Annals of Clinical and Translational Neurology最新文献

Objective: Several genetic loci known to confer risk for Parkinson's disease (PD) function in lysosomal pathways. We systematically screened common variants linked to PD risk by genome-wide association studies (GWAS) for impact on cerebrospinal fluid (CSF) proteins reflecting lysosomal function.

Methods: Starting with 525 candidate gene-single nucleotide polymorphism (SNPs) pairs nominated by Mendelian randomization from published PD GWAS, we filtered SNPs for downstream evaluation, based on strength of association with PD and impact on brain gene expression. We genotyped top SNPs in 173 PD participants, adding three SNPs capturing variation at the TMEM106B, CTSB, and RAB29 loci, encoding genes with known lysosomal function. In the same 173 individuals, we measured 15 CSF proteins (nine lysosomal proteins and six other proteins implicated in neurodegeneration) by parallel reaction monitoring mass spectrometry. We tested SNPs for association with lysosomal proteins. For our top SNP associating with multiple lysosomal proteins, we characterized expression of its target gene CAMLG in human brain tissue.

Results: Sixteen SNPs emerged from our analysis of GWAS-nominated loci. Genotypes at rs12657663 (CAMLG) associated with CSF levels of multiple lysosomal markers (cathepsin F, cathepsin L, hexosaminidase B, and tripeptidyl peptidase I) and genotypes at rs7910668 (ITGA8) with CSF levels of cathepsin B. The protein encoded by CAMLG, calcium modulating ligand (CAML), is highly expressed in neurons of multiple human brain regions, with higher expression in Lewy body disease cases.

Interpretation: Systematic analysis of PD risk loci nominates CAMLG as a neuronally expressed risk gene with effects on lysosomes.

Objective: Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) share clinical, pathological, and genetic risk factors, including GBA1 and APOEε4 mutations. Biomarkers associated with the pathways of these mutations, such as glucocerebrosidase enzyme (GCase) activity and amyloid-beta 42 (Aβ42) levels, may hold potential as predictive indicators, providing valuable insights into the likelihood of cognitive decline within these diagnoses. Our objective was to determine their association with cognitive decline in DLB and PD.

Methods: A total of 121 DLB patients from the European-DLB Consortium and 117 PD patients from the Norwegian ParkWest Study were included in this study. The four most commonly associated variants of GBA1 mutations (E326K, T369M, N370S, L444P), APOEε4 status, and cerebrospinal fluid (CSF) Aβ42 levels and GCase activity were assessed, as well as global cognition using the Mini-Mental State Examination. Linear mixed-effects regression models were used to evaluate the association of CSF biomarkers with cognitive decline in each diagnostic group, adjusted for age, sex, education, and genetic mutation profile.

Results: Low CSF Aβ42 levels were associated with accelerated cognitive decline in DLB, whereas reduced CSF GCase activity predicted faster cognitive decline in PD. These associations were independent of GBA1 gene mutations or APOEε4 status.

Interpretation: Our study provides important evidence on the relationship between brain Aβ deposition and GCase activity in the Lewy body disease spectrum independent of their genetic mutation profile. This information could be relevant for designing future clinical trials targeting these pathways.

Diagnosing frontal variant Alzheimer's disease (fvAD) is difficult and could be even more difficult when amyloid-beta (Aβ) PET retention is low. A 63-year-old woman presenting with a 3-year history of apathy and memory impairment showed executive dysfunction, memory impairment, and severe bilateral frontotemporal atrophy on MRI. Aβ PET showed only equivocal findings in the right frontal lobe and was negative. However, CSF showed a severely decreased Aβ42/40 ratio and increased phospho-tau181. AD-tau-specific (18F)-MK6240 PET revealed increased tracer retention predominantly in the bilateral frontal lobes, confirming the fvAD diagnosis. (18F)-MK6240 PET can be valuable in resolving diagnostic uncertainties in atypical patients with low Aβ retention.

Objective: Music interventions have been shown to have beneficial effects on hemodynamic parameters, pain, and anxiety in various medical settings. However, music interventions in the setting of acute stroke have not been studied. The objective of this trial was to perform a pilot feasibility study of music interventions in the setting of acute stroke to inform a larger efficacy trial.

Methods: Open label parallel group, randomized controlled trial with objective endpoints.

Results: The percentage of eligible patients approached for consent who were recruited into the trial was 85.7% (95% CI 75.9%-98%; 30/35) and the percentage of eligible patients recruited into the trial was 66.7% (95% CI 52.9%-80.4%; 30/45). Twenty-nine participants completed the first 6 h of the trial 96.7% (95% CI 82.8%-99.9%, 29/30). Participants were highly supportive of music interventions in the target setting (mean value of 8 (SD ± 1.6) on a scale of 1-10). 95% Confidence Intervals for efficacy included clinically important differences. Specifically, the SBPV was non-significantly lower in the intervention arm (mean difference - 1.31 mmHg, [95% CI -4.8 to 2.2 mmHg]). Similarly, the adjusted β was non-significantly lower in the intervention arm for change in pain burden (-3.9 [95% CI -11.4 to 3.7]) and change in anxiety burden (-9.9 [-98.2 to 78.5]).

Interpretation: Our findings support a larger trial of music or sound interventions in hyperacute and acute stroke patients as alternatives to or synergists with pharmacologic management.

Objective: To examine the relationship of early BMI change with subsequent cognitive decline, CSF AD biomarkers alterations, and progression to dementia in patients with PD.

Methods: Study data were prospectively collected from the PPMI cohort. Weight/height data at enrollment and second-year clinical visit were utilized to calculate BMI change. Cognitive tests and CSF AD biomarkers were measured at enrollment and each visit during the 5-year follow-up. Generalized linear mixed analyses were employed to identify the impact of BMI change on the deterioration of cognitive performance and CSF AD biomarkers alterations. Cox regression analyses were employed to assess the relationship of BMI change with dementia conversion.

Results: BMI loss predicted a more rapid deterioration in global cognitive performance over time. Regarding specific cognitive domains, participants in the BMI loss group experienced a significantly more rapid decline in verbal episodic memory, language, and processing speed/attention compared with those in the stable BMI group. Additionally, patients in the BMI gain group showed a slower decline in verbal episodic memory than those in the stable BMI group. BMI loss predicted a more rapid longitudinal decrease of CSF Aβ42 over time. BMI change was not associated with the risk of progression to dementia.

Conclusions: Early BMI loss is a risk factor for faster decline in cognition and longitudinal decrease of CSF Aβ42. These findings emphasize the need to monitor early BMI change in PD patients. Attention to early BMI change may help identify those at greater risk of cognitive decline.

Background: Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive dysfunction in the elderly, and frequently coexists with Alzheimer's disease and tau pathology. Dual-phase ¹¹C-PiB PET detects amyloid deposition and cerebral perfusion changes and may have diagnostic value for identifying tau in CAA.

Methods: We prospectively enrolled patients with probable CAA for dynamic PiB and AV1451 scans. We compared early-phase (0-6 min after tracer injection) and late-phase (40-70 min) PiB PET between the tau(+) and tau(-) groups (based on AV1451 PET) and investigated their diagnostic values for detecting tau.

Results: CAA/tau(+) had lower early-phase temporal PiB uptake than CAA/tau(-) (p = 0.014) and higher late-phase uptake in the whole cortex and temporal and parietal lobes (all p < 0.05). Early-phase temporal PiB SUVR correlated with tau burden (r = -0.34, p = 0.038). Using Youden's cut-off, early-phase and late-phase PET had sensitivities of 55% and 80% and specificities of 85% and 65% for detecting tau, respectively. Combining early- and late-phase scans provided a rule-out sensitivity of 90% and rule-in specificity of 100% for tau pathology in CAA.

Conclusions: Dual-phase ¹¹C-PiB PET represents a reliable approach for assessing tau and could potentially identify CAA patients for tau biomarker testing.

Objective: The hereditary spastic-ataxia spectrum disorders are a group of disabling neurological diseases. The traditional genetic testing pathway is complex, multistep and leaves many cases unsolved. We aim to streamline and improve this process using long-read sequencing.

Methods: We developed a targeted long-read sequencing strategy with the capacity to characterise the genetic variation of all types and sizes within 469 disease-associated genes, in a single assay. We applied this to a cohort of 34 individuals with unsolved spastic-ataxia. An additional five individuals with a known genetic diagnosis were included as positive controls.

Results: We identified causative pathogenic variants that would be sufficient for genetic diagnosis in 14/34 (41%) unsolved participants. The success rate was 5/11 (45%) in those who were naïve to genetic testing and 9/23 (39%) in those who were undiagnosed after prior genetic testing, completed on a clinical basis. Short tandem repeat expansions in FGF14 were the most common (7/34, 21%). Two individuals (2/34, 6%) had biallelic pathogenic expansions in RFC1 and one individual had a monoallelic pathogenic expansion in ATXN8OS/ATXN8. Causative pathogenic sequence variants other than short tandem repeat expansions were found in four individuals, including in VCP, STUB1, ANO10 and SPG7. Furthermore, all five positive controls were identified.

Interpretation: Our results demonstrate the utility of targeted long-read sequencing in the genetic evaluation of patients with spastic-ataxia spectrum disorders, highlighting both the capacity to increase overall diagnostic yield and to streamline the testing pathway by capturing all known genetic causes in a single assay.

Objectives: This study sought to evaluate proteomic, metabolomic, and immune signatures in the cerebrospinal fluid of individuals with Down Syndrome Regression Disorder (DSRD).

Methods: A prospective case-control study comparing proteomic, metabolomic, and immune profiles in individuals with DSRD was performed. Samples were obtained from a biorepository of affected individuals and compared to clinically available data and previously obtained neurodiagnostic studies. Individuals with DSRD were compared to individuals with established neuroinflammatory conditions (e.g., multiple sclerosis), and neurotypical controls undergoing a lumbar puncture for headaches. Samples underwent high-throughput proteomic, metabolomic, and immune marker profiling. Data was compared across groups and clinical phenotypes. Gene set enrichment analysis and pathway analyses were utilized to analyze the data.

Results: In total, 34 individuals with DSRD, 22 neuroinflammatory controls, and 27 neurotypical controls were enrolled in the study. We observed a highly significant concordance in dysregulated proteomics signatures in DSRD and neuroinflammatory controls versus healthy controls, most prominently upregulation of many immunoglobulin sequences. In addition, individuals with DSRD displayed strong upregulation of liver-derived plasma proteins and erythrocyte proteins in the CSF, indicating poor blood-brain barrier integrity. The immune marker profile of DSRD is clearly similar to other neuroimmunological conditions, including strong elevation of MIP3-α, eotaxin, and IFN-γ.

Interpretation: Individuals with DSRD have unique CSF proteomic and metabolomic signatures consistent with neuroinflammation and increased blood-brain barrier permeability. The CSF of individuals with DSRD was more comparable to individuals with neuroinflammatory disorders than neurotypical controls, indicating the potential for an immune etiology of disease.

Background: LGI1-antibody encephalitis (LGI1-Ab-E) is a common form of autoimmune encephalitis where most patients demonstrate 'good' clinician-rated outcomes. However, more targeted questionnaires reveal numerous debilitating symptoms for many years. To better quantify these persistent features, we designed the LGI1-Antibody Encephalitis Rating (LANTERN) scale, a quantified, disease-specific patient-reported outcome measure (PROM), adhering to FDA guidelines.

Methods: A participant-driven mixed-methods approach to develop a clinically valid questionnaire over three stages: (1) Item generation through semi-structured interviews; (2) Repeated cognitive debriefing rounds to advance comprehensibility, relevance and comprehensiveness; (3) Psychometric survey to condense the most sensitive and valid questions. Analyses incorporated sensitivity testing with multiple internal and external validations.

Results: From 73 items across six domains (Stage 1; n = 18), a questionnaire assessing the frequency and severity of 43 symptoms (80 questions), plus nine activities of daily living (ADL), was developed through cognitive debriefing (Stage 2; n = 15). This 89-question survey was completed (Stage 3; n = 66 patients and 32 relatives) and distilled, using exploratory factor analyses, to a three-factor symptom-burden questionnaire comprising 41 questions (19 symptoms and 6 ADL), separated into physical, cognitive/behavioural and ADL domains. These factors demonstrated strong internal reliability (Cronbach alpha: 0.85-0.91), correlations with relative-completed questionnaires (R = 0.73-0.85; p < 0.001), good-to-excellent intraclass re-testing correlations (0.81-0.98; n = 19) and strong associations with numerous predefined external measures.

Discussion: LANTERN represents a PROM for LGI1-Ab-E, with initial content, structural and construct validity and test-retest reliability. It can be used as a reliable, tailored, efficient and sensitive method to establish symptom burden in people with LGI1-Ab-E, both in clinical practice and trials.