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Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicityin vivo, we prion-challenged conditional knockout mice (male and female) havingHrsdeleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration.SIGNIFICANCE STATEMENTPrion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrPC), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrPC-mediated neurotoxic signaling.

Grey matter involvement is a well-known feature in sporadic Creutzfeldt-Jakob disease (sCJD), yet precise anatomy-based quantification of reduced diffusivity is still not fully understood. Default Mode Network (DMN) areas have been recently demonstrated as selectively involved in sCJD, and functional connectivity has never been investigated in prion diseases. We analyzed the grey matter involvement using a quantitatively multi-parametric MRI approach. Specifically, grey matter mean diffusivity of 37 subjects with sCJD was compared with that of 30 age-matched healthy controls with a group-wise approach. Differences in mean diffusivity were also examined between the cortical (MM(V)1, MM(V)2C, and VV1) and subcortical (VV2 and MV2K) subgroups of sCJD for those with autopsy data available (n = 27, 73%). We also assessed resting-state functional connectivity of both ventral and dorsal components of DMN in a subset of subject with a rs-fMRI dataset available (n = 17). Decreased diffusivity was predominantly present in posterior cortical regions of the DMN, but also outside of the DMN in temporal areas and in a few limbic and frontal areas, in addition to extensive deep nuclei involvement. Both subcortical and cortical sCJD subgroups showed decreased diffusivity subcortically, whereas only the cortical type expressed significantly decreased diffusivity cortically, mainly in parietal, occipital, and medial-inferior temporal cortices bilaterally. Interestingly, we found abnormally increased connectivity in both dorsal and ventral components of the DMN in sCJD subjects compared with healthy controls. The significance and possible utility of functional imaging as a biomarker for tracking disease progression in prion disease needs to be explored further.

Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt–Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann–Sträussler–Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt–Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt–Jakob disease-E200K, Gerstmann–Sträussler–Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.

Introduction People with suspected Alzheimer’s disease and related dementias (ADRD) and their families experience a burdensome process while seeking a diagnosis. These challenges are problematic in the most common dementia syndromes, but they can be even more distressing in rarer, atypical syndromes such as rapidly progressive dementias (RPDs), which can be fatal within months from onset. This study is an examination of the diagnostic journey experience from the perspective of caregivers of people who died from the prototypic RPD, sporadic Creutzfeldt-Jakob Disease (sCJD). Methods eIn this mixed-methods study, qualitative data were drawn from interviews with former caregivers of 12 people who died from sCJD. Chart review data were drawn from research and clinical chart data about the person with sCJD. Data were analyzed by a multidisciplinary research team using qualitative and descriptive statistical analysis. Results We identified 4 overarching themes that characterized the experience of the diagnostic journey in sCJD: clinician knowledge, clinician communication, experiences of uncertainty, and the caregiver as advocate. We also identified 4 phases along the diagnostic journey: recognition, the diagnostic workup, diagnosis, and post-diagnosis. Sub-themes within each phase include struggles to recognize what is wrong, complex processes of testing and referrals, delay and disclosure of diagnosis, and access to resources post-diagnosis. Conclusions Findings suggest that more work is needed to improve clinician diagnostic knowledge and communication practices. Furthermore, caregivers need better support during the diagnostic journey. What we learn from studying sCJD and other RPDs is likely applicable to other more common dementias.

Movement disorders are a prominent and common feature in many autoantibody-mediated neuropsychiatric disorders and are caused by an expanding spectrum of antibodies. Depending on the presenting and early symptoms, patients with these disorders are often referred to psychiatrists or general, movement disorder and/or behavioral neurologists. Clinicians need to be aware of these conditions in order to know when to consider and test for them, as many are treatable if not reversible. Improved awareness and understanding of these disorders will help with early identification and prompt treatment, thereby reducing long-term morbidity and mortality. This chapter will focus on the most common autoimmune, especially antibody-mediated, syndromes associated with psychiatric and movement disorders. Many of the autoimmune-mediated movement disorders discussed in this chapter are often associated with other features, including psychiatric/behavioral disorders, limbic encephalitis, and other symptoms. Autoimmune limbic encephalitis (ALE) is a syndrome in which parts of the limbic system are involved and classically presents with features including short-term memory loss, irritability, depression, hallucinations, sleep disturbances, and/or seizures.

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion - maximum normal repeat length) /maximum normal repeat length) × (current age - age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal and potentially transmissible neurodegenerative disease caused by misfolded prion proteins (PrP(Sc)). To date, effective therapeutics are not available and accurate diagnosis can be challenging. Clinical diagnostic criteria employ a combination of characteristic neuropsychiatric symptoms, cerebrospinal fluid (CSF) proteins 14–3-3, MRI, and EEG. Supportive biomarkers such as high CSF total Tau may aid the diagnostic process. Discordant results of studies however, have led to controversies about the clinical value of some established surrogate biomarkers. The recent development and clinical application of disease-specific protein aggregation and amplification assays such as Real-time Quaking Induced Conversion (RT-QuIC) have constituted major breakthroughs for the confident pre-mortem diagnosis of sCJD. Updated criteria for the diagnosis of sCJD including RT-QuIC will improve early clinical confirmation, surveillance, assessment of PrP(Sc) seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under current investigation.

Quantitative susceptibility mapping (QSM) is a promising tool for investigating iron dysregulation in neurodegenerative diseases, including Huntington's disease (HD). A diverse range of methods have been proposed to generate accurate and robust QSM images. In this study, we evaluated the performance of different dipole inversion algorithms for iron-sensitive susceptibility imaging at 7T on healthy subjects of large age range and patients with HD. We compared an iterative least-squares-based method (iLSQR), iterative methods that use regularization, single-step approaches, and deep learning-based techniques. Their performance was evaluated by comparing: (1) deviations from a multiple-orientation QSM reference; (2) visual appearance of QSM maps and the presence of artifacts; (3) susceptibility in subcortical brain regions with age; (4) regional brain susceptibility with published postmortem brain iron quantification; and (5) susceptibility in HD-affected basal ganglia regions between HD subjects and healthy controls. We found that single-step QSM methods with either total variation or total generalized variation constraints (SSTV/SSTGV) and the single-step deep learning method iQSM generally provided the best performance in terms of correlation with iron deposition and were better at differentiating between healthy controls and premanifest HD individuals, while deep learning QSM methods trained with multiple-orientation susceptibility data created QSM maps that were most similar to the multiple orientation reference and with the best visual scores.

Objective Real‐time quaking‐induced conversion (RT‐QuIC) assays detect prion‐seeding activity in a variety of human biospecimens, including cerebrospinal fluid and olfactory mucosa swabs. The assay has shown high diagnostic accuracy in patients with prion disorders. Recently, advances in these tests have led to markedly improved diagnostic sensitivity and reduced assay times. Accordingly, an algorithm has been proposed that entails the use of RT‐QuIC analysis of both sample types to diagnose sporadic Creutzfeldt‐Jakob disease with nearly 100% accuracy. Here we present a multi‐center evaluation (ring trial) of the reproducibility of these improved “second generation” RT‐QuIC assays as applied to these diagnostic specimens. Methods Cerebrospinal fluid samples were analyzed from subjects with sporadic Creutzfeldt‐Jakob (n = 55) or other neurological diseases (n = 45) at multiple clinical centers. Olfactory mucosa brushings collected by multiple otolaryngologists were obtained from nine sporadic Creutzfeldt‐Jakob disease cases and 19 controls. These sample sets were initially tested blindly by RT‐QuIC by a coordinating laboratory, recoded, and then sent to five additional testing laboratories for blinded ring trial testing. Results Unblinding of the results by a third party indicated 98‐100% concordance between the results obtained by the testing of these cerebrospinal fluid and nasal brushings at the six laboratories. Interpretation This second‐generation RT‐QuIC assay is highly transferrable, reproducible, and therefore robust for the diagnosis of sporadic Creutzfeldt‐Jakob disease in clinical practice.

Purpose of review To systematically review the clinical features, diagnosis, and management of anti-gamma-aminobutyric acid receptor Type A (GABAA) autoimmune encephalitis with a focus on recent data. Recent findings In a review of published reports, we identified 50 cases of anti-GABAA receptor encephalitis with clinical features reported. The median age at presentation was 47 years old (range, 2.5 months-88 years old), 64% were adults, 36% were children and it occurred in both males and females. Eight-two percent (41/50) presented with seizures, 72% (36/50) with encephalopathy, and 58% (29/50) with both. Of those presenting with seizures, 42% developed status epilepticus during their disease course. Ninety-six percent (48/50) had MRI results reported, with 83% of these cases having abnormal findings, most commonly multifocal/diffuse cortical and subcortical T2/FLAIR hyperintense lesions without associated gadolinium enhancement. Almost one-third, 28% (14/50), had an associated malignancy detected by the time of diagnosis, 64% (9/14) of which was thymoma. Of 44 patients with outcomes reported, 80% had partial or complete recovery, whereas 20% had poor outcomes including 11% (5/44) who died. Of the 42 patients with type of treatment(s) and outcomes reported, 54% (23/42) received only first-line immunotherapy and 31% (13/42) received first-line and second-line immunotherapy. Receiving a combination of first-line and second-line immunotherapy may be associated with higher likelihood of complete recovery. When follow-up MRIs were reported, all showed improvement, and sometimes complete resolution, of T2/FLAIR hyperintensities. Summary Anti-GABAA receptor encephalitis can present across the age spectrum and should be considered in patients who present with rapidly progressive encephalopathy and/or seizures. Brain MRI often shows a distinctive pattern of multifocal cortical and subcortical T2/FLAIR hyperintense lesions, generally not typical of other known central nervous system autoantibody associated encephalitis syndromes. High clinical suspicion and early diagnosis are important given the potential for clinical improvement with immunotherapy.

ImportanceAutoimmune encephalitis misdiagnosis can lead to harm.ObjectiveTo determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.Design, Setting, and ParticipantsThis retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), Washington University in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded.Main Outcomes and MeasuresData were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions.ResultsA total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficits from comorbidities (11 [10%]), cerebral neoplasm (10 [9.5%]), and other (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 [46%] vs 7 of 91 [8%]) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-d-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]).Conclusions and RelevanceWhen evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.

Highlights • Quantitative MRI metrics (MD, Volume) can be combined to stage sCJD radiologically. • Quantitative multiparametric approach improves sCJD clinical-imaging correlation. • MRI Disease-Staging might be useful to track sCJD progression., Diffusion imaging is very useful for the diagnosis of sporadic Creutzfeldt-Jakob disease, but it has limitations in tracking disease progression as mean diffusivity changes non-linearly across the disease course. We previously showed that mean diffusivity changes across the disease course follow a quasi J-shaped curve, characterized by decreased values in earlier phases and increasing values later in the disease course. Understanding how MRI metrics change over-time, as well as their correlations with clinical deficits are crucial steps in developing radiological biomarkers for trials. Specifically, as mean diffusivity does not change linearly and atrophy mainly occurs in later stages, neither alone is likely to be a sufficient biomarker throughout the disease course. We therefore developed a model combining mean diffusivity and Volume loss (MRI Disease-Staging) to take into account mean diffusivity’s non-linearity. We then assessed the associations between clinical outcomes and mean diffusivity alone, Volume alone and finally MRI Disease-Staging. In 37 sporadic Creutzfeldt-Jakob disease subjects and 30 age- and sex-matched healthy controls, high angular resolution diffusion and high-resolution T1 imaging was performed cross-sectionally to compute z-scores for mean diffusivity (MD) and Volume. Average MD and Volume were extracted from 41 GM volume of interest (VOI) per hemisphere, within the images registered to the Montreal Neurological Institute (MNI) space. Each subject’s volume of interest was classified as either “involved” or “not involved” using a statistical threshold of ± 2 standard deviation (SD) for mean diffusivity changes and/or −2 SD for Volume. Volumes of interest were MRI Disease-Staged as: 0 = no abnormalities; 1 = decreased mean diffusivity only; 2 = decreased mean diffusivity and Volume; 3 = normal (“pseudo-normalized”) mean diffusivity, reduced Volume; 4 = increased mean diffusivity, reduced Volume. We correlated Volume, MD and MRI Disease-Staging with several clinical outcomes (scales, score and symptoms) using 4 major regions of interest (Total, Cortical, Subcortical and Cerebellar gray matter) or smaller regions pre-specified based on known neuroanatomical correlates. Volume and MD z-scores correlated inversely with each other in all four major ROIs (cortical, subcortical, cerebellar and total) highlighting that ROIs with lower Volumes had higher MD and vice-versa. Regarding correlations with symptoms and scores, higher MD correlated with worse Mini-Mental State Examination and Barthel scores in cortical and cerebellar gray matter, but subjects with cortical sensory deficits showed lower MD in the primary sensory cortex. Volume loss correlated with lower Mini-Mental State Examination, Barthel scores and pyramidal signs. Interestingly, for both Volume and MD, changes within the cerebellar ROI showed strong correlations with both MMSE and Barthel. Supporting using a combination of MD and Volume to track sCJD progression, MRI Disease-Staging showed correlations with more clinical outcomes than Volume or MD alone, specifically with Mini-Mental State Examination, Barthel score, pyramidal signs, higher cortical sensory deficits, as well as executive and visual-spatial deficits. Additionally, when subjects in the cohort were subdivided into tertiles based on their Barthel scores and their percentile of disease duration/course (“Time-Ratio”), subjects in the lowest (most impaired) Barthel tertile showed a much greater proportion of more advanced MRI Disease-Stages than the those in the highest tertile. Similarly, subjects in the last Time-Ratio tertile (last tertile of disease) showed a much greater proportion of more advanced MRI Disease-Stages than the earliest tertile. Therefore, in later disease stages, as measured by time or Barthel, there is overall more Volume loss and increasing MD. A combined multiparametric quantitative MRI Disease-Staging is a useful tool to track sporadic Creutzfeldt-Jakob- disease progression radiologically.

ObjectiveTo describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures.MethodsSEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with SEZ6L2 to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons.ResultsIn addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54–69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons.ConclusionsSEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.

Author(s): Sundaram, Saranya E; Staffaroni, Adam M; Walker, Nicole C; Casaletto, Kaitlin B; Casey, Megan; Golubjatnikov, Aili; Metcalf, Stacy; O'Leary, Kelly; Wong, Katherine; Benisano, Kendra; Forner, Sven; Gonzalez Catalan, Marta; Allen, Isabel E; Rosen, Howard J; Kramer, Joel H; Geschwind, Michael D | Abstract: ObjectiveFew studies have captured the neuropsychological profile of sporadic Creutzfeldt-Jakob disease (sCJD) with neuropsychological testing, and little is known about cognitive predictors of survival. We characterized baseline neuropsychological performance in sCJD and investigated associations with survival.MethodssCJD participants who completed the MMSE (n = 118), 61 sCJD of whom also completed a neuropsychological battery at baseline, and 135 age-matched healthy controls, were included. Composite scores of global cognition, memory, executive functions, visuospatial, and language were derived. Cox proportional hazard models estimated survival time, controlling for age and education. Additional models adjusted for Barthel Index and PRNP codon 129 polymorphism.ResultssCJD participants performed significantly worse than controls on all cognitive tasks and composites with most showing very large effect sizes. The three tests showing the largest group differences were delayed verbal recall (Hedges'g = 4.08, P l 0.0001), Stroop Inhibition (Hedges'g = 3.14, P l 0.0001), and Modified Trails (Hedges'g = 2.94, P l 0.0001). Memory (95%) and executive functioning (87%) composites were most commonly impaired. Poorer global (HR = 0.65, P l 0.0001), visuospatial (HR = 0.82, P l 0.0001), and memory (HR = 0.82, P = 0.01) composites predicted shorter survival. Visuospatial cognition remained a significant predictor even after adjusting for all other cognitive composites; each standard deviation decrease in visuospatial cognition was associated with an 18% higher chance of death (HR = 0.82, P l 0.003). Global (HR = 0.68, P = 0.03) and visuospatial (HR = 0.82, P = 0.001) composites remained significant predictors after controlling for Barthel Index and codon 129.InterpretationsCJD participants exhibit a broad range of cognitive impairments, with memory and executive functioning deficits in the vast majority. Neuropsychological assessment, particularly of visuospatial abilities, informs prognostication in sCJD.

To systematically review the clinical features, diagnosis, and management of anti-gamma-aminobutyric acid receptor Type A (GABAA) autoimmune encephalitis with a focus on recent data.In a review of published reports, we identified 50 cases of anti-GABAA receptor encephalitis with clinical features reported. The median age at presentation was 47 years old (range, 2.5 months-88 years old), 64% were adults, 36% were children and it occurred in both males and females. Eight-two percent (41/50) presented with seizures, 72% (36/50) with encephalopathy, and 58% (29/50) with both. Of those presenting with seizures, 42% developed status epilepticus during their disease course. Ninety-six percent (48/50) had MRI results reported, with 83% of these cases having abnormal findings, most commonly multifocal/diffuse cortical and subcortical T2/FLAIR hyperintense lesions without associated gadolinium enhancement. Almost one-third, 28% (14/50), had an associated malignancy detected by the time of diagnosis, 64% (9/14) of which was thymoma. Of 44 patients with outcomes reported, 80% had partial or complete recovery, whereas 20% had poor outcomes including 11% (5/44) who died. Of the 42 patients with type of treatment(s) and outcomes reported, 54% (23/42) received only first-line immunotherapy and 31% (13/42) received first-line and second-line immunotherapy. Receiving a combination of first-line and second-line immunotherapy may be associated with higher likelihood of complete recovery. When follow-up MRIs were reported, all showed improvement, and sometimes complete resolution, of T2/FLAIR hyperintensities.Anti-GABAA receptor encephalitis can present across the age spectrum and should be considered in patients who present with rapidly progressive encephalopathy and/or seizures. Brain MRI often shows a distinctive pattern of multifocal cortical and subcortical T2/FLAIR hyperintense lesions, generally not typical of other known central nervous system autoantibody associated encephalitis syndromes. High clinical suspicion and early diagnosis are important given the potential for clinical improvement with immunotherapy.

Background Dysphagia is a common symptom and may be a cause of death in patients with spinocerebellar ataxias (SCAs). However, little is known about at which disease stage dysphagia becomes clinically relevant. Therefore, our study aims to investigate the prevalence of dysphagia in different disease stages of SCA 1, 2, 3 and 6. Methods We studied 237 genetically confirmed patients with SCA 1, 2, 3, 6 from the Clinical Research Consortium for SCAs and investigated the prevalence of self-reported dysphagia and the association between dysphagia and other clinical characteristics. We further stratified ataxia severity and studied the prevalence of dysphagia at each disease stage. Results Dysphagia was present in 59.9% of SCA patients. Patients with dysphagia had a longer disease duration and more severe ataxia than patients without dysphagia (patients with dysphagia vs. without dysphagia, disease duration (years): 14.51 ± 8.91 vs. 11.22 ± 7.82, p = .001, scale for the assessment and rating of ataxia [SARA]: 17.90 ± 7.74 vs. 13.04 ± 7.51, p = .000). Dysphagia was most common in SCA1, followed by SCA3, SCA 6, and SCA 2. Dysphagia in SCA1 and 3 was associated robustly with ataxia severity, whereas this association was less obvious in SCA2 and 6, demonstrating genotype-specific clinical variation. Conclusion Dysphagia is a common clinical symptom in SCAs, especially in the severe disease stage. Understanding dysphagia in SCA patients can improve the care of these patients and advance knowledge on the roles of the cerebellum and brainstem control in swallowing.

Mammalian prions are lethal pathogens composed of fibrillar assemblies of misfolded prion protein. Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the gene that encodes prion protein (PRNP) are strong risk factors for sCJD, but although the condition has heritability similar to other neurodegenerative disorders, no other risk loci have yet been confirmed. By genome-wide association in European ancestry populations, we found three replicated loci (cases n=5208, within PRNP, STX6, and GAL3ST1) and two further unreplicated loci were significant in gene-wide tests (within PDIA4, BMERB1). Exome sequencing in 407 sCJD cases, conditional and transcription analyses suggest that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 and PDIA4 associate with increased expression of the major transcripts in disease-relevant brain regions. Alteration of STX6 expression does not modify prion propagation in a neuroblastoma cell model of mouse prion infection. We went on to analyse the proteins histologically in diseased tissue and examine the effects of risk variants on clinical phenotypes using deep longitudinal clinical cohort data. Risk SNPs in STX6, a protein involved in the intracellular trafficking of proteins and vesicles, are shared with progressive supranuclear palsy, a neurodegenerative disease associated with the misfolded protein tau. We present the first evidence of statistically robust associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism.

We describe a rare case of a patient with rapid onset, prominent cognitive and behavioral changes who presented to our rapidly progressive dementia program with symptoms ultimately attributed to bilateral basal ganglia infarcts involving the caudate heads. We review the longitudinal clinical presentation and neuropsychological testing for this patient, and discuss the implicated basal ganglia and frontal lobe neuroanatomy.

Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1+/-) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.

Background For a variety of sporadic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, it is well-established that ethnicity does affect the disease phenotypes. However, how ethnicity contributes to the clinical symptoms and disease progressions in monogenetic disorders, such as spinocerebellar ataxia type 3 (SCA3), remains less studied. Methods We used multivariable linear and logistical regression models in 257 molecularly-confirmed SCA3 patients (66 Caucasians, 43 African Americans, and 148 Asians [composed of 131 Chinese and 17 Asian Americans]) to explore the influence of ethnicity on age at onset (AAO), ataxia severity, and non-ataxia symptoms (i.e. depression, tremor, and dystonia). Results We found that Asians had significantly later AAO, compared to Caucasians (β = 4.75, p = 0.000) and to African Americans (β = 6.64, p = 0.000) after adjusting for the pathological CAG repeat numbers in ATXN3. African Americans exhibited the most severe ataxia as compared to Caucasians (β = 3.81, p = 0.004) and Asians (β = 4.39, p = 0.001) after taking into consideration of the pathological CAG repeat numbers in ATXN3 and disease duration. Caucasians had a higher prevalence of depression than African Americans (β = 1.23, p = 0.040). Ethnicity had no influence on tremor or dystonia. Conclusions Ethnicity plays an important role in clinical presentations of SCA3 patients, which could merit further clinical studies and public health consideration. These results highlight the role of ethnicity in monogenetic, neurodegenerative disorders.

Background and ObjectivesTo study human leukocyte antigen (HLA) allele associations in anti-leucine–rich glioma-inactivated 1 (LGI1) encephalitis.MethodsA multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using χ2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable.ResultsDRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e−50) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequently female (p = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, p = 4.57 × 10−6 and OR = 8.93, p = 2.50 × 10−3, respectively). DRB1*04:02 was also independently associated with younger age at onset (β = −6.68, p = 9.78 × 10−3). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms.DiscussionIn addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.

Prions diseases are uniformly fatal neurodegenerative diseases that occur in sporadic, genetic, and acquired forms. Acquired prion diseases, caused by infectious transmission, are least common. Most prion diseases are not infectious, but occur spontaneously through misfolding of normal prion proteins or genetic mutations in the prion protein gene. Although most prion diseases are not caused by infection, they can be transmitted accidentally. Certain infection control protocols should be applied when handling central nervous system and other high-risk tissues. New diagnostic methods are improving premortem and earlier diagnosis. Treatment trials have not shown improved survival, but therapies may be available soon.

Background Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. Methods We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Findings Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17–1·30], p=2·68 × 10 −15; heterozygous model p=1·01 × 10 −135), STX6 (rs3747957; OR 1·16 [1·10–1·22], p=9·74 × 10 −9), and GAL3ST1 (rs2267161; OR 1·18 [1·12–1·25], p=8·60 × 10 −10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. Interpretation We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Funding Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.

ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.

Jakob–Creutzfeldt disease (JCD) is a rare prion-mediated disease that causes rapidly progressive dementia. Prions are pathogenic, misfolded proteins that propagate via an infection-like mechanism from person to person (e.g., kuru and iatrogenic JCD) and through zoonotic means (e.g., variant JCD). Prions also occur sporadically and genetically. JCD has a broad range of phenotypic and clinical characteristics, which overlap with many neurological and psychiatric disorders, making diagnosis difficult. New diagnostic techniques, including diffusion-weighted magnetic resonance imaging and real-time quaking-induced conversion have increased the accuracy of JCD diagnosis. Despite these improvements, JCD continues to be difficult to diagnose, and clinicians often need to generate a broad differential diagnosis and systematically rule out mimicking disorders before confidently diagnosing JCD. Although there are currently no effective disease-modifying treatments, clinical trials, emerging treatment approaches, and interventions for preventing prion disease transmission are discussed in this chapter.

ObjectiveWe sought to validate methods for detection and confirmation of GABAA receptor (R)-IgG and clinically characterize seropositive cases.MethodsArchived serum and CSF specimens (185 total) suspected to harbor GABAAR-IgG were evaluated by indirect immunofluorescence assay (IFA). Twenty-six specimens from 19 patients appeared suspicious for GABAAR–IgG positivity by IFA, based on prior reports and comparison with commercial GABAAR antibody staining. Aliquots of those specimens were tested at the University of Oxford, United Kingdom, and Euroimmun, Lubeck, Germany, for GABAAR-IgG by cell-based assays (CBAs) using HEK293-indicator cells transfected with plasmids encoding different GABAAR subunits.ResultsEight specimens (of 26 tested; 4 serums, 4 CSFs) from 5 patients were confirmed by CBA to be GABAAR-IgG positive. Patient IgGs were always reactive with α1β3 GABAAR subunits. One more patient was identified clinically after this validation study. Median age for the 6 patients at serologic diagnosis was 44 years (range, 1–71 years), and 4 of them were male. Among the 4 for whom clinical information was available (2 treated by the authors), all had encephalitis and antiepileptic drug refractory seizures. Three out of 4 patients treated with a combination of immunotherapies had good outcomes. The fourth, recognized to have an autoimmune cause late in the clinical course, had severe permanent neurologic sequelae and brain atrophy.ConclusionsThough not as common as NMDA-R encephalitis, GABAAR encephalitis generally has a characteristic clinical-radiologic presentation and is treatable, making accurate laboratory diagnosis critical.

Objective We sought to validate methods for detection and confirmation of GABAA receptor (R)-IgG and clinically characterize seropositive cases. Methods Archived serum and CSF specimens (185 total) suspected to harbor GABAAR-IgG were evaluated by indirect immunofluorescence assay (IFA). Twenty-six specimens from 19 patients appeared suspicious for GABAAR–IgG positivity by IFA, based on prior reports and comparison with commercial GABAAR antibody staining. Aliquots of those specimens were tested at the University of Oxford, United Kingdom, and Euroimmun, Lubeck, Germany, for GABAAR-IgG by cell-based assays (CBAs) using HEK293-indicator cells transfected with plasmids encoding different GABAAR subunits. Results Eight specimens (of 26 tested; 4 serums, 4 CSFs) from 5 patients were confirmed by CBA to be GABAAR-IgG positive. Patient IgGs were always reactive with α1β3 GABAAR subunits. One more patient was identified clinically after this validation study. Median age for the 6 patients at serologic diagnosis was 44 years (range, 1–71 years), and 4 of them were male. Among the 4 for whom clinical information was available (2 treated by the authors), all had encephalitis and antiepileptic drug refractory seizures. Three out of 4 patients treated with a combination of immunotherapies had good outcomes. The fourth, recognized to have an autoimmune cause late in the clinical course, had severe permanent neurologic sequelae and brain atrophy. Conclusions Though not as common as NMDA-R encephalitis, GABAAR encephalitis generally has a characteristic clinical-radiologic presentation and is treatable, making accurate laboratory diagnosis critical.

BACKGROUND: Cerebellar degenerative pathology has been identified in tremor patients; however, how the degenerative pathology could contribute to tremor remains unclear. If the cerebellar degenerative pathology can directly drive tremor, one would hypothesize that tremor is likely to occur in the diseases of cerebellar ataxia and follows the disease progression in such disorders. METHODS: To further test this hypothesis, we studied the occurrence of tremor in different disease stages of classical cerebellar degenerative disorders: spinocerebellar ataxias (SCAs). We further separately analyzed postural tremor and rest tremor, two forms of tremor that both involve the cerebellum. We also explored tremor in different subtypes of SCAs. RESULTS: We found that 18.1% of SCA patients have tremor. Interestingly, SCA patients with tremor have worse ataxia than those without tremor. When stratifying patients into mild, moderate, and severe disease stages according to the severity of ataxia, moderate and severe SCA patients more commonly have tremor than those with mild ataxia, the effect most prominently observed in postural tremor of SCA3 and SCA6 patients. Finally, tremor can independently contribute to worse functional status in SCA2 patients, even after adjusting for ataxia severity. CONCLUSIONS: Tremor is more likely to occur in the severe stage of cerebellar degeneration when compared to mild stages. Our results partially support the cerebellar degenerative model of tremor.

Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Sträussler-Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. © 2016 Wiley Periodicals, Inc.

Summary How mutations in the microtubule-associated protein tau (MAPT) gene cause frontotemporal dementia (FTD) remains poorly understood. We generated and characterized multiple induced pluripotent stem cell (iPSC) lines from patients with MAPT IVS10+16 and tau-A152T mutations and a control subject. In cortical neurons differentiated from these and other published iPSC lines, we found that MAPT mutations do not affect neuronal differentiation but increase the 4R/3R tau ratio. Patient neurons had significantly higher levels of MMP-9 and MMP-2 and were more sensitive to stress-induced cell death. Inhibitors of MMP-9/MMP-2 protected patient neurons from stress-induced cell death and recombinant MMP-9/MMP-2 were sufficient to decrease neuronal survival. In tau-A152T neurons, inhibition of the ERK pathway decreased MMP-9 expression. Moreover, ectopic expression of 4R but not 3R tau-A152T in HEK293 cells increased MMP-9 expression and ERK phosphorylation. These findings provide insights into the molecular pathogenesis of FTD and suggest a potential therapeutic target for FTD with MAPT mutations., Highlights • New iPSC lines with MAPT p.A152T and IVS10+16 mutations are generated • MMP-2 and MMP-9 production is elevated in human neurons with MAPT mutations • Elevated MMP-2 and MMP-9 contribute to stress-induced neuronal cell death • Mutant tau increases ERK phosphorylation that activates MMP-9 expression, In this article, Gao and colleagues generated multiple iPSC lines from patients with MAPT IVS10+16 and tau-A152T mutations and found that significantly higher levels of MMP-9/MMP-2 in patient neurons contribute to stress-induced neuronal cell death. 4R but not 3R tau-A152T activates ERK, which in turn increases MMP-9 expression. These results provide insights into the molecular pathogenesis of FTD.

PurposeHuntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content.MethodsNew item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD.ResultsModerate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose.ConclusionsHDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

ObjectiveTo determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.MethodsWe assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.ResultsGenetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.ConclusionThe characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.