Neuropathologically-directed profiling of PRNP somatic and germline variants in sporadic human prion disease.

Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, ~1% were transmitted by misfolded PrP, ~15% are inherited, and ~85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate focal initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of >5,000X across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a focal presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.

Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Creutzfeldt-Jakob disease and other prion diseases.

Prion diseases share common clinical and pathological characteristics such as spongiform neuronal degeneration and deposition of an abnormal form of a host-derived protein, termed prion protein. The characteristic features of prion diseases are long incubation times, short clinical courses, extreme resistance of the transmissible agent to degradation and lack of nucleic acid involvement. Sporadic and genetic forms of prion diseases occur worldwide, of which genetic forms are associated with mutations in PRNP. Human to human transmission of these diseases has occurred due to iatrogenic exposure, and zoonotic forms of prion diseases are linked to bovine disease. Significant progress has been made in the diagnosis of these disorders. Clinical tools for diagnosis comprise brain imaging and cerebrospinal fluid tests. Aggregation assays for detection of the abnormally folded prion protein have a clear potential to diagnose the disease in peripherally accessible biofluids. After decades of therapeutic nihilism, new treatment strategies and clinical trials are on the horizon. Although prion diseases are relatively rare disorders, understanding their pathogenesis and mechanisms of prion protein misfolding has significantly enhanced the field in research of neurodegenerative diseases.

Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease.

INTRODUCTION: Recent data suggest that distinct prion-like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown. METHODS: Previously known AD risk loci were examined in rpAD cases. Genome-wide association studies (GWAS) were performed to identify variants that influence rpAD. RESULTS: We identified 115 pathology-confirmed rpAD cases and 193 clinical rpAD cases, 80% and 69% were of non-Hispanic European ancestry. Compared to the clinical cohort, pathology-confirmed rpAD had higher frequencies of apolipoprotein E (APOE) ε4 and rare missense variants in AD risk genes. A novel genome-wide significant locus (P < 5×10-8 ) was observed for clinical rpAD on chromosome 21 (rs2832546); 102 loci showed suggestive associations with pathology-confirmed rpAD (P < 1×10-5 ). DISCUSSION rpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD. Highlights Rapidly progressive Alzheimer's disease (rpAD) was defined with different criteria. Whole genome sequencing identified rare missense variants in rpAD. Novel variants were identified for clinical rpAD on chromosome 21.

Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases.

Definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrPSc). Our previous study revealed that PrPSc-seeding activity (PrPSc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrPSc seed amplification assay (PrPSc-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2-3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrPSc-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrPSc-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrPSc types (#1 or #2), and gene mutations in deceased patients. RT-QuIC assays of the cohort #1 by two independent laboratories gave 87.3% or 91.3% sensitivity and 94.7% or 100% specificity, respectively. The cohort #2 showed sensitivity of 89.4% and specificity of 95.5%. RT-QuIC of CSF available from 212 cases gave 89.7% sensitivity and 94.1% specificity. The sensitivity of skin RT-QuIC was subtype dependent, being highest in sCJDVV1-2 subtype, followed by VV2, MV1-2, MV1, MV2, MM1, MM1-2, MM2, and VV1. The skin area next to the ear gave highest sensitivity, followed by lower back and apex of the head. Although no difference in brain PrPSc-SA was detected between the cases with false negative and true positive skin RT-QuIC results, the disease duration was significantly longer with the false negatives [12.0 ± 13.3 (months, SD) vs. 6.5 ± 6.4, p < 0.001]. Our study validates skin PrPSc-SA as a biomarker for the detection of prion diseases, which is influenced by the PrPSc types, PRNP 129 polymorphisms, dermatome sampled, and disease duration.

Gerstmann-Sträussler-Scheinker Disease Presenting as Late-Onset Slowly Progressive Spinocerebellar Ataxia, and Comparative Case Series with Neuropathology.

BACKGROUND: Genetic prion diseases, including Gerstmann-Sträussler-Scheinker disease (GSS), are extremely rare, fatal neurodegenerative disorders, often associated with progressive ataxia and cognitive/neuropsychiatric symptoms. GSS typically presents as a rapidly progressive cerebellar ataxia, associated with cognitive decline. Late-onset cases are rare. OBJECTIVE: To compare a novel GSS phenotype with six other cases and present pathological findings from a single case. METHODS: Case series of seven GSS patients, one proceeding to autopsy. RESULTS: Case 1 developed slowly progressive gait difficulties at age 71, mimicking a spinocerebellar ataxia, with a family history of balance problems in old age. Genome sequencing revealed a heterozygous c.392G > A (p.G131E) pathogenic variant and a c.395A > G resulting in p.129 M/V polymorphism in the PRNP gene. Probability analyses considering family history, phenotype, and a similar previously reported point mutation (p.G131V) suggest p.G131E as a new pathogenic variant. Clinical features and imaging of this case are compared with those six additional cases harboring p.P102L mutations. Autopsy findings of a case are described and were consistent with the prion pathology of GSS. CONCLUSIONS: We describe a patient with GSS with a novel p.G131E mutation in the PRNP gene, presenting with a late-onset, slowly progressive phenotype, mimicking a spinocerebellar ataxia, and six additional cases with the typical P102L mutation.

Efficient transmission of human prion diseases to a glycan-free prion protein-expressing host.

It is increasingly evident that the association of glycans with the prion protein (PrP), a major post-translational modification, significantly impacts the pathogenesis of prion diseases. A recent bioassay study has provided evidence that the presence of PrP glycans decreases spongiform degeneration and disease-related PrP (PrPD) deposition in a murine model. We challenged (PRNPN181Q/197Q) transgenic (Tg) mice expressing glycan-free human PrP (TgGlyc-), with isolates from sporadic Creutzfeldt-Jakob disease subtype MM2 (sCJDMM2), sporadic fatal insomnia and familial fatal insomnia, three human prion diseases that are distinct but share histotypic and PrPD features. TgGlyc- mice accurately replicated the basic histotypic features associated with the three diseases but the transmission was characterized by high attack rates, shortened incubation periods and a greatly increased severity of the histopathology, including the presence of up to 40 times higher quantities of PrPD that formed prominent deposits. Although the engineered protease-resistant PrPD shared at least some features of the secondary structure and the presence of the anchorless PrPD variant with the wild-type PrPD, it exhibited different density gradient profiles of the PrPD aggregates and a higher stability index. The severity of the histopathological features including PrP deposition appeared to be related to the incubation period duration. These findings are clearly consistent with the protective role of the PrP glycans but also emphasize the complexity of the conformational changes that impact PrPD following glycan knockout. Future studies will determine whether these features apply broadly to other human prion diseases or are PrPD-type dependent.

Pathological findings in autoimmune encephalitis autopsy specimens from cases of suspected prion disease.

OBJECTIVE: The underlying pathology of autoimmune encephalitis is not well characterized due to the limited opportunities to study tissue specimens. Autopsy specimens available at prion surveillance centers from patients with suspected Creutzfeldt-Jakob disease offer a unique opportunity to study the pathology of autoimmune encephalitis. Our objective was to describe pathological findings of autoimmune encephalitis specimens submitted to the U.S. National Prion Disease Pathology Surveillance Center. METHODS: Pathology reports were obtained from the National Prion Center. Specimens negative for prion disease were screened for inflammatory pathology and those suggestive of autoimmune encephalitis were analyzed. Cases identified on autopsy were compared to institutional cases with fatal seronegative autoimmune encephalitis and available brain biopsy. RESULTS: Between 1998 and 2022, 7934 specimens were evaluated of which 2998 (38%) were negative for prion protein. Querying the database for alternative diagnoses of encephalitis/encephalopathy yielded 43 cases that were screened by an experienced neuropathologist yielding 14 (0.5%) cases consistent with autoimmune encephalitis. Most specimens showed diffuse inflammation involving the limbic system (86%), basal ganglia (86%), cortex (71%), diencephalon (71%), and in some cases the brainstem (43%) and cerebellum (43%). Lymphocytic inflammatory infiltrate was predominantly perivascular with parenchymal extension in 64%. Microglial activation/nodules were seen in 64% of cases. Neuronal loss was present only in 50%. Pathological findings were identical to biopsy specimens from our institutional cohort. DISCUSSION: Seronegative AE may have consistent pathology with diffuse or multifocal perivascular inflammation and microglial activation. Half the patients do not have neuronal loss suggesting a potential for neurological recovery. These findings are preliminary and require further confirmation.

Novel histotypes of sporadic Creutzfeldt-Jakob disease linked to 129MV genotype.

The MV1 and MV2 subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) are linked to the heterozygous methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene. MV2 is phenotypically heterogeneous, whereas MV1, due to its low prevalence, is one of the least well characterized subtypes. In this study, we investigated the biochemical properties of PrPSc and phenotypic expression of cases diagnosed as sCJD MV1 and MV2. We describe four MV2 histotypes: 2C, with cortical (C) coarse pathology; 2K, with kuru (K) plaque deposits; 2C-K, with co-existing C and K histotypic features; and the novel histotype 2C-PL that mimics 2C in the cerebral cortex and cerebellum, but exhibits plaque-like (PL) PrP deposits in subcortical regions (e.g., basal nuclei, thalamus and midbrain). Histotype prevalence is highest for 2C-K (55%), intermediate for 2C (31%), and lowest for 2C-PL and 2K (7%). Nearly every MV2 case expressed both PrPSc types, with T2 being the predominant type ("MV2-1"). MV1 cases typically show a rapid disease course (≤ 4 months), and feature the 1C histotype, phenotypically identical to sCJDMM1. Co-existing PrPSc types, with T1 significantly exceeding T2 ("MV1-2"), are detected in patients diagnosed as MV1 with longer disease courses. We observed four histotypes among MV1-2 cases, including two novel histotypes: 1V, reminiscent of sCJDVV1; 1C-2C, resembling sCJDMM1-2 with predominant MM1 histotypic component; and novel histotypes 1C-2PL and 1C-2K, overall mimicking 1C in the cerebral cortex, but harboring T2 and plaque-like PrP deposits in subcortical regions (1C-2PL), and T2 and kuru plaques in the cerebellum (1C-2K). Lesion profiles of 1C, 1V, and 1C-2C are similar, but differ from 1C-2PL and 1C-2K, as the latter two groups show prominent hippocampal and nigral degeneration. We believe that the novel "C-PL" histotypes are distinct entities rather than intermediate forms between "C" and "C-K" groups, and that 1C-2PL and 1C-2K histotypes may be characterized by different T1 variants of the same size.

Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.

OBJECTIVE: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. METHODS: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. RESULTS: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. INTERPRETATION: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

A novel subtype of sporadic Creutzfeldt-Jakob disease with PRNP codon 129MM genotype and PrP plaques.

The presence of amyloid kuru plaques is a pathological hallmark of sporadic Creutzfeldt-Jakob disease (sCJD) of the MV2K subtype. Recently, PrP plaques (p) have been described in the white matter of a small group of CJD (p-CJD) cases with the 129MM genotype and carrying resPrPD type 1 (T1). Despite the different histopathological phenotype, the gel mobility and molecular features of p-CJD resPrPD T1 mimic those of sCJDMM1, the most common human prion disease. Here, we describe the clinical features, histopathology, and molecular properties of two distinct PrP plaque phenotypes affecting the gray matter (pGM) or the white matter (pWM) of sCJD cases with the PrP 129MM genotype (sCJDMM). Prevalence of pGM- and pWM-CJD proved comparable and was estimated to be ~ 0.6% among sporadic prion diseases and ~ 1.1% among the sCJDMM group. Mean age at onset (61 and 68 years) and disease duration (~ 7 months) of pWM- and pGM-CJD did not differ significantly. PrP plaques were mostly confined to the cerebellar cortex in pGM-CJD, but were ubiquitous in pWM-CJD. Typing of resPrPD T1 showed an unglycosylated fragment of ~ 20 kDa (T120) in pGM-CJD and sCJDMM1 patients, while a doublet of ~ 21-20 kDa (T121-20) was a molecular signature of pWM-CJD in subcortical regions. In addition, conformational characteristics of pWM-CJD resPrPD T1 differed from those of pGM-CJD and sCJDMM1. Inoculation of pWM-CJD and sCJDMM1 brain extracts to transgenic mice expressing human PrP reproduced the histotype with PrP plaques only in mice challenged with pWM-CJD. Furthermore, T120 of pWM-CJD, but not T121, was propagated in mice. These data suggest that T121 and T120 of pWM-CJD, and T120 of sCJDMM1 are distinct prion strains. Further studies are required to shed light on the etiology of p-CJD cases, particularly those of T120 of the novel pGM-CJD subtype.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Creutzfeldt-Jakob Disease Misdiagnosed as Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar syndromes. Although consensus criteria have been widely used to diagnose MSA, accurate clinical diagnosis remains challenging. Other neurodegenerative disorders, such as Lewy body disease, can mimic MSA. Objectives: We described clinical and neuropathologic findings of two patients with Creutzfeldt-Jakob disease (CJD) who had antemortem clinical diagnoses of MSA. Methods: The brain bank for neurodegenerative disorders was queried for cases with a clinical diagnosis of MSA, but neuropathologic findings of CJD. Results: Case 1 was a 55-year-old man with a 6-month history of orthostatic hypotension, parkinsonism, cerebellar ataxia, bradyphrenia, and memory impairment. Case 2 was a 65-year-old man who had a 5-year history of cerebellar ataxia, parkinsonism, and cognitive impairment, as well as a 7-year history of dream enactment behavior. Neither case had characteristic α-synuclein immunoreactive neuronal or glial inclusions typical of MSA. Instead, they had spongiform encephalopathy with neuronal loss and gliosis with prion protein-immunoreactive kuru-like plaques. Genetic analyses in case 1 had wild-type PRNP, whereas case 2 revealed a 4-octapeptide repeat insertion in PRNP. Conclusions: Even when clinical features suggest MSA, CJD should also be considered if the progression is rapid or the disease course is atypical, such as the absence of autonomic dysfunction for an extended period.

A discriminative event-based model for subtype diagnosis of sporadic Creutzfeldt-Jakob disease using brain MRI.

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) comprises multiple subtypes (MM1, MM2, MV1, MV2C, MV2K, VV1, and VV2) with distinct disease durations and spatiotemporal cascades of brain lesions. Our goal was to establish the ante mortem diagnosis of sCJD subtype, based on patient-specific estimates of the spatiotemporal cascade of lesions detected by diffusion-weighted magnetic resonance imaging (DWI). METHODS: We included 488 patients with autopsy-confirmed diagnosis of sCJD subtype and 50 patients with exclusion of prion disease. We applied a discriminative event-based model (DEBM) to infer the spatiotemporal cascades of lesions, derived from the DWI scores of 12 brain regions assigned by three neuroradiologists. Based on the DEBM cascades and the prion protein genotype at codon 129, we developed and validated a novel algorithm for the diagnosis of the sCJD subtype. RESULTS: Cascades of MM1, MM2, MV1, MV2C, and VV1 originated in the parietal cortex and, following subtype-specific orderings of propagation, went toward the striatum, thalamus, and cerebellum; conversely, VV2 and MV2K cascades showed a striatum-to-cortex propagation. The proposed algorithm achieved 76.5% balanced accuracy for the sCJD subtype diagnosis, with low rater dependency (differences in accuracy of ± 1% among neuroradiologists). DISCUSSION: Ante mortem diagnosis of sCJD subtype is feasible with this novel data-driven approach, and it may be valuable for patient prognostication, stratification in targeted clinical trials, and future therapeutics. HIGHLIGHTS: Subtype diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) is achievable with diffusion MRI. Cascades of diffusion MRI abnormalities in the brain are subtype-specific in sCJD. We proposed a diagnostic algorithm based on cascades of diffusion MRI abnormalities and demonstrated that it is accurate. Our method may aid early diagnosis, prognosis, stratification in clinical trials, and future therapeutics. The present approach is applicable to other neurodegenerative diseases, enhancing the differential diagnoses.

Multisite ALLFTD study modeling progressive empathy loss from the earliest stages of behavioral variant frontotemporal dementia.

INTRODUCTION: Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress. METHODS: Four hundred thirty-one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51). RESULTS: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy. DISCUSSION: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

Genetic aspects of human prion diseases.

Human prion diseases are rapidly progressive and fatal neurodegenerative conditions caused by a disease-causing isoform of the native prion protein. The prion protein gene (PRNP) encodes for the cellular prion protein, which is the biological substrate for prion disease transmission and neurotoxicity. Human prion diseases have three etiologies: sporadic, genetic, and acquired. PRNP polymorphisms and pathogenic variants play a large role in the frequency, age at onset, and clinicopathologic phenotype of prion diseases. Genetic prion diseases will be covered in detail and information necessary for clinical care, predictive genetic testing, and genetic counseling will be reviewed. Because the prion protein is necessary for transmission and neurotoxicity, many experimental treatments targeting its production are being investigated and hold potential promise as a disease modifying treatment for all forms of prion disease, including asymptomatic mutation carriers. This article will review genetic aspects of human prion disease and their influence on epidemiology, clinicopathologic phenotype, diagnostics, clinical management, and potential treatment approaches.

Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration.

BACKGROUND AND OBJECTIVES: Familial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes. METHODS: We screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy-Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test. RESULTS: We identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants. DISCUSSION: We present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders. TRIAL REGISTRATION INFORMATION: NCT02365922, NCT02372773, and NCT04363684.

Sensitivity of the Social Behavior Observer Checklist to Early Symptoms of Patients With Frontotemporal Dementia.

BACKGROUND AND OBJECTIVES: Changes in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes. METHODS: Asymptomatic individuals and neurodegenerative disease patients were selected from the multisite ALLFTD cohort study. In a sample of participants with at least one timepoint of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy. RESULTS: 1082 FTLD mutation carriers and non-carriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 non-fluent variant primary progressive aphasia, 137 progressive supranuclear palsy, 113 Alzheimer's clinical syndrome). The Disorganized score increased between asymptomatic to very mild (p=0.016, estimate=-1.10, 95%CI=[-1.99, -0.22]), very mild to mild (p=0.013, -1.17, [-2.08, -0.26]), and mild to moderate/severe (p<0.001, -2.00, [-2.55, -1.45]) disease stages in behavioral variant frontotemporal dementia regardless of mutation status. Asymptomatic GRN pathogenic gene variant carriers showed more Reactive behaviors (preoccupation with time: p=0.001, 1.11, [1.06, 1.16]; self-consciousness: p=0.003, 1.77, [1.52, 2.01]) than asymptomatic non-carriers (1.01, [0.98, 1.03]; 1.31, [1.20, 1.41]). Insensitive score increased to a clinically abnormal level in advanced stages of behavioral variant frontotemporal dementia (p=0.003, -0.73, [-1.18, -0.29]). Higher scores on each subscale corresponded with higher caregiver burden (p<0.001). Greater change over time corresponded to greater fronto-subcortical atrophy in the semantic-appraisal and fronto-parietal intrinsically connected networks. DISCUSSION: The SBOCL is sensitive to early symptoms and reflects disease severity, with some evidence for progression across asymptomatic and symptomatic stages of FTLD syndromes; thus it may hold promise for early measurement and monitoring of behavioral symptoms in clinical practice and treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the Social Behavior Observer Checklist is sensitive to early behavioral changes in FTLD pathogenic variants and early symptomatic individuals in a highly educated patient cohort.