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Introduction: Incorporation of the real-time quaking-induced conversion (RT-QuIC) assays for diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) has transformed diagnosis largely related to its extremely high specificity. However, the test has a c.10% false-negative result and we aim to characterize the clinical features, investigation profile, and molecular subtype in this cohort of patients., Methods: 250 individuals diagnosed with definite sporadic CJD were identified from the UK National CJD Research and Surveillance Unit from 2012 to 2023. We compared the clinical features and investigation profile in those with a negative CSF RT-QuIC to those with a positive RT-QuIC., Results: 27 individuals (10.8%) were CSF RT-QuIC negative. Median age of onset was younger (62 years vs 68 years, p = 0.002), median disease duration was longer (4.4 months vs 10.5 months, p < 0.001), and these individuals were less likely to present with gait difficulties (73% vs 93%, p = 0.003) or motor symptoms (62% vs 80%, p = 0.04). The sensitivity of electroencephalography and diffusion-weighted MRI were similar in both groups. In those who were RT-QuIC negative, there was an overrepresentation of the VV1 (32% vs 1%) and MM2 molecular subtypes (21% vs 3%). Co-occurring neurodegenerative disease was found in 33% (9/27) of those who were RT-QuIC negative., Conclusions: Individuals with sporadic CJD and a negative CSF RT-QuIC present with younger age of onset, different clinical features and are over-represented with the VV1 and MM2 subtypes of sporadic CJD. Further work is required to better understand the biochemical properties contributing to RT-QuIC negative results in these cases., (© 2024. The Author(s).)

Prion real-time quaking-induced conversion (RT-QuIC) is emerging as the most potent assay for the in vivo diagnosis of Creutzfeldt-Jakob disease (CJD), but its full application, especially as a screening test, is limited by suboptimal substrate availability, reagent costs, and incomplete assay standardization. Therefore, the search for the most informative cerebrospinal fluid (CSF) surrogate biomarker is still of primary importance. We compared the diagnostic accuracy of CSF protein 14-3-3, measured with both western blot (WB) and enzyme-linked immunosorbent assay (ELISA), total (t)-tau and neurofilament light chain protein (NfL) alone or in combination with RT-QuIC in 212 subjects with rapidly progressive dementia in which we reached a highly probable clinical diagnosis at follow-up or a definite neuropathological diagnosis. T-tau performed best as surrogate CSF biomarker for the diagnosis of CJD (91.3% sensitivity and 78.9% specificity). The 14-3-3 ELISA assay demonstrated a slightly higher diagnostic value compared to the WB analysis (76.9% vs. 72.2%), but both methods performed worse than the t-tau assay. NfL was the most sensitive biomarker for all sCJD subtypes (> 95%), including those with low values of t-tau or 14-3-3, but showed the lowest specificity (43.1%). When ELISA-based biomarkers were adopted as screening tests followed by RT-QuIC, t-tau correctly excluded a higher number of non-CJD cases compared to NfL and 14-3-3 ELISA. Our study showed that among the CSF surrogate biomarkers of potential application for the clinical diagnosis of CJD, t-tau performs best either alone or as screening test followed by RT-QuIC as a second-level confirmatory test.

Background: Evaluation of the application of CSF real-time quaking-induced conversion in Creutzfeldt-Jakob disease surveillance to investigate test accuracy, influencing factors, and associations with disease incidence., Methods: In a prospective surveillance study, CSF real-time quaking-induced conversion was performed in patients with clinical suspicion of prion disease (2014-2022). Clinically or histochemically characterized patients with sporadic Creutzfeldt-Jakob disease (n = 888) and patients with final diagnosis of non-prion disease (n = 371) were included for accuracy and association studies., Results: The overall test sensitivity for sporadic Creutzfeldt-Jakob disease was 90% and the specificity 99%. Lower sensitivity was associated with early disease stage (p = 0.029) and longer survival (p < 0.001). The frequency of false positives was significantly higher in patients with inflammatory CNS diseases (3.7%) than in other diagnoses (0.4%, p = 0.027). The incidence increased from 1.7 per million person-years (2006-2017) to 2.0 after the test was added to diagnostic the criteria (2018-2021)., Conclusion: We validated high diagnostic accuracy of CSF real-time quaking-induced conversion but identified inflammatory brain disease as a potential source of (rare) false-positive results, indicating thorough consideration of this condition in the differential diagnosis of Creutzfeldt-Jakob disease. The surveillance improved after amendment of the diagnostic criteria, whereas the incidence showed no suggestive alterations during the COVID-19 pandemic., (© 2023. The Author(s).)

Multiple system atrophy is a rare, debilitating, adult-onset neurodegenerative disorder that manifests clinically as a diverse combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is pathologically characterized by oligodendroglial cytoplasmic inclusions containing abnormally aggregated α-synuclein. According to the updated Movement Disorder Society diagnostic criteria for multiple system atrophy, the diagnosis of clinically established multiple system atrophy requires the manifestation of autonomic dysfunction in combination with poorly levo-dopa responsive parkinsonism and/or cerebellar syndrome. Although symptomatic management of multiple system atrophy can substantially improve quality of life, therapeutic benefits are often limited, ephemeral, and they fail to modify the disease progression and eradicate underlying causes. Consequently, effective breakthrough treatments that target the causes of disease are needed. Numerous preclinical and clinical studies are currently focusing on a set of hallmarks of neurodegenerative diseases to slow or halt the progression of multiple system atrophy: pathological protein aggregation, synaptic dysfunction, aberrant proteostasis, neuronal inflammation, and neuronal cell death. Meanwhile, specific biomarkers and measurements with higher specificity and sensitivity are being developed for the diagnosis of multiple system atrophy, particularly for early detection of the disease. More intriguingly, a growing number of new disease-modifying candidates, which can be used to design multi-targeted, personalized treatment in patients, are being investigated, notwithstanding the failure of most previous attempts., (© 2024. The Author(s).)

Parkinson's disease (PD) may be misdiagnosed due to the clinical overlap between PD and atypical parkinsonism. The utility of α-Synuclein (αSyn) Seed Amplification Assay (SAA) as a diagnostic indicator for PD has been reported in numerous studies, but never when administered as a validated clinical laboratory test. This study compares results from αSyn-SAA validation testing performed using well-characterized cohorts from two biorepositories to better understand the accuracy of PD clinical diagnosis. Blinded cerebrospinal fluid (CSF) specimens from a repository that included cohorts of subjects clinically diagnosed as PD or healthy controls, both with confirmatory dopamine transporter single-photon emission computed tomography (DAT SPECT) imaging, and blinded CSF specimens from a repository that included cohorts of subjects clinically diagnosed as PD or healthy controls based on clinical diagnosis alone, were tested as part of the validation studies for the diagnostic αSyn-SAA test (SYNTap® Biomarker Test). Measured αSyn-SAA test accuracy was 83.9% using clinical diagnosis as comparator, and 93.6% using clinical diagnosis with confirmatory DAT- SPECT imaging as comparator. The statistically significant discordance between accuracy determinations using specimens classified using different diagnostic inclusion criteria indicates that there is some symbiosis between dopamine-weighted imaging and αSyn-SAA results, both of which are associated with higher accuracy compared with the clinical diagnosis alone., (© 2023. The Author(s).)

Introduction: Sporadic Creutzfeldt-Jakob Disease (sCJD) is the commonest human prion disease, with a median age of onset of 68 years. We characterise the clinical, investigation, and neuropathological features in young individuals with sCJD using data from UK national CJD surveillance., Methods: Referrals between 2011 and 2021 were examined, with definite (post-mortem confirmed) or probable sCJD cases included. Clinical features, MRI, EEG, CSF RT-QuIC, 14-3-3, PRNP sequencing and neuropathological findings were examined. We compared younger (≤ 50 years age of onset) with older individuals. Records of Non-sCJD referrals were also reviewed., Results: 46 (4%) young individuals were identified (age at onset 25-50) from 1178 cases. 15 (33%) were autopsy confirmed. Psychiatric disturbance (37% vs 22%, p = 0.02) and headache (11% vs 3%, p = 0.01) at presentation, and longer disease duration (by 1.45 months, 95% CI 0.43-2.79, logrank p = 0.007) were commoner. CSF RT-QuIC showed lower sensitivity (82% vs 93%, p = 0.02). There was no difference in sensitivity of MR brain or CSF 14-3-3. There were no significant co-pathologies in autopsy-confirmed cases. For non-sCJD referrals, 41 cases were of other CJD subtypes, and 7 non-prion diagnoses., Conclusions: Young-onset sCJD is more likely to present with neuropsychiatric symptoms and headache, longer disease duration, and lower sensitivity of RT-QuIC. These findings may be driven by the underlying molecular subtypes. Our results guide the evaluation of younger individuals presenting with rapidly progressive cognitive, neuropsychiatric, and motor decline, and emphasise the need for additional vigilance for atypical features by clinicians and CJD surveillance programmes worldwide., (© 2022. The Author(s).)

Creutzfeldt-Jakob disease (CJD) is a rare, uniformly fatal prion disease. Although CJD commonly presents with rapidly progressive dementia, ataxia, and myoclonus, substantial clinicopathological heterogeneity is observed in clinical practice. Unusual and predominantly cognitive clinical manifestations of CJD mimicking common dementia syndromes are known to pose as an obstacle to early diagnosis and prognosis. We report a series of three patients with probable or definite CJD (one male and two females, ages 52, 58 and 68) who presented to our tertiary behavioral neurology clinic at Mayo Clinic Rochester that met criteria for a newly defined progressive dysexecutive syndrome. Glucose hypometabolism patterns assessed by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) strongly resembled those of dysexecutive variant of Alzheimer's disease (dAD). However, magnetic resonance imaging (MRI) demonstrated restricted diffusion in neocortical areas and deep nuclei, while cerebrospinal fluid biomarkers indicated abnormal levels of 14-3-3, total-tau, and prion seeding activity (RT-QuIC), establishing the diagnosis of CJD. Electroencephalogram (EEG) additionally revealed features previously documented in atypical cases of CJD. This series of clinical cases demonstrates that CJD can present with a predominantly dysexecutive syndrome and FDG-PET hypometabolism typically seen in dAD. This prompts for the need to integrate information on clinical course with multimodal imaging and fluid biomarkers to provide a precise etiology for dementia syndromes. This has important clinical implications for the diagnosis and prognosis of CJD in the context of emerging clinical characterization of progressive dysexecutive syndromes in neurodegenerative diseases like dAD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Accurate definition and operational criteria for diagnosing Parkinson's disease (PD) are crucial for evidence-based, patient-centered care., Objective: To offer evidence-based recommendations for defining and diagnosing PD, incorporating contemporary clinical, imaging, biomarker, and genetic insights., Methods: The guideline development began with the steering committee establishing key PICO (patient, intervention, comparison, outcome) questions, which were refined by the coauthors. Systematic literature searches identified relevant studies, reviews, and meta-analyses. Recommendations were drafted, evaluated, optimized, and voted upon by the German Parkinson's Guideline Group., Results: Parkinson's disease (PD) is now understood to encompass a broader spectrum of etiologies than previously recognized. Advances in molecular pathogenesis, neuroimaging, and early clinical phenotypes suggest that PD is not a uniform disease entity and is often not idiopathic. This necessitates an updated framework for PD definition and diagnosis. The German Society for Neurology now endorses a broader concept of PD, incorporating both idiopathic and hereditary forms, as opposed to the previously narrower concept of "idiopathic Parkinson syndrome." The revised guidelines recommend using the 2015 Movement Disorders Society diagnostic criteria, emphasize the importance of long-term clinical follow-up for improved diagnostic accuracy, and highlight the significance of non-motor symptoms in clinical diagnosis. Specific recommendations are provided for the use of imaging and fluid biomarkers and genetic testing to support the clinical diagnosis., Conclusion: The updated guidelines from the German Society for Neurology enhance diagnostic accuracy for PD, promoting optimized clinical care., Competing Interests: Declarations Conflicts of interest None., (© 2024. The Author(s).)

Objective: This study aimed to determine the prevalence and clinical features of Parkinson's disease (PD)/PD dementia (PD/PDD) or dementia with Lewy bodies (DLB) in idiopathic normal pressure hydrocephalus (iNPH)., Methods: Patients with iNPH who were admitted to the Department of Neurology, Juntendo University School of Medicine over the past 10 years have been retrospectively analyzed. The diagnosis of iNPH and concomitant PD/PDD or DLB was established using diagnostic criteria. Motor symptoms were assessed by the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III. 123 I-ioflupane single-photon emission computed tomography (DaT-SPECT) and cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC)-based assay were performed for alpha synuclein aggregation., Results: Overall, 79 patients met the criteria for iNPH, of which 34 developed iNPH without accompanying disorders (iNPHa; 43%), 23 developed iNPH with comorbid PD/PDD (iNPHc + PD/PDD; 29.1%), and 8 developed iNPH with comorbid DLB (iNPHc + DLB; 10.1%). Significant differences in facial expansion and upper-limb parkinsonism were observed with a comorbidity of either PD/PDD or DLB. The specific binding ratio (SBR) of DaTscan was reduced in iNPHa (p = 0.02), but it reduced further with comorbid PD/PDD (p < 0.01) or DLB (p < 0.01). RT-QuIC was positive for all 13 comorbid PD/PDD and negative for all 19 iNPHa., Conclusion: These results highlight that synucleinopathies coexist with iNPH. These can be differentiated by performing DaTscan and RT-QuIC, which can affect its clinical features., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate brain MRI abnormalities in a cohort of patients with rapidly progressive dementia (RPD) with and without a diagnosis of Creutzfeldt-Jakob disease (CJD)., Methods: One hundred and seven patients with diagnosis of prion disease (60 with definite sCJD, 33 with probable sCJD and 14 with genetic prion disease) and 40 non-prion related RPD patients (npRPD) underwent brain MRI including DWI and FLAIR. MRIs were evaluated with a semiquantitative rating score, which separately considered abnormal signal extent and intensity in 22 brain regions. Clinical findings at onset, disease duration, cerebrospinal-fluid 14-3-3 and t-tau protein levels, and EEG data were recorded., Results: Among patients with definite/probable diagnosis of CJD or genetic prion disease, 2/107 had normal DWI-MRI: in one patient a 2-months follow-up DWI-MRI showed CJD-related changes while the other had autopsy-proven CJD despite no DWI abnormalities 282 days after clinical onset. CJD-related cortical changes were detected in all lobes and involvement of thalamus was common. In the npRPD groups, 6/40 patients showed DWI alterations that clustered in three different patterns: (1) minimal/doubtful signal alterations (limbic encephalitis, dementia with Lewy bodies); (2) clearly suggestive of alternative diagnoses (status epilepticus, Wernicke or metabolic encephalopathy); (3) highly suggestive of CJD (mitochondrial disease), though cortical swelling let exclude CJD., Conclusions: In the diagnostic work-up of RPD, negative/doubtful DWI makes CJD diagnosis rather unlikely, while specific DWI patterns help differentiating CJD from alternative diagnoses. The pulvinar sign is not exclusive of the variant form., (© 2023. The Author(s).)

Background: Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is considered as a prodromal stage of either multiple system atrophy (MSA) or Lewy body disease (LBD; Parkinson's disease and dementia with Lewy bodies). However, current knowledge is limited in predicting and differentiating the type of future phenoconversion in iRBD patients. We investigated the role of plasma neurofilament light chain (NfL) and cardiac metaiodobenzylguanidine (MIBG) uptake as predictors for phenoconversion., Methods: Forty patients with iRBD were enrolled between April 2018 and October 2019 and prospectively followed every 3 months to determine phenoconversion to either MSA or LBD. Plasma NfL levels were measured at enrollment. Cardiac MIBG uptake and striatal dopamine transporter uptake were assessed at baseline., Results: Patients were followed for a median of 2.92 years. Four patients converted to MSA and 7 to LBD. Plasma NfL level at baseline was significantly higher in future MSA-converters (median 23.2 pg/mL) when compared with the rest of the samples (median 14.1 pg/mL, p = 0.003). NfL level above 21.3 pg/mL predicted phenoconversion to MSA with the sensitivity of 100% and specificity of 94.3%. Baseline MIBG heart-to-mediastinum ratio of LBD-converters (median 1.10) was significantly lower when compared with the rest (median 2.00, p < 0.001). Heart-to-mediastinum ratio below 1.545 predicted phenoconversion to LBD with the sensitivity of 100% and specificity of 92.9%., Conclusions: Plasma NfL and cardiac MIBG uptake may be useful biomarkers in predicting phenoconversion of iRBD. Elevated plasma NfL levels may suggest imminent phenoconversion to MSA, whereas low cardiac MIBG uptake suggests phenoconversion to LBD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Contact sports such as football are associated with late development of neurodegenerative diseases, in part due to the deleterious effect of repetitive head impacts during participation. Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of neurodegenerative diseases including Parkinson disease (RBD) and dementia with Lewy bodies (DLB). We hypothesized that former professional football participation would be overrepresented in IRBD., Objective: To assess former participation in professional football as an occupation in IRBD., Methods: In a case-control retrospective study, having played football as a professional occupation in the Spanish Football Professional Leagues was examined interviewing polysomnographically confirmed IRBD patients and matched controls without IRBD., Results: Among 228 Caucasian Spanish IRBD patients with 68.5 ± 7.2 years, six (2.63%) were retired professional footballers. Length professional football career ranged between 11 and 16 years. Interval between football retirement and IRBD diagnosis was 39.5 ± 6.4 years. At IRBD diagnosis, the six footballers had synucleinopathy biomarkers including pathologic synuclein in the CSF and tissues, nigrostriatal dopaminergic deficit and hyposmia. Follow-up showed that three footballers developed PD and two DLB. None of the controls was a professional footballer. The percentage of professional footballers was higher in IRBD patients than in controls (2.63% versus 0.00%; p = 0.030) and among the general Spanish population (2.63% versus 0.62%; p < 0.0001)., Conclusion: We found an overrepresentation of former professional footballers in IRBD patients who later developed PD and DLB after four decades from professional retirement. In professional footballers the development of a neurodegenerative disease may be first manifested by IRBD. Screening for IRBD in former footballers might identify individuals with underlying synucleinopathies. Further studies with larger samples are needed to confirm our observations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Movement disorders as well as peripheral neuropathies are extremely frequent in the general population; therefore, it is not uncommon to encounter patients with both these conditions. Often, the coexistence is coincidental, due to the high incidence of common causes of peripheral neuropathy, such as diabetes and other age-related disorders, as well as of Parkinson disease (PD), which has a typical late onset. Nonetheless, there is broad evidence that PD patients may commonly develop a sensory and/or autonomic polyneuropathy, triggered by intrinsic and/or extrinsic mechanisms. Similarly, some peripheral neuropathies may develop some movement disorders in the long run, such as tremor, and rarely dystonia and myoclonus, suggesting that central mechanisms may ensue in the pathogenesis of these diseases. Although rare, several acquired or hereditary causes may be responsible for the combination of movement and peripheral nerve disorders as a unique entity, some of which are potentially treatable, including paraneoplastic, autoimmune and nutritional aetiologies. Finally, genetic causes should be pursued in case of positive family history, young onset or multisystemic involvement, and examined for neuroacanthocytosis, spinocerebellar ataxias, mitochondrial disorders and less common causes of adult-onset cerebellar ataxias and spastic paraparesis. Deep phenotyping in terms of neurological and general examination, as well as laboratory tests, neuroimaging, neurophysiology, and next-generation genetic analysis, may guide the clinician toward the correct diagnosis and management., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Gerstmann-Sträussler-Scheinker disease (GSS) is a rare neurodegenerative illness that belongs to the group of hereditary or familial Transmissible Spongiform Encephalopathies (TSE). Due to the presence of different pathogenic alterations in the prion protein (PrP) coding gene, it shows an enhanced proneness to misfolding into its pathogenic isoform, leading to prion formation and propagation. This aberrantly folded protein is able to induce its conformation to the native counterparts forming amyloid fibrils and plaques partially resistant to protease degradation and showing neurotoxic properties. PrP with A117V pathogenic variant is the second most common genetic alteration leading to GSS and despite common phenotypic and neuropathological traits can be defined for each specific variant, strikingly heterogeneous manifestations have been reported for inter-familial cases bearing the same pathogenic variant or even within the same family. Given the scarcity of cases and their clinical, neuropathological, and biochemical variability, it is important to characterize thoroughly each reported case to establish potential correlations between clinical, neuropathological and biochemical hallmarks that could help to define disease subtypes. With that purpose in mind, this manuscript aims to provide a detailed report of the first Spanish GSS case associated with A117V variant including clinical, genetic, neuropathological and biochemical data, which could help define in the future potential disease subtypes and thus, explain the high heterogeneity observed in patients suffering from these maladies., (© 2022. The Author(s).)

Cerebrospinal fluid (CSF) non-phosphorylated tau (non-p-tau) is increased in sporadic Creutzfeldt-Jakob disease (CJD), but its accuracy in the differential diagnosis has not been previously established. Here, we first used a retrospective cohort of non-CJD (n = 135) and CJD (n = 137) cases to determine the optimal cutoff point for the discrimination of CJD cases. Next, we prospectively quantified non-p-tau and 14-3-3 protein in a cohort of 1427 cases received for CSF testing at the German National Reference Center for transmissible spongiform encephalopathies. Among them, 36 were subsequently diagnosed as CJD. The diagnostic accuracy of both proteins discriminating CJD cases was evaluated. Using a cutoff of 650 pg/mL, non-p-tau displayed 94.39% accuracy in discriminating CJD cases, while 92.92% accuracy was achieved by 14-3-3 using a cutoff of 20,000 AU/mL. Diagnostic test evaluation for both proteins showed a slightly better performance of non-p-tau compared to 14-3-3. The two biomarkers' concentrations showed a significant positive correlation, both in the total population and in CJD cases (p < 0.001). Finally, the analysis of CSF non-p-tau concentrations when undergoing pre-analytical factors showed high stability in front of temperature storage and freeze/thaw cycles. Therefore, we conclude that when used in the appropriate clinical context of a prion disease surveillance center, non-p-tau is a highly sensitive and specific diagnostic marker for CJD.

Background: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive and fatal prion disease with significant public health implications. Survival is heterogenous, posing challenges for prognostication and care planning. We developed a survival model using diagnostic data from comprehensive UK sCJD surveillance., Methods: Using national CJD surveillance data from the United Kingdom (UK), we included 655 cases of probable or definite sCJD according to 2017 international consensus diagnostic criteria between 01/2017 and 01/2022. Data included symptoms at diagnosis, CSF RT-QuIC and 14-3-3, MRI and EEG findings, as well as sex, age, PRNP codon 129 polymorphism, CSF total protein and S100b. An artificial neural network based multitask logistic regression was used for survival analysis. Model-agnostic interpretation methods was used to assess the contribution of individual features on model outcome., Results: Our algorithm had a c-index of 0.732, IBS of 0.079, and AUC at 5 and 10 months of 0.866 and 0.872, respectively. This modestly improved on Cox proportional hazard model (c-index 0.730, IBS 0.083, AUC 0.852 and 0863) but was not statistically significant. Both models identified codon 129 polymorphism and CSF 14-3-3 to be significant predictive features., Conclusions: sCJD survival can be predicted using routinely collected clinical data at diagnosis. Our analysis pipeline has similar levels of performance to classical methods and provide clinically meaningful interpretation which help deepen clinical understanding of the condition. Further development and clinical validation will facilitate improvements in prognostication, care planning, and stratification to clinical trials., Competing Interests: Declarations. Conflicts of interest: No competing interests to declare., (© 2024. The Author(s).)