Larsen, Rachel A.

Abstract Background Immunohistochemically detected phosphorylated α‐synuclein (p‐α‐syn) in cutaneous nerves has been found in >95% of patients meeting consensus criteria for dementia with Lewy bodies (DLB); however, its performance in prodromal stages (mild cognitive impairment‐Lewy body [MCI‐LB]) and clinical practice is unknown. Objective We evaluated skin biopsy for p‐α‐syn in a convenience cohort of patients with suspected MCI‐LB or DLB in a tertiary care setting. Methods 53 patients underwent commercially available skin biopsy for skin nerve p‐α‐syn as part of a clinical evaluation for suspected MCI‐LB/DLB. Consensus MCI‐LB/DLB criteria blinded to skin biopsy result were applied through retrospective chart review; those not definitively meeting criteria were considered questionable synucleinopathy (QS). Results Median age at skin biopsy was 70 years (range, 43–87 years) with 81% men. 36 patients (68%) had positive skin biopsies. 32/43 (74%) patients meeting clinical consensus criteria for DLB/MCI‐LB had a positive skin biopsy, with higher frequency in MCI‐LB (87%) compared with DLB (60%). 4/10 (40%) QS had positive biopsies. One patient with a positive skin biopsy had no evidence of central nervous system (CNS) α‐syn on autopsy. Conclusions Positive skin biopsy for p‐α‐syn occurs across the spectrum of cognitive presentations of Lewy body disease including prodromal DLB, albeit at a lower frequency in this retrospective review of atypical cases compared with typical clinical presentations. A positive skin biopsy may not reflect CNS synucleinopathy as the etiology for a patient's symptoms in some cases. Longitudinal studies of skin biopsies for p‐α‐syn in suspected MCI‐LB/DLB with autopsy confirmation are needed. © 2025 International Parkinson and Movement Disorder Society.

Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4 , we corroborated abundant LILRB4 expression in microglia wrapping around Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ load, mitigated some Aβ-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.

Abstract Objectives Active RA has been associated with an increased risk of both cardiovascular and peripheral vascular disease. We aimed to compare cerebrovascular changes in patients with and without RA, both with and without a neuropathologic diagnosis of neurodegenerative disease. Methods Patients with RA (n = 32) who died and underwent autopsy between 1994 and 2021 were matched to non-RA controls (n = 32) on age, sex and level of neurodegenerative proteinopathy. Routine neuropathologic examination was performed at the time of autopsy. Cerebrovascular disease severity was evaluated using modified Kalaria and Strozyk scales. Clinical dementia diagnoses were manually collected from patients’ medical records. Results Prior to death, 15 (47%) RA patients and 14 (44%) controls were diagnosed with dementia; 9 patients in each group (60% and 64%, respectively) had Alzheimer’s disease. The prevalence of cerebral amyloid angiopathy, microinfarcts, infarcts or strokes was found to be similar between groups. Patients with RA were more likely to have more severe vascular changes in the basal ganglia by Kalaria scale (P = 0.04), but not in other brain areas. There were no significant differences in the presence of large infarcts, lacunar infarcts or leukoencephalopathy by Strozyk scale. Among patients with RA and no clinical diagnosis of dementia, the majority had mild–moderate cerebrovascular abnormalities, and a subset of patients had Alzheimer’s disease neuropathologic changes. Conclusion In this small series of autopsies, patients with and without RA had largely similar cerebrovascular pathology when controlling for neurodegenerative proteinopathies, although patients with RA exhibited more pronounced cerebrovascular disease in the basal ganglia.

Abstract The literature regarding the neuropathological findings in cases of SARS-CoV-2 infection, which causes coronavirus disease 2019 (COVID-19), is expanding. We identified 72 patients who died of COVID-19 (n = 48) or had recovered shortly before death (n = 24) and had autopsies performed at our institution (49 males, 23 females; median age at death 76.4 years, range: 0.0–95.0 years). Droplet digital polymerase chain reaction (ddPCR) for the detection of SARS-CoV-2 was performed (n = 58) in multiple brain regions. In cases the assay was successfully completed (n = 50), 98.0% were negative (n = 49) and 2% were indeterminate (n = 1). Most histologic findings were typical of the patient age demographic, such as neurodegenerative disease and arteriolosclerosis. A subset of cases demonstrated findings which may be associated with sequelae of critical illness. We identified 3 cases with destructive perivascular lesions with axonal injury, one of which also harbored perivascular demyelinating lesions. These rare cases may represent a parainfectious process versus sequelae of vascular injury. The lack of detectable SARS-CoV-2 by ddPCR or significant histologic evidence of direct infection suggests that active encephalitis is not a feature of COVID-19.