IMPORTANCE Neuronal and axonal destruction are hallmarks of neurodegenerativa diseases, but it is difficult to estimate the extent and progress of the damage in the disease process. OBJECTIVE To Investigate cerebrospinal fluid (CSF) levels of neurofllament light (NFL) protein, a marker of neuroaxonal degeneration, in control participants and patients with dementia, motor neuron disease, and parkinsonian disorders (determined by clinical criteria and autopsy), and determine Its association with longitudinal cognitive decline. DESIGN, SETTING, AND PARTICIPANTS In this case-control study, we Investigated NFL levels In CSF obtained from controls and patients with several neurodegenerative diseases. Collection of samples occurred between 1996 and 2014, patients were followed up longitudinally for cognitive testing, and a portion were autopsied in a single center (University of Pennsylvania). Data were analyzed throughout 2016. EXPOSURES Concentrations of NFL in CSF. MAIN OUTCOMES AND MEASURES Levels of CSF NFL and correlations with cognition scores. RESULTS A total of 913 participants (mean [SD] age, 68.7 [10.0] years; 456 [49.9%] women) were included: 75 control participants plus 114 patients with mild cognitive impairment (MCI), 397 with Alzheimer disease, 96 with frontotemporal dementia, 68 with amyotrophic lateral sclerosis, 41 with Parkinson disease (PD), 19 with PD with MCI, 29 with PD dementia, 33 with dementia with Lewy bodies, 21 with corticobasal syndrome, and 20 with progressive supranuclear palsy. Cognitive testing follow-up occurred for 1 to 18 years (mean [SD], 0.98 [2.25] years); autopsy-verified diagnoses were available for 120 of 845 participants with diseases (14.2%). There was a stepwise increase in CSF NFL levels between control participants (median [range] score, 536 [398–777] pg/mL), participants with MCI (831 [526–1075] pg/mL), and those with Alzheimer disease (951 [758–1261] pg/mL), indicating that NFL levels increase with Increasing cognitive impairment. Levels of NFL correlated inversely with baseline Mini-Mental State Examination scores (ρ, −0.19; P < .001) in the full cohort (n = 822) and annual score decline in the full cohort (ρ, 0.36, P < .001), participants with AD (ρ, 0.25; P < .001), and participants with FTD (ρ, 0.46; P = .003). Concentrations of NFL were highest in participants with amyotrophic lateral sclerosis (median [range], 4185 [2207–7453] pg/mL) and frontotemporal dementia (2094 [230–7744] pg/mL). In Individuals with parkinsonian disorders, NFL concentrations were highest In those with progressive supranuclear palsy (median [range], 1578 [1287–3104] pg/mL) and corticobasal degeneration (1281 [828–2713] pg/mL). The NFL concentrations in CSF correlated with TDP-43 load in 13 of 17 brain regions in the full cohort. Adding NFL to β-amyloid 42, total tau, and phosphorylated tau Increased accuracy of discrimination of diseases. CONCLUSIONS AND RELEVANCE Levels of CSF NFL are associated with cognitive Impairments In patients with Alzheimer disease and frontotemporal dem...

Adeno-associated virus-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations affecting the CNS. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRNdeficient frontotemporal dementia and neuronal ceroid lipofuscinosis, and recent studies using intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that, despite a global increase in progranulin, overexpression resulted in dramatic and selective hippocampal toxicity and degeneration affecting neurons and glia. Hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid similarly resulted in T cell infiltration, as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression prior to progressing to the clinic.

BackgroundParkinson’s disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression.Methods and findingsIn 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log10 of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson’s Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log10 of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 × 10−2, Replication FDR-corrected p = 1.03 × 10−4), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 × 10−2, Replication FDR-corrected p = 9.14 × 10−5), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 × 10−3, Replication FDR-corrected p = 2.18 × 10−2), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 × 10−4, Replication FDR-corrected p = 2.97 × 10−3). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04–5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24–7.0, p = 0.014] for ACY1). GHR’s association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20–11.1, p = 0.02]). The main limitations of this study...

Background The effect of surgery on impulse control disorders (ICDs) remains unclear in Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS). Objective To examine changes in ICD symptoms in PD patients undergoing DBS compared to a medication‐only control group. Methods The study was a 2‐center, 12‐month, prospective, observational investigation of PD patients undergoing DBS and a control group matched on age, sex, dopamine agonist use, and baseline presence of ICDs. Questionnaire for Impulsive‐Compulsive Disorders in Parkinson's Disease‐Rating Scale (QUIP‐RS) and total levodopa equivalent daily dose (LEDD) were collected at baseline, 3, 6, and 12 months. Linear mixed‐effects models assessed changes in mean QUIP‐RS score (sum of buying, eating, gambling, and hypersexuality items). Results The cohort included 54 participants (DBS = 26, controls = 28), mean (SD) age 64.3 (8.1) and PD duration 8.0 (5.2) years. Mean baseline QUIP‐RS was higher in the DBS group at baseline (8.6 (10.7) vs. 5.3 (6.9), P = 0.18). However, scores at 12 months follow‐up were nearly identical (6.6 (7.3) vs. 6.0 (6.9) P = 0.79). Predictors of change in QUIP‐RS score were baseline QUIP‐RS score (β = 0.483, P < 0.001) and time‐varying LEDD (β = 0.003, P = 0.02). Eight patients (four in each group) developed de novo ICD symptoms during follow‐up, although none met diagnostic criteria for an impulse control disorder. Conclusions ICD symptoms (including de novo symptoms) at 12 months follow‐up were similar between PD patients undergoing DBS and patients treated with pharmacological therapy only. Monitoring for emergence of ICD symptoms is important in both surgically‐ and medication‐only‐treated PD patients.

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