Autoimmunity in Lewy body dementia Lewy body dementia (LBD) is a brain disease that leads to progressive decline in thinking, movement, and independent function. It results from the build-up of microscopic deposits called Lewy bodies, which develop from the aggregation of a misfolded protein called α-synuclein. Gate et al . observed immune cells known as T cells in the brains of LBD patients (see the Perspective by Krot and Rolls). Genomics analysis revealed that T cells traffic to the LBD brain and are associated with neuronal damage. When stimulated with α-synuclein, LBD patient T cells secrete an inflammatory protein known to damage neurons. These findings suggest an unexpected detrimental role of the immune system in LBD. —SMH

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease and affects 1% of the population above 60 years old. Although Parkinson’s disease commonly manifests with motor symptoms, a majority of patients with Parkinson’s disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson’s disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer’s disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson’s disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer’s disease. Given the known association of microglial activation with advancing Parkinson’s disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson’s disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson’s disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson’s disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson’s disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson’s disease.

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Vaping behavior changes across e-liquids and influences nicotine intake. Research is needed to understand the mechanisms that underlie these behavioral changes, including e-liquid pH and related sensory effects, subjective liking, and nicotine effects.

Background People with Parkinson's disease (PD) can develop multidomain cognitive impairments; however, it is unclear whether different pathologies underlie domain‐specific cognitive dysfunction. Objectives We investigated the contribution of vascular copathology severity and location, as measured by MRI white matter hyperintensities (WMHs), to domain‐specific cognitive impairment in PD. Methods We studied 85 PD (66.6 ± 9.2 years) and 18 control (65.9 ± 6.6) participants. Using the Fazekas scale for rating the severity of WMH, we subdivided PD into 14 PD–WMH+ and 71 PD–WMH–. Participants underwent global, executive, visuospatial, episodic memory, and language testing. We performed nonparametric permutation testing to create WMH probability maps based on PD‐WMH group and cognitive test performance. Results The PD–WMH+ group showed worse global and executive cognitive performance than the PD–WMH– group. On individual tests, the PD–WMH+ group showed worse Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities Test (SDMT), and Digit Span scores. WMH probability maps showed that in the PD–WMH+ group, worse Stroop was associated with lesions centered around the corticospinal tract (CST), forceps major, inferior‐fronto‐occipital fasciculus, and superior longitudinal fasciculus; worse SDMT with lesions around the CST, forceps major, and posterior corona radiata; worse Digit Span with lesions around the posterior corona radiata; and worse MoCA with lesions around the CST. Conclusions We found that WMH severity was associated with PD executive dysfunction, including worse attention, working memory, and processing speed. Disruption of key white matter tracts in proximity to vascular lesions could contribute to these specific cognitive impairments. Early treatment of vascular disease might mitigate some executive dysfunction in a subset of patients with PD.

Objective: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Aβ-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Aβ-42 compared to patients with normal levels.Methods: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Aβ-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF Aβ at baseline, PD participants with normal CSF Aβ, and both groups combined). Having at least one copy of the APOE ε4 allele, time, and the interaction of APOE ε4 and time were predictor variables for cognitive change, adjusting for age, gender and education.

Background The recent promise of disease-modifying therapies for Alzheimer’s disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation. Methods We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer’s Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid β peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change. Results The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Aβ42/Aβ40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Aβ+ and Aβ− groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years. Conclusions This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

Objective: This study was undertaken to study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions. Methods: We studied illusory responses on the Noise Pareidolia Task in 300 participants (38 cognitively impaired LB, 65 cognitively unimpaired LB, 51 Alzheimer disease spectrum [AD-s], 146 controls). Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions. Results: Cognitively impaired LB participants were 12.3, 4.9, and 4.6 times more likely than control, cognitively unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex, and education, the probability of endorsing 1 or more illusory responses was 61% in the cognitively impaired LB group, compared to 26% in AD-s, 25% in cognitively unimpaired LB, and 12% in control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least 1 illusory response. Interpretation: We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients.