profile were LATE-NC (stages 2–3) (47%), LB limbic/neocortical (44%), and AGD (stages II–III) (33%), while in the CSF A + T + profile, LB limbic/neocortical (28%) and LATE-NC (stages 2–3) (22%) predominated. The CSF A + T − profile showed 17% ADNC dominant, 61% mixed ADNC, and 22% non-ADNC dominant pathology, whereas the CSF A + T + profile showed 51% ADNC dominant and 49% mixed ADNC pathology (p = 0.001). Within the mixed ADNC subgroup, individuals with a CSF A + T − profile more often exhibited two or more non-ADNC co-pathologies compared to those with a CSF A + T + profile (73% vs. 21%, p = 0.009). Despite clinical similarities among cognitively impaired individuals with CSF A + T − and A + T + profiles, the CSF A + T − profile may reflect a greater burden of non-ADNC pathology. Extending biomarker profiling beyond Aβ and tau may facilitate more personalized care.