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BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged

Abstract Objective Currently, it is unknown whether infectious prions are present in peripheral tissues and biological fluids of patients affected by sporadic Creutzfeldt–Jakob disease (sCJD), the most common prion disorder in humans. This represents a potential risk for inter‐individual prion infection. The main goal of this study was to evaluate the presence of prions in urine of patients suffering from the major subtypes of sCJD. Methods Urine samples from sCJD patients spanning the six major subtypes were tested. As controls, we used urine samples from people affected by other neurological or neurodegenerative diseases as well as healthy controls. These samples were analyzed blinded. The presence of prions was detected by a modified version of the PMCA technology, specifically optimized for high sensitive detection of sCJD prions. Results The PMCA assay was first optimized to detect low quantities of prions in diluted brain homogenates from patients affected by all subtypes of sCJD spiked into healthy urine. Twenty‐nine of the 81 patients affected by sCJD analyzed in this study were positive by PMCA testing, whereas none of the 160 controls showed any signal. These results indicate a 36% sensitivity and 100% specificity. The subtypes with the highest positivity rate were VV1 and VV2, which combined account for about 15–20% of all sCJD cases, and no detection was observed in MV1 and MM2. Interpretation Our findings indicate that potentially infectious prions are secreted in urine of some sCJD patients, suggesting a possible risk for inter‐individual transmission. Prion detection in urine might be used as a noninvasive preliminary screening test to detect sCJD.

Abstract Introduction Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD‐mApp). Methods A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC‐FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD‐mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys. Results It was feasible for participants to complete the ALLFTD‐mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests. Discussion These findings suggest that the ALLFTD‐mApp study protocol is feasible and acceptable for remote FTD research. HIGHLIGHTS The ALLFTD Mobile App is a smartphone‐based platform for remote, self‐administered data collection. The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities. Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders. Remote digital data collection was well accepted by participants with a variety of diagnoses.

Abstract Definitive diagnosis of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) relies on postmortem finding of disease-associated alpha-synuclein (αSynD) as misfolded protein aggregates in the central nervous system (CNS). The recent development of the real-time quaking induced conversion (RT-QuIC) assay for ultrasensitive detection of αSynD aggregates has revitalized the diagnostic values of clinically accessible biospecimens, including cerebrospinal fluid (CSF) and peripheral tissues. However, the current αSyn RT-QuIC assay platforms vary widely and are thus challenging to implement and standardize the measurements of αSynD across a wide range of biospecimens and in different laboratories. We have streamlined αSyn RT-QuIC assay based on a second generation assay platform that was assembled entirely with commercial reagents. The streamlined RT-QuIC method consisted of a simplified protocol requiring minimal hands-on time, and allowing for a uniform analysis of αSynD in different types of biospecimens from PD and DLB. Ultrasensitive and specific RT-QuIC detection of αSynD aggregates was achieved in million-fold diluted brain homogenates and in nanoliters of CSF from PD and DLB cases but not from controls. Comparative analysis revealed higher seeding activity of αSynD in DLB than PD in both brain homogenates and CSF. Our assay was further validated with CSF samples of 214 neuropathologically confirmed cases from tissue repositories (88 PD, 58 DLB, and 68 controls), yielding a sensitivity of 98% and a specificity of 100%. Finally, a single RT-QuIC assay protocol was employed uniformly to detect seeding activity of αSynD in PD samples across different types of tissues including the brain, skin, salivary gland, and colon. We anticipate that our streamlined protocol will enable interested laboratories to easily and rapidly implement the αSyn RT-QuIC assay for various clinical specimens from PD and DLB. The utilization of commercial products for all assay components will improve the robustness and standardization of the RT-QuIC assay for diagnostic applications across different sites. Due to ultralow sample consumption, the ultrasensitive RT-QuIC assay will facilitate efficient use and sharing of scarce resources of biospecimens. Our streamlined RT-QuIC assay is suitable to track the distribution of αSynD in CNS and peripheral tissues of affected patients. The ongoing evaluation of RT-QuIC assay of αSynD as a potential biomarker for PD and DLB in clinically accessible biospecimens has broad implications for understanding disease pathogenesis, improving early and differential diagnosis, and monitoring therapeutic efficacies in clinical trials.

Abstract Introduction Conventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z‐scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z‐scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency. Methods In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance). Results Corrected Z‐scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted‐R2. Discussion Nonlinearly corrected Z‐scores with respect to age, sex, and education with age‐varying residual standard deviation allow for improved detection of non‐normative extreme cognitive scores.

Abstract Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive traumatic brain injury (TBI). CTE is generally found in athletes participating in contact sports and military personnel exposed to explosive blasts but can also affect civilians. Clinically and pathologically, CTE overlaps with post-traumatic stress disorder (PTSD), a term mostly used in a clinical context. The histopathology of CTE is defined by the deposition of hyperphosphorylated tau protein in neurons and astrocytes preferentially with perivascular distribution and at the depths of the cortical sulci. In addition to hyperphosphorylated tau, other pathologic proteins are deposited in CTE, including amyloid β (Aβ), transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and α-synuclein. However, the coexistence of prion disease in CTE has not been observed. We report three cases of histopathologically validated CTE with co-existing sporadic prion disease. Two were identified in a cohort of 55 pathologically verified cases of CTE submitted to the CTE Center of Boston University. One was identified among brain tissues submitted to the National Prion Disease Pathology Surveillance Center of Case Western Reserve University. The histopathological phenotype and properties of the abnormal, disease-related prion protein (PrPD) of the three CTE cases were examined using lesion profile, immunohistochemistry, electrophoresis and conformational tests. Subjects with sporadic Creutzfeldt-Jakob disease (sCJD) matched for age, PrP genotype and PrPD type were used as controls. The histopathology phenotype and PrPD properties of the three CTE subjects showed no significant differences from their respective sCJD controls suggesting that recurring neurotrauma or coexisting CTE pathology did not detectably impact the prion disease phenotype and PrPD conformational characteristics. Based on the reported incidence of sporadic prion disease, the detection of two cases with sCJD in the CTE Center series of 55 CTE cases by chance alone would be highly unlikely (p = 8.93*10− 6). Nevertheless, examination of a larger cohort of CTE is required to conclusively determine whether the risk of CJD is significantly increased in patients with CTE.

Abstract Background Prion diseases are a group of lethal neurodegenerative conditions that occur when the normal, cellular form of the prion protein (PrPC) is converted into an abnormal, scrapie, form of the protein (PrPSc). Disease may be caused by genetic, infectious, or sporadic etiologies. The genetic form of prion disease comprises~10%–15% of all cases. Prion disease is typically inherited in an autosomal dominant manner. The low incidence of disease makes it highly unlikely that a patient would have two different pathogenic variants. However, we recently identified a case in which the patient did have two pathogenic PRNP variants and presented with an atypical phenotype. Methods The patient was evaluated at the Washington Hospital Healthcare System in Fremont, CA. The clinical information for this case report was obtained retrospectively. Variants in the PRNP were identified by polymerase chain reaction (PCR) amplification of exon two of the gene followed by bi‐directional sequence analysis. To determine the phase of the identified variants, a restriction enzyme digestion was utilized, followed by sequence analysis of the products. Cerebral spinal fluid (CSF) was analyzed for surrogate markers of prion disease, 14–3–3 and Tau proteins. CSF real‐time quaking‐induced conversion (RT‐QuIC) assays were also performed. Results The patient was a compound heterozygote for the well‐characterized c.628G>A (p.Val210Ile) variant and the rare octapeptide deletion of two repeats [c.202_249del48 (p.P68_Q83del)]. Clinically, the patient presented with an early onset demyelinating peripheral neuropathy, followed by later onset cognitive symptoms. Conclusion This presentation is reminiscent of prion protein knockout mice whose predominate symptom, due to complete loss of PrP, was late‐onset peripheral neuropathy. To our knowledge this is the first case reported of a patient with prion disease who had two different pathogenic variants in PRNP.