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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).)

The accumulation of misfolded proteins as amyloid fibrils in the brain is characteristic of most neurodegenerative disorders. These misfolded proteins are capable of self-amplifying through protein seeding mechanisms, leading to accumulation in the host. First shown for PrP prions and prion diseases, it is now recognized that self-propagating misfolded proteins occur broadly in neurodegenerative diseases and include amyloid-β (Aβ) and tau in Alzheimer's disease (AD), tau in chronic traumatic encephalopathy (CTE), Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), and α-synuclein (α-syn) in Parkinson's disease (PD) and Lewy body dementias (LBD). Techniques able to directly measure these bioactive protein seeds include the real-time quaking-induced conversion (RT-QuIC) assays. Initially developed for the detection of PrP prions and subsequently for the detection of other misfolded protein seeds, these assays take advantage of the mechanism of protein-based self-propagation to result in exponential amplification of the initial protein seeds from biospecimens. Disease-specific "protein seeds" recruit and template the misfolding of native recombinant protein substrates to elongate amyloid fibrils. The amplification power of these assays allows for detection of minute amounts of disease-specific protein seeds to better support early and accurate diagnosis. In addition to the diagnostic capabilities, assay readouts have been shown to reveal biochemical, structural, and kinetic information of protein seed self-propagation. This review examines the various protein seed amplification assays currently available for distinct neurodegenerative diseases, with a focus on RT-QuIC assays, along with the insights their readouts provide into protein seed structures and strain differences., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Real-time quaking-induced conversion (RT-QuIC) is a cell-free abnormal form of prion protein (PrP Sc ) amplification method using recombinant prion protein from Escherichia coli that can measure prion seeding activity in samples with high sensitivity. The advantages of this method are that it is much more sensitive than Western blotting, which is usually used to detect PrP Sc , and that prion seeding activity can be easily quantified by combining it with endpoint dilution of the sample, and that it can be amplified in most species and prion strains. A decade has passed since the development of RT-QuIC, and many studies have been reported that take advantage of its characteristics. In particular, its usefulness in the diagnosis of sporadic CJD has been clarified, and it is recommended to be one of the diagnostic criteria. Future challenges include the establishment of a method to differentiate prion strains and application of RT-QuIC to early diagnosis of prion diseases and determination of treatment efficacy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The development of the real-time quaking-induced conversion (RT-QuIC), an in vitro protein misfolding amplification assay, was an innovation in the scientific field of protein misfolding diseases. In prion diseases, these types of assays imitate the pathological conversion of the cellular prion protein (PrP C ) into a protease-resistant and/or amyloid form of PrP, called PrP resistant (PrP Res ). The RT-QuIC is an automatic assay system based on real-time measuring of thioflavin-T (Th-T) incorporation into amyloid fibrils using shaking for disaggregation. It has already been applied in diagnostics, drug pre-screening, and to distinguish between different prion strains. The seeded conversion efficiency and the diagnostic accuracy of the RT-QuIC assay strongly depend on the kind of recombinant PrP (rec PrP) substrate. The DNA sequences of different substrates may originate from different species, such as human, bank vole, and hamster, or from a combination of two species, e.g., hamster-sheep chimera. In routine use, either full-length (FL) or truncated substrates are applied which can accelerate the conversion reaction, e.g., to a more sensitive version of RT-QuIC assay. In the present review, we provide an overview on the different types of PrP substrates (FL and truncated forms), recapitulate the production and purification process of different rec PrP substrates, and discuss the diagnostic value of CSF RT-QuIC in human prion disease diagnostics., (© 2022. 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).)

Human cerebral organoids are an exciting and novel model system emerging in the field of neurobiology. Cerebral organoids are spheres of self-organizing, neuronal lineage tissue that can be differentiated from human pluripotent stem cells and that present the possibility of on-demand human neuronal cultures that can be used for non-invasively investigating diseases affecting the brain. Compared with existing humanized cell models, they provide a more comprehensive replication of the human cerebral environment. The potential of the human cerebral organoid model is only just beginning to be elucidated, but initial studies have indicated that they could prove to be a valuable model for neurodegenerative diseases such as prion disease. The application of the cerebral organoid model to prion disease, what has been learned so far and the future potential of this model are discussed in this review., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

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).)

The majority of patients with Parkinson's disease (PD) develop swallowing, speech, and voice (SSV) disorders. Importantly, swallowing difficulty or dysphagia and related aspiration are life-threatening conditions for PD patients. Although PD treatments have significant therapeutic effects on limb motor function, their effects on SSV disorders are less impressive. A large gap in our knowledge is that the mechanisms of SSV disorders in PD are poorly understood. PD was long considered to be a central nervous system disorder caused by the death of dopaminergic neurons in the basal ganglia. Aggregates of phosphorylated α-synuclein (PAS) underlie PD pathology. SSV disorders were thought to be caused by the same dopaminergic problem as those causing impaired limb movement; however, there is little evidence to support this. The pharynx, larynx, and tongue play a critical role in performing upper airway (UA) motor tasks and their dysfunction results in disordered SSV. This review aims to provide an overview on the neuromuscular organization patterns, functions of the UA structures, clinical features of SSV disorders, and gaps in knowledge regarding the pathophysiology underlying SSV disorders in PD, and evidence supporting the hypothesis that SSV disorders in PD could be associated, at least in part, with PAS damage to the peripheral nervous system controlling the UA structures. Determining the presence and distribution of PAS lesions in the pharynx, larynx, and tongue will facilitate the identification of peripheral therapeutic targets and set a foundation for the development of new therapies to treat SSV disorders in PD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this narrative review, we address mild cognitive impairment, a frequent complication of Parkinson's disease (PD) and atypical parkinsonian disorders (APDs). Recent diagnostic criteria have blurred the lines between PD and dementia with Lewy bodies (DLB), particularly in the cognitive domain. Additionally, atypical parkinsonian syndromes like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) often present with significant cognitive decline. Even multiple system atrophy (MSA) can be associated with cognitive impairment in some cases. Several biomarkers, including imaging techniques, such brain magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET), as well as pathological proteins either of the cerebrospinal fluid (CSF), such as Tau, amyloid beta, and synuclein, or of the serum, such as neurofilament light chain (Nfl) are more and more often utilized in the early differential diagnosis of APDs. The complex interplay between these conditions and the evolving understanding of their underlying pathologies highlight the need for further research to refine diagnostic criteria, possibly incorporate the new findings from the biomarker's field into the diagnostic criteria and develop targeted therapeutic strategies., Competing Interests: Declarations. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose. Ethics approval: Our institution does not require ethical approval for narrative reviews. Informed consent: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Purpose: Although neuropathological comorbidities, including Alzheimer's disease neuropathological change (AD-NC) and limbic-predominant age-related TAR DNA-binding protein 43encephalopathy neuropathological change (LATE-NC), are associated with medial temporal atrophy in patients with Lewy body disease (LBD), the diagnostic performance of magnetic resonance imaging (MRI)-derived indices remains unclear. This study aimed to investigate the diagnostic performance of MRI-derived indices representing medial temporal atrophy in differentiating between LBD with AD-NC and/or LATE-NC (mixed LBD [mLBD]) and without these comorbidities (pure LBD [pLBD])., Methods: This study included 24 and 16 patients with pathologically confirmed mLBD and pLBD, respectively. In addition to the well-known medial temporal atrophy and entorhinal cortex atrophy (ERICA) scores, the cross-sectional areas of the bilateral entorhinal cortices/parahippocampal gyri (ABEP) were segmented manually., Results: Even incorporating various covariates such as age at MRI examination, sex, argyrophilic grain, the MRI-derived indices, especially ABEP, significantly correlated with the severity of AD-NC, and showed a trend of correlation with LATE-NC. For the differentiation between all mLBD and pLBD, the ERICA score and ABEP demonstrated higher diagnostic performance (area under the receiver-operating-characteristic curve [AUC] of 0.80 and 0.87, respectively). Additionally, the highest diagnostic performance for ABEP (AUC, 0.94; sensitivity, 100%; specificity, 88.9%; accuracy, 96%) was observed in differentiating between pLBD and mLBD with two comorbidities (AD-NC and LATE-NC)., Conclusion: In patients with pathologically confirmed LBD, medial temporal atrophy was significantly correlated with AD-NC, and showed a trend of correlation with LATE-NC. Moreover, MRI-derived indices indicative of medial temporal atrophy were useful in diagnosing these comorbidities., Competing Interests: Declarations Ethical approval We declare that this study has been approved by the Institutional Review Board of Fukushimura Hospital (Research ID: 444, 2023), and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed consent Postmortem consent was obtained from the bereaved families of all patients for the use of their data for academic purposes. Competing interests The authors declared that they have no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.)

The abnormal accumulation of α-synuclein in the brain is a common feature of Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), and synucleinopathies that present with overlapping but distinct clinical symptoms that include motor and cognitive deficits. Synapse degeneration is the crucial neuropathological event in these synucleinopathies and the neuropathological correlate of connectome dysfunction. The cognitive and motor deficits resulting from the connectome dysfunction are currently measured by scalar systems that are limited in their sensitivity and largely subjective. Ideally, a marker of synapse degeneration would correlate with measures of cognitive or motor impairment, and could therefore be used as a more objective, surrogate biomarker of the core clinical features of these diseases. Furthermore, an objective surrogate biomarker that can detect and monitor the progression of synapse degeneration would improve patient management and clinical trial design, and could provide a measure of therapeutic response. Here, we review the published findings relating to candidate biomarkers of synapse degeneration in PD, PDD, DLB, and MSA patient-derived biofluids and discuss the findings in the context of the mechanisms associated with α-synuclein-mediated synapse degeneration. Understanding these mechanisms is essential not only for discovery of biomarkers, but also to improve our understanding of the earliest changes in disease pathogenesis of synucleinopathies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, 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).)

Dementia with Lewy bodies (DLB), the second most common degenerative neurocognitive disorder after Alzheimer disease (AD), is frequently preceded by a period of mild cognitive impairment (MCI), in which cognitive decline is associated with impairment of executive functions/attention, visuospatial deficits, or other cognitive domains and a variety of noncognitive and neuropsychiatric symptoms, many of which are similar but less severe than in prodromal AD. While 36-38% remain in the MCI state, at least the same will convert to dementia. Biomarkers are slowing of the EEG rhythms, atrophy of hippocampus and nucleus basalis of Meynert, temporoparietal hypoperfusion, signs of degeneration of the nigrostriatal dopaminergic, cholinergic and other neurotransmitter systems, and inflammation. Functional neuroimaging studies revealed disturbed connectivity of frontal and limbic networks associated with attention and cognitive controls, dopaminergic and cholinergic circuits manifested prior to overt brain atrophy. Sparse neuropathological data showed varying Lewy body and AD-related stages associated with atrophy of entorhinal, hippocampal, and mediotemporal cortices. Putative pathomechanisms of MCI are degeneration of limbic, dopaminergic, and cholinergic systems with Lewy pathology affecting specific neuroanatomical pathways associated with progressing AD-related lesions, but many pathobiological mechanisms involved in the development of MCI in LBD remain to be elucidated as a basis for early diagnosis and future adequate treatment modalities to prevent progression of this debilitating disorder., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

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.)

Prion diseases are fatal neurodegenerative disorders, for which there are no effective therapeutic and diagnostic agents. The main pathological hallmark has been identified as conformational changes of the cellular isoform prion protein (PrP C ) to a misfolded isoform of the prion protein (PrP Sc ). Targeting PrP C and its conversion to PrP Sc is still the central dogma in prion drug discovery, particularly in in silico and in vitro screening endeavors, leading to the identification of many small molecules with therapeutic potential. Nonetheless, multiple pathological targets are critically involved in the intricate pathogenesis of prion diseases. In this context, multi-target-directed ligands (MTDLs) emerge as valuable therapeutic approach for their potential to effectively counteract the complex etiopathogenesis by simultaneously modulating multiple targets. In addition, diagnosis occurs late in the disease process, and consequently a successful therapeutic intervention cannot be provided. In this respect, small molecule theranostics, which combine imaging and therapeutic properties, showed tremendous potential to cure and diagnose in vivo prion diseases. Herein, we review the major advances in prion drug discovery, from anti-prion small molecules identified by means of in silico and in vitro screening approaches to two rational strategies, namely MTDLs and theranostics, that have led to the identification of novel compounds with an expanded anti-prion profile., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The fascinating history of prion diseases is intimately linked to the use of nonhuman primates as experimental models, which brought so fundamental and founding information about transmissibility, pathogenesis, and resistance of prions. These models are still of crucial need for risk assessment of human health and may contribute to pave a new way towards the moving field of prion-like entities which now includes the main human neurodegenerative diseases (especially Alzheimer's and Parkinson's diseases)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

While much of what we know about the general principles of protein-based information transfer derives from studies of experimentally adapted rodent prions, these laboratory strains are limited in their ability to recapitulate features of human and animal prions and the diseases they produce. Here, we review how recent approaches using genetically modified mice have informed our understanding of naturally occurring prion diseases, their strain properties, and the factors controlling their transmission and evolution. In light of the increasing importance of chronic wasting disease, the application of mouse transgenesis to study this burgeoning and highly contagious prion disorder, in particular recent insights derived from gene-targeting approaches, will be a major focus of this review., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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).)

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.)

Creutzfeldt-Jakob disease (CJD) is the leading human prion disease and is a major public health concern, with the risk of secondary iatrogenic transmission. Screening for CJD is often based on the detection of 14-3-3 protein in cerebrospinal fluid (CSF) through western blot assay and, in a second step, on a more specific method such as RT-QuIC (Real-Time Quaking-Induced Conversion). Alternatives to the detection of 14-3-3 in CSF have recently been proposed, specifically CSF tau proteins, tau/p-tau(181) ratio, and alpha-synuclein. In the present work, we compare the diagnostic performance of these biomarkers with that of 14-3-3 protein in a cohort of suspected CJD patients. Our results indicate that tau detection is the most effective and suitable approach for routine disease detection in a clinical setting. Combination with other biomarkers does not improve overall performance, while the tau/p-tau(181) ratio remains useful for differentiating Alzheimer's from CJD. In the end, the performance of tau protein detection in CSF reached 78% sensitivity and 80% specificity for the detection of CJD. It is interesting to note that the use of an automated method with a high concentration range allows for rapid and accurate results, which is very useful in clinical practice and allows for confirmatory testing such as RT-QuIC without delay., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)