Annals of Clinical and Translational Neurology最新文献

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.

Background: Cognitive impairment is one of the most common and debilitating symptoms of relapsing-remitting multiple sclerosis (RRMS). Digital cognitive biomarkers require less time and resources and are rapidly gaining popularity in clinical settings. We examined the longitudinal trajectory of the iPad-based Processing Speed Test (PST) and predictors of PST scores.

Methods: We prospectively enrolled RRMS patients between 2017 and 2021 across six Australian MS centres. Longitudinal data was analysed with mixed effect modelling and latent class mixed models. We then examined whether latent class group membership predicted confirmed decrease in correct PST responses.

Results: We recruited a total of 1093 participants, of which 724 had complete baseline data with a median follow up duration of 2 years. At a population level, PST trajectory was stable. A small practice effect was present up to the 4th visit. Age, baseline disability, T2 lesion volume, male sex and depression were associated with lower correct PST responses, whilst years of education and full/part-time employment were associated with more correct PST responses. We identified four latent class trajectories of PST. The worst latent class was typified by low baseline PST and lack of a practice effect. Being in the worst latent class was associated with a greater hazard of time to sustained 5% decrease in PST (HR 2.84, 95% CI 1.16-6.94, p = 0.02).

Conclusion: Worse baseline cognitive performance and lack of a practice effect predicted future cognitive decline in RRMS.

Dietary manipulations like ketogenic diets are established interventions for recalcitrant epilepsy. However, it remains unknown whether specific macronutrient exposure through dietary environments could possibly extend to primary preventive qualities, associated with changes in epilepsy disease burden (prevalence and incidence). Here, macronutrient supply, GDP, and idiopathic epilepsy disease burden data were collated from more than 150 countries from 1990 to 2018. Nutritional geometry generalized additive mixed models (GAMMs) modeling unraveled that dietary environments with high-fat and low-carbohydrate supplies were linked to lower epilepsy incidence and prevalence. Our analyses suggested a plausible primary preventive role of dietary manipulations for epilepsy.