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Transthyretin abnormalities in amyotrophic lateral sclerosis: High molecular weight species in cerebrospinal fluid and stromal deposits in choroid plexus.
No full textTransthyretin (TTR) is a plasma and cerebrospinal fluid (CSF) protein involved in transporting thyroid hormone and retinol, with additional roles in the central nervous system (CNS). The tetrameric structure of TTR is essential for its functions and tetramer dissociation and aggregation into pathological amyloid fibrils is implicated in multiple diseases. Altered levels of TTR have previously been described in amyotrophic lateral sclerosis (ALS) in both CSF and CNS tissue. However, whether altered TTR levels in ALS reflect TTR pathology in CSF or in the choroid plexus (CP) cells that synthesize CNS TTR is unknown. Here, we comprehensively assayed native and aggregated TTR in ALS patient CSF and postmortem ALS CP. Using a nondenaturing native polyacrylamide gel electrophoresis-based assay, we identified high molecular weight TTR aggregates in the CSF of ALS patients. We also observed increased levels of TTR RNA and protein in ALS CP, as well as TTR granule deposits in CP stroma of ALS but not control cases. Taken together, our results reveal new forms of TTR dysfunction in ALS and uncover TTR-related morphological abnormalities in the CP in ALS patients
Attention/Working Memory and Executive Function in Parkinson\u27s Disease: Review, Critique, and Recommendations
No full textBACKGROUND: Cognitive impairment in Parkinson\u27s disease (PD) is a well-established non-motor complication that significantly affects the quality of life and well-being of both patients and care partners. To optimally detect mild cognitive impairment or dementia, extensive neuropsychological assessment is essential. A wide range of cognitive tests and clinical outcome assessments have been used in clinical settings, often without regard to their clinimetric quality. METHODS: We performed a literature review of tests assessing attention/working memory and executive domains in PD (tests on other domains are included in an accompanying review). The selected tests were evaluated for their clinimetric properties and categorized by a panel of experts as recommended, recommended with caveats, suggested, or listed according to the International Parkinson and Movement Disorder Society Clinical Outcome Assessment Scientific Evaluation Committee guidelines. RESULTS: A total of 30 tests were reviewed. Eight tests were recommended, including four tests assessing attention/working memory abilities (WAIS-IV Digit Span, Coding and Symbol Search subtests, and Trail Making Test) and four tests assessing executive abilities (WAIS-IV Similarities, Wisconsin Card Sorting Test, Fluency Tests, and Stroop Color-Word Test). These tests demonstrated good to excellent levels of reliability and validity, have normative datasets, and are sensitive to change. Eight other tests were recommended with caveats , eleven were suggested, and three were listed. CONCLUSIONS: The recommended tests for attention/working memory and executive functioning in PD can guide PD cognitive assessment. Other tests were identified as potentially useful; however, caution is advised due to their clinimetric limitations. Further validation studies are required for these tests. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Catecholamine Dysregulation in Former American Football Players: Findings From the DIAGNOSE CTE Research Project
No full textBACKGROUND AND OBJECTIVES: Disturbances in brain catecholamine activity may be associated with symptoms after exposure to repetitive head impacts (RHIs) or related chronic traumatic encephalopathy (CTE). In this article, we studied CSF catecholamines in former professional and college American football players and examined the relationship with football proxies of RHI exposure, CTE probability, cognitive performance, neuropsychiatric symptoms, and parkinsonism. METHODS: In this observational cross-sectional study, we examined male former American football players, professional ( PRO ) or college ( COL ) level, and asymptomatic unexposed male ( UE ) individuals from the DIAGNOSE CTE Research Project. Catecholamines-norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), and dopamine (DA) and its precursor, 3,4-dihydroxyphenylalanine (l-DOPA), and metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC)-were measured in CSF with high-performance liquid chromatography and compared across groups with analysis of covariance. Multivariable linear regression models tested the relationship between CSF catecholamines and proxies of RHI exposure (e.g., total years of playing American football), factor scores for cognition, and neurobehavioral dysregulation (explosivity, emotional dyscontrol, impulsivity, affective lability), as well as depressive/anxiety symptoms, measured with the Beck Depression/Anxiety Inventories. CTE probability and parkinsonism were assessed using the National Institute of Neurological Disorders and Stroke consensus diagnostic criteria for traumatic encephalopathy syndrome (TES), and biomarkers were compared among different diagnostic groups. RESULTS: The cohort consisted of 120 former American football players (85 PRO players, 35 COL players) and 35 UE participants (age 45-75). Former players had significantly lower levels of NE (mean difference = -0.114, 95% CI -0.190 to -0.038), l-DOPA (-0.121, 95% CI -0.109 to -0.027), and DOPAC (-0.116, 95% CI -0.177 to -0.054) than UE participants. For NE and DOPAC, these overall group differences were primarily due to differences between the PRO and UE cohorts. No significant differences were found across TES-CTE probability subgroups or TES-parkinsonism diagnostic groups. Within the COL cohort, tested as post hoc analyses, higher CSF NE and l-DOPA were associated with higher neurobehavioral dysregulation factor scores, BAI total score, and worse executive functioning and processing speed. CSF DHPG and DOPAC were associated with impulsivity only in this subgroup. DISCUSSION: We observed reduced CSF catecholamine concentrations in former elite American football players, although the relationship with degree of RHI exposure and the clinical impact needs further study
Cholinergic dysfunction in occupational manganese exposure
No full textBACKGROUND AND OBJECTIVE: Excessive exposure to manganese (Mn) produces a clinical syndrome of parkinsonism and cognitive impairment. However, our understanding of the mechanisms of Mn neurotoxicity remains limited. This study aimed to evaluate the relationships between Mn exposure, cholinergic function, and cognitive impairment in exposed workers. METHODS: We assessed brain cholinergic function using vesicular acetylcholine transporter (VAChT) radiotracer (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone (VAT) with positron emission tomography (PET) in 21 Mn-exposed workers. We estimated occupational Mn exposure from work histories and the MRI pallidal index. A cognitive control battery consisting of the Verbal Fluency (VF), Letter Number Sequencing (LNS), Two-Back Letter Task (2B), Go-No-Go (GnG), and Simon Task assessed cognitive function. We applied generalized linear models to Mn exposure, voxel-based cholinergic PET, and cognitive control measures, estimating coefficients for cholinergic-mediated associations between Mn and cognitive function. We utilized bootstrapping techniques to validate the mediation coefficients. RESULTS: Both Mn exposure metrics were associated with low cholinergic VAT binding in the caudate and cortical regions including the precuneus, pars triangularis, pars opercularis, middle temporal lobe, and entorhinal cortex. Regional cholinergic function mediated the relationship between Mn exposure and both the composite cognitive control score (mean of the 5 cognitive tests) [β = -0.661, 90 % confidence interval (CI) -2.130, -0.032] and the individual VF assessment (β = -0.944, 90 % CI -2.157, -0.065). DISCUSSION: Higher Mn exposure is associated with lower cholinergic activity in multiple brain regions. Cholinergic function also mediates a portion of the relationship between Mn exposure and cognitive control performance. Caudate and cortical cholinergic activity may be a biomarker of early Mn neurotoxicity and represent an important mechanism of cognitive dysfunction in parkinsonian syndromes
Exploring the neuroprotective potential of immunosuppressants in Parkinson\u27s disease
No full textINTRODUCTION: Neuroprotective therapy to slow Parkinson\u27s disease (PD) progression is a critical unmet need. Neuroinflammation likely represents an important pathophysiologic mechanism for disease progression. Medications that target this inflammation, such as immunosuppressants, represent potential disease-modifying therapies for PD. The relation between these medications and PD risk might inform candidate selection. METHODS: We conducted a population-based case-control study using Medicare data from the United States. The study included 207,532 incident PD cases and 975,177 controls from 2016 to 2018, age 67-110. We examined the association between PD risk and immunosuppressant use before PD diagnosis/control selection. We considered 37 immunosuppressants, representing \u3e10 medication classes, in Part D prescription claims. We used logistic regression to estimate the relative risk (RR) and 95 % confidence interval (CI) between each medication and PD, while accounting for age, sex, race/ethnicity, smoking, and healthcare utilization. In sensitivity analyses we applied exposure lagging, restricted to immunosuppressant users, and corrected for multiple comparisons. RESULTS: Medicare beneficiaries using the calcineurin inhibitor tacrolimus (RR 0.49, CI 0.40-0.60) and mTOR inhibitors everolimus (RR 0.38, CI 0.26-0.56) and sirolimus (RR 0.59, CI 0.37-0.93) had a lower risk of PD compared to those not taking the medication. The TNF inhibitor certolizumab was also associated with lower PD risk (RR 0.54, CI 0.34-0.84). Tacrolimus and everolimus remained significant after Bonferroni correction. Sensitivity analyses otherwise confirmed results for all four medications. CONCLUSION: Calcineurin or mTOR inhibition might reduce PD risk. Future studies should examine whether these medications or structurally similar agents might have potential as disease-modifying therapies for PD
Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer\u27s disease
No full textBACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer\u27s Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer\u27s disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer\u27s disease
Repurposing glucagon-like peptide-1 receptor agonists for the treatment of neurodegenerative disorders
No full textWith therapeutic progress in Alzheimer\u27s disease (AD), more molecular and mechanistic targets are coming into focus. Beyond amyloid, emerging targets include tau, neuroinflammation and neurotransmitters. Targeting neuroinflammation in neurodegenerative diseases has been explored using cyclooxygenase inhibitors, but it has mostly been unsuccessful. Among the drug classes under investigation for AD are the glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are approved for the treatment of type 2 diabetes (T2D), obesity and cardiovascular disease. GLP-1RAs are candidate treatments for AD based on several concepts. First, epidemiological data reveal that patients with T2D and cardiovascular disease receiving GLP-1RAs have substantial reductions in the risk of developing all-cause dementia. Second, GLP-1RAs reduce neuroinflammatory changes in preclinical models. Clinical trials have not yet shown that GLP-1RAs can slow the rate of cognitive decline in mild cognitive impairment and mild dementia due to AD. Here, we summarize data supporting the use of GLP-1RAs for the treatment of neurodegenerative diseases, with a focus on AD
Devaluing memories of reward: a case for dopamine
No full textMidbrain dopamine cells encode differences in predictive and expected value to support learning through reward prediction error. Recent findings have questioned whether reward prediction error can fully account for dopamine function and suggest a more complex role for dopamine in encoding detailed features of the reward environment. In this series of studies, we describe a novel role for dopamine in devaluing sensory features of reward. Mesencephalic dopamine cells activated during a mediated devaluation phase were later chemogenetically reactivated. This retrieval of the devalued reward memory elicited a reduction in the hedonic evaluation of sucrose reward. Through optogenetic and chemogenetic manipulations, we confirm dopamine cells are both sufficient and necessary for mediated devaluation, and retrieval of these memories reflected dopamine release in the nucleus accumbens. Consistent with our computational modeling data, our findings indicate a critical role for dopamine in encoding predictive representations of the sensory features of reinforcement. Overall, we elucidate a novel role for dopamine function in mediated devaluation and illuminate a more elaborate framework through which dopamine encodes reinforcement signals
Disease-modifying, multidimensional efficacy of putaminal Ca1.3-shRNA gene therapy in aged parkinsonism male and female macaques
No full textThere remain several unmet clinical needs in Parkinson\u27s disease (PD) including waning and incomplete efficacy of symptomatic therapies, development of medication side effects (i.e., levodopa-induced dyskinesias [LID]) and unfettered disease progression. Ca1.3 calcium channels are therapeutic targets of intense interest in PD. We developed an RNA interference (RNAi)-based vector approach utilizing adeno-associated virus (AAV) expressing a short-hairpin (sh)RNA against Ca1.3 channels to provide potent, target-specific silencing of these channels that become dysfunctional in the parkinsonian striatum. We report here unprecedented evidence that magnetic resonance imaging-guided intraputaminal AAV-Ca1.3-shRNA in aged (25-29 years) male and female nonhuman primates with long-standing (8 months) advanced parkinsonian motor deficits results in a significant progressive reversal of functional deficits in the absence of pharmacotherapy, with some aspects including postural instability and motivation-based fine-motor performance returning to normal/pre-parkinsonian baseline. This contrasts maintenance of stable moderate-to-severe disability in those receiving the control/scrambled vector (AAV-SCR-shRNA). AAV-Ca1.3-shRNA recipients also demonstrate maintained levodopa motor benefit lost in these aged, parkinsonian subjects receiving the AAV-SCR-shRNA vector, similar to end-stage PD. Last, AAV-Ca1.3-shRNA recipients showed unprecedented, near-complete prevention of LID induction despite long-term (5.5 months), twice-daily, dose-escalation levodopa. The realization of these first-in-class multimodal gene therapy attributes in the clinic would represent a major therapeutic advancement for PD
Protoporphyrin IX plasma and blood pharmacokinetics and brain tumor distribution determined by a validated LC-MS/MS method
No full textProtoporphyrin IX (PPIX) is a fluorescent metabolite in the heme biosynthesis pathway, and cancer cells accumulate it when 5-aminolevulinic acid (5-ALA), a precursor, is administered. In the U.S., 5-ALA is approved for visualizing high-grade gliomas (HGG) during fluorescence-guided surgery. PPIX is also central to experimental photodynamic and sonodynamic therapies for HGG. Additionally, PPIX measurement is critical for diagnosing and monitoring porphyrias. Despite the need for a sensitive and rapid bioanalytical method for accurate quantification of PPIX in biospecimens, no reliable validation of an LC-MS/MS method is available due to challenges related to its chemical instability, poor solubility, and tendency to aggregate. This work is the first to present a fully validated, sensitive, and rapid LC-MS/MS method for determining PPIX levels in human plasma, blood, and brain tumors. The method overcomes stability concerns, achieving a 3.5-min total run-time with a concentration range of 1-2000 nmol/L for plasma and tumors, and 10-2000 nmol/L for blood. Application of the method in a clinical trial, which assesses sonodynamic therapy for HGG patients, shows significant PPIX production, peaking in plasma and blood six hours post-5-ALA administration. In recurrent HGG patients, PPIX levels were notably higher in gadolinium-enhancing tumor regions compared to non-enhancing areas, indicating preferential accumulation in tumors