IMPORTANCE Individuals with tuberous sclerosis complex can develop a progressive neuropsychiatric syndrome known as tuberous sclerosis-associated neuropsychiatric disorders. Tuberous sclerosis-associated neuropsychiatric disorders symptoms overlap with clinical criteria for frontotemporal dementia, yet the association between the 2 has not been explored.OBJECTIVE To investigate the potential association between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia. DESIGN, SETTING, AND PARTICIPANTSCase-control study that enrolled patients with tuberous sclerosis complex with normal IQs in an observational clinical study at the University of California, San Francisco, from 2017 to 2019 where they underwent a comprehensive clinical evaluation including neuropsychologic testing, cerebral spinal fluid biomarker profiling, and structural neuroimaging. The study included adults who fulfilled the clinical criteria for tuberous sclerosis complex and had normal IQs, had frontotemporal dementia, or were healthy control individuals. MAIN OUTCOMES AND MEASURESTuberous sclerosis-associated neuropsychiatric disorders checklist severity score, neuropsychologic test scores, cerebral spinal fluid concentrations of phosphorylated tau 181 , total tau, amyloid-β 42, and neurofilament light chain. Amyloid and tau positron emission tomography scans were obtained in a subset of patients.RESULTS Eighteen patients with tuberous sclerosis complex (mean [SD] age, 48 years [9.54]; 13 women [72%]), 16 with frontotemporal dementia (60 [6.93] years; 7 women [44%]) and 18 healthy control individuals (63 [3.85] years; 9 women [50%]) were included. The tuberous sclerosis-associated neuropsychiatric disorders checklist and neuropsychological test results were not significantly different when the tuberous sclerosis complex and frontotemporal dementia cohorts were compared. The tuberous sclerosis complex cohort exhibited elevated cerebral spinal fluid phosphorylated tau 181 and neurofilament light chain with a mean of 32 pg/mL and 2300 pg/mL, respectively, when compared to healthy control individuals. All 3 patients with tuberous sclerosis complex who underwent fluorine 1B-labeled flortaucipir tau positron emission tomographic neuroimaging showed punctate foci of elevated [ 18 F]flortaucipir binding in the frontal and temporal regions.CONCLUSIONS AND RELEVANCE Adults with tuberous sclerosis complex showed phenotypic overlap with frontotemporal dementia. The results support a possible clinical continuum between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia and highlights a potential pathophysiological link between neurodevelopmental and neurodegenerative processes. Quantitative neuropsychological testing and the tuberous sclerosis-associated neuropsychiatric disorders checklist, potentially supplemented by cerebral spinal fluid and imaging biomarkers, could be used to screen and prognosticate for risk of a neurodegenerative process in adult patients with tuberous sclerosis complex.

Objective:To develop a patient/care-giver reported scale capable of easily and reliably assessing functional disability in 4 repeat tauopathies (4RTs).Background:4R tauopathies including progressive supranuclear palsy, corticobasal degeneration and a subset of frontotemporal dementias manifest a range of overlapping clinical phenotypes. No available rating scale is capable of evaluating the functional impact of these complex disorders.Methods:A multi-staged modified Delphi process was used to propose, evaluate and rank potential scale items providing content validity ratios. Staged cognitive pretesting involving input from examiners, patients and caregivers was followed by validation testing in patients participating in the 4R Tauopathy Neuroimaging Initiative or the PROgressive Supranuclear Palsy CorTico-Basal Syndrome MSA Longitudinal Study. Clinimetric properties were examined using classical test theory and item response methods, assessing data quality, reliability, construct validity, convergent validity and known-group validity.Results:The resultant Cortical Basal ganglia Functional Scale (CBFS) included questions on Motor Experiences in Daily Living (14 items) and Non-Motor Experiences of Daily Living (17 items). Reliability was acceptable for internal consistency, test-retest stability, item discrimination, item-scaling thresholds and item-fit. Examination of construct validity revealed a parsimonious two-factor solution, and concurrent validity demonstrated significant correlations between the CBFS and other measures of disease severity and functional impairment. The CBFS significantly discriminated between all diagnostic groups and controls (all AUCs>90). The CBFS scores demonstrated sensitivity to change over a 12 follow-up in patients with probable 4RTs. Conclusions:The CBFS is a patient/care-giver reported outcome measure with excellent clinimetric properties that captures disability correlated with motor, cognitive and psychiatric impairments.

BackgroundChronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored.MethodsPlasma neurofilament light chain (NfL) levels were measured from ReBUILD trial’s participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period.ResultsNfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=−0.035 [−0.068 to −0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [−0.0004 to 0.007], p=0.081). Based on a Cohen’s d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power.ConclusionsIn pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination.Trial registration numberNCT02040298.