Identification of distinct clinical profiles and trajectories in individuals at high risk of developing psychosis: A latent profile analysis of the north American prodrome longitudinal study consortium-3 dataset.

AIM: People at clinical high risk (CHR) for psychosis are a heterogeneous population in regard to clinical presentation and outcome. It is unclear, however, if their baseline clinical characteristics can be used to construct orthogonal subgroups that differ in their clinical trajectory to provide early identification of individuals in need of tailored interventions. METHODS: We used latent profile analysis (LPA) to determine the number of distinct clinical profiles within the CHR population using the NAPLS-3 dataset, focusing on the clinical features incorporated in the NAPLS psychosis risk calculator (including age, unusual thought content and suspiciousness, processing speed, verbal learning and memory function, social functioning decline, life events, childhood trauma, and family history of psychosis). We then conducted a between-profile comparisons of clinical trajectories based on psychotic and depressive symptoms as well as substance use disorder (SUD) related features over time. RESULTS: Two distinct profiles emerged. One profile, comprising approximately 25% of the sample, was significantly older, displayed better cognitive performance, experienced more types of traumatic and undesirable life events, exhibited a greater decline in functioning in the past year, and was more likely to have relatives with psychosis. This group showed worse positive symptoms and SUD-related features over time, although groups did not differ in the proportion of individuals who developed psychosis. CONCLUSIONS: LPA results suggest CHRs can be segregated into two profiles with different clinical trajectories. Characterizing individuals within these clinical profiles may help understand the divergent outcomes of this population and ultimately facilitate the development of specialized interventions.

Clinical high risk state of major depressive episodes: Assessment of prodromal phase, its occurrence, duration and symptom patterns by the instrument the DEpression Early Prediction-INventory (DEEP-IN).

BACKGROUND: To decrease the incidence of major depressive episodes, indicated prevention that targets clinical high-risk individuals with first detectable signs that forecast mental disorder is a highly relevant topic of preventive psychiatry. Still little is known about the prodrome of MDE. The aim of the current study was to identify the occurrence of a clinical high-risk state of depression, its duration and symptom constellation. METHODS: Seventy-three patients with a diagnosed affective disorder in partial remission were assessed with our newly developed semi-structured extensive clinical instrument, the DEpression Early Prediction-INventory (DEEP-IN). Within DEEP-IN the course of prodromal symptoms was explored by using a life-chart method. RESULTS: The significant majority of patients (93.2 %) reported a prodromal phase. The mean duration was 7.9 months (SD = 12.5). Within the group with an identified prodromal phase, psychopathological (95.6 %) as well as somatic symptoms (88.2 %) were reported. Somatic symptoms showed a moderate-to-strong effect of sex with higher prevalence in females than in males (97.6 % vs 73.1 %; V = 0.370). LIMITATIONS: This feasibility study had only a small sample size. CONCLUSIONS: The majority of patients with affective disorders reported a clinical prodromal phase with both psychopathological and somatic symptoms that developed months before the onset of the depressive episode. The development of structured instruments for the assessment of depressive risk states is a promising approach for indicated prevention of depression in the future.

RBD and hyposmia in Moroccan patients with a synucleinopathy: prevalence and the timing of occurrence in a large cohort.

INTRODUCTION: Rapid Eye Movement Sleep Behavior Disorder (RBD) and hyposmia are common in synucleinopathies and they tend to occur in connection to the prodromal development of these disorders. In this study, we sought to determine the prevalence of RBD and hyposmia and the timeline of their occurrence in a large cohort of Moroccan patients. METHODS: We recruited 774 consecutive patients with synucleinopathy and tauopathy at Ibn Rochd University Hospital of Casablanca. A group of 100 healthy controls was also recruited. We relied on a questionnaire to collect general characteristics and clinical data filled by the patient and his companion under the supervision of a qualified health professional. RESULTS: The study included 697 patients with PD, 37 with DLB and 40 had a tauopathy disorder (PSP or CBD). The proportion of patients who have RBD was 52% in PD, 100% in DLB, 0% in tauopathies and 12% among healthy controls. Hyposmia symptom was found in 47% of patients with PD, 68% in patients with DLB, 0% in tauopathy patients and in 10% of healthy controls. Moreover, 46% of PD patients and 75% of DLB patients developed RBD during the prodromal phase. Meanwhile, hyposmia occurred in association with the prodromal phase among 67% of PD cases and 85% of DLB patients. CONCLUSION: RBD and hyposmia are both prevalent among Moroccan patients with synucleinopathy and they occur frequently during the prodromal phase. Identifying these premotor signs will improve early and differential diagnosis and enhance our understanding of how a specific synucleinopathy progresses.

α-Synuclein induces prodromal symptoms of Parkinson's disease via activating TLR2/MyD88/NF-κB pathway in Schwann cells of vagus nerve in a rat model.

BACKGROUND: Increasing evidence suggests that patients with Parkinson's disease (PD) present with peripheral autonomic dysfunction (AutD) that even precedes motor deficits, through which α-synuclein can spread to the central nervous system. However, the pathological mechanisms underlying AutD in prodromal PD remain unclear. Here, we investigated the role of α-synuclein and its interplay with the activation of Schwann cells (SCs) of the vagus nerve in AutD. METHODS: Rats were subjected to injection with adeno-associated viruses containing the human mutated A53T gene (AAV-A53T) or an empty vector into the left cervical vagus nerve and evaluated for gastrointestinal symptoms, locomotor functions, intestinal blood flow, and nerve electrophysiology. Further, we examined the impact of α-synucleinopathy on vagus nerves, SCs, and central nervous system neurons using electron microscopy, immunofluorescence, immunohistochemistry, and western blot. Finally, the role of Toll-like receptor 2 (TLR2) in regulating the neuroinflammation in the vagus nerve via MyD88 and NF-κB pathway was determined using genetic knockdown. RESULTS: We found that rats injected with AAV-A53T in the vagus nerve exhibited prominent signs of AutD, preceding the onset of motor deficits and central dopaminergic abnormalities by at least 3 months, which could serve as a model for prodromal PD. In addition, reduced intestinal blood flow and decreased nerve conduction velocity were identified in AAV-A53T-injected rats, accompanied by disrupted myelin sheaths and swollen SCs in the vagus nerve. Furthermore, our data demonstrated that p-α-synuclein was deposited in SCs but not in axons, activating the TLR2/MyD88/NF-κB signaling pathway and leading to neuroinflammatory responses. In contrast, silencing the TLR2 gene not only reduced inflammatory cytokine expression but also ameliorated vagal demyelination and secondary axonal loss, consequently improving autonomic function in rats. CONCLUSIONS: These observations suggest that overexpression of α-synuclein in the vagus nerve can induce symptoms of AutD in prodromal PD, and provide support for a deeper understanding of the pathological mechanisms underlying AutD and the emergence of effective therapeutic strategies for PD.

The prodromal phase of hereditary spastic paraplegia type 4: the preSPG4 cohort study.

This cohort study aimed to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) using biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities. Fifty-six first-degree relatives at risk of developing SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analysed for neurofilament light chain (NfL), tau, and amyloid-ß (Aß). Thirty participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski's sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of 2 points or more, only two non-mutation carriers reached more than 1 point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or Aß to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers. This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.

Curso optativo sobre ataxia espinocerebelosa tipo 2 en la Universidad de Ciencias Médicas de Holguín

Introducción: Recientemente inició la formación de profesionales en una nueva modalidad de Programas Técnico Superior de Ciclo Corto en la especialidad Neurofisiología Clínica, en la Universidad de Ciencias Médicas de Holguín, atendiendo a la alta incidencia de enfermedades neurológicas, como la ataxia espinocerebelosa tipo 2, que constituye un serio problema de salud en Cuba. Un programa de curso optativo que aborde esta temática, contribuye al conocimiento de esta enfermedad para su investigación y posibles tratamientos. Objetivo: Diseñar un programa de curso optativo sobre diagnóstico e intervención físico-terapéutica en la fase prodrómica de la ataxia espinocerebelosa tipo 2 para estudiantes de Neurofisiología Clínica Primer Año en la Facultad de Enfermería ¨Arides Estévez Sánchez¨ de Holguín. Método: Se realizó una investigación didáctica metodológica utilizando los métodos empíricos: observación; teóricos: histórico-lógico, estudio documental, dialéctico; análisis-síntesis e inducción-deducción. Resultados: Se propuso un programa para curso optativo basado en la búsqueda de información científica y métodos empíricos, el cual fue estructurado en cuatro temas, con carácter presencial y duración de 24 horas. Se presentaron los contenidos por temas, objetivos, conocimientos esenciales a adquirir, habilidades principales a dominar y sistema de evaluación. Conclusiones: La aplicación de este programa contribuye a desarrollar habilidades en los profesionales en formación, en el conocimiento de la fase prodrómica de esta enfermedad.

Introduction: It recently began the training of professionals in a new modality of Programas Técnico Superior de Ciclo Corto (Short Cycle Superior Technical Programs) in the Clinical Neurophysiology specialty, at the Universidad de Ciencias Médicas de Holguín, attending to the high incidence of neurological diseases, such as spinocerebellar ataxia type 2, which constitutes a serious health problem in Cuba. This is an elective course program that addresses this topic and contributes to the knowledge of this disease, in order to improve research and possible treatments. Objective: To design an elective course program on diagnosis and physical-therapeutic intervention in the prodromal phase of spinocerebellar ataxia type 2 for first year Clinical Neurophysiology students at the ¨Arides Estévez Sánchez¨ School of Nursing in Holguín. Method: A methodological didactic research was carried out using the empirical methods: observation; theoretical: historical-logical, documentary study, dialectical; analysis-synthesis and induction-deduction. Results: A program was proposed for an optional course, based on the search for scientific information and empirical methods, which was structured in four themes, in face-to-face modality and with a duration of 24 hours. The contents were presented by themes, objectives, essential knowledge to acquire, main skills to master and evaluation system. Conclusions: The application of this program contributes to developing skills in training professionals, in the knowledge of the prodromal phase of this disease.

Introdução: Iniciou-se recentemente a formação de profissionais em uma nova modalidade de Programas Técnicos Superiores de Ciclo Curto na especialidade de Neurofisiologia Clínica, na Universidad de Ciencias Médicas de Holguín, atendendo à alta incidência de doenças neurológicas, como a ataxia espinocerebelar tipo 2, que constitui um grave problema de saúde em Cuba. Um programa de disciplina eletiva que aborde esse tema contribui para o conhecimento dessa doença para sua investigação e possíveis tratamentos. Objetivo: Elaborar um programa de disciplina eletiva sobre diagnóstico e intervenção fisioterapêutica na fase prodrômica da ataxia espinocerebelar tipo 2 para alunos do primeiro ano de Neurofisiologia Clínica da Escola de Enfermagem ¨Arides Estévez Sánchez¨ de Holguín. Método: Foi realizada uma pesquisa didática metodológica utilizando os métodos empíricos: observação; teórico: histórico-lógico, estudo documental, dialético; análise-síntese e indução-dedução. Resultados: Foi proposto um programa para um curso opcional baseado na busca de informações científicas e métodos empíricos, o qual foi estruturado em quatro temas, com caráter presencial e duração de 24 horas. Os conteúdos foram apresentados por temas, objetivos, conhecimentos essenciais a adquirir, principais competências a dominar e sistema de avaliação. Conclusões: A aplicação deste programa contribui para o desenvolvimento de competências nos profissionais em formação, no conhecimento da fase prodrómica desta doença.

Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model.

Symptoms of schizophrenia (SZ) typically emerge during adolescence to young adulthood, which gives a window before full-blown psychosis for early intervention. Strategies for preventing the conversion from the prodromal phase to the psychotic phase are warranted. Heterozygous (Het) Disc1 mutant mice are considered a prodromal model of SZ, suitable for studying psychotic conversion. We evaluated the preventive effect of chronic N-acetylcysteine (NAC) administration, covering the prenatal era to adulthood, on the reaction following the Amph challenge, which mimics the outbreak or conversion of psychosis, in adult Het Disc1 mice. Biochemical and morphological features were examined in the striatum of NAC-treated mice. Chronic NAC treatment normalized the Amph-induced activity in the Het Disc1 mice. Furthermore, the striatal phenotypes of Het Disc1 mice were rescued by NAC including dopamine receptors, the expression of GSK3s, MSN dendritic impairments, and striatal PV density. The current study demonstrated a potent preventive effect of chronic NAC treatment in Disc1 Het mice on the acute Amph test, which mimics the outbreak of psychosis. Our findings not only support the benefit of NAC as a dietary supplement for SZ prodromes, but also advance our knowledge of striatal dopamine receptors, PV neurons, and GSK3 signaling pathways as therapeutic targets for treating or preventing the pathogenesis of mental disorders.

Preclinical Autoimmune Disease: a Comparison of Rheumatoid Arthritis, Systemic Lupus Erythematosus, Multiple Sclerosis and Type 1 Diabetes.

The preclinical phase of autoimmune disorders is characterized by an initial asymptomatic phase of varying length followed by nonspecific signs and symptoms. A variety of autoimmune and inflammatory manifestations can be present and tend to increase in the last months to years before a clinical diagnosis can be made. The phenotype of an autoimmune disease depends on the involved organs, the underlying genetic susceptibility and pathophysiological processes. There are different as well as shared genetic or environmental risk factors and pathophysiological mechanisms between separate diseases. To shed more light on this, in this narrative review we compare the preclinical disease course of four important autoimmune diseases with distinct phenotypes: rheumatoid arthritis (RA), Systemic Lupus Erythematosus (SLE), multiple sclerosis (MS) and type 1 diabetes (T1D). In general, we observed some notable similarities such as a North-South gradient of decreasing prevalence, a female preponderance (except for T1D), major genetic risk factors at the HLA level, partly overlapping cytokine profiles and lifestyle risk factors such as obesity, smoking and stress. The latter risk factors are known to produce a state of chronic systemic low grade inflammation. A central characteristic of all four diseases is an on average lengthy prodromal phase with no or minor symptoms which can last many years, suggesting a gradually evolving interaction between the genetic profile and the environment. Part of the abnormalities may be present in unaffected family members, and autoimmune diseases can also cluster in families. In conclusion, a promising strategy for prevention of autoimmune diseases might be to address adverse life style factors by public health measures at the population level.

Impact of Early Intervention for Idiopathic Normal Pressure Hydrocephalus on Long-Term Prognosis in Prodromal Phase.

Objectives: Because the progression of idiopathic normal pressure hydrocephalus (iNPH) is partially irreversible, we hypothesized that early intervention would markedly improve its prognosis. To test this hypothesis, we retrospectively investigated the long-term prognosis of patients with early intervention in the prodromal phase of iNPH. Methods: We defined the prodromal phase of iNPH as a 3m Timed Up and Go (TUG) of 13.5 s or less and a Mini-Mental State Examination (MMSE) of 24 or more. Of the 83 iNPH patients who underwent shunt surgery at Osaka Medical and Pharmaceutical University Hospital over 3 years from January 2015, 12 prodromal phase cases (73.3 ± 6.2 years, 10 males and 2 females) were included in the study. The iNPH grading scale (INPHGS), MMSE, Frontal Assessment Battery (FAB), intermittent gait disturbance (IGD), social participation status, and development of comorbidities were evaluated over 4 years. Results: Preoperative MMSE was 27.2 ± 1.5, FAB was 14.1 ± 1.8, TUG was 10.7 ± 1.4 s, and total iNPHGS was 2.8 ± 1.4. At 1, 2, 3, and 4 years postoperatively, total INPHGS improved to 0.8, 0.9, 1.5, and 1.7, respectively, and remained significantly better than preoperatively except at 4 years postoperatively. The MMSE improved slightly to 27.5 after 1 year and then declined by 0.35 per year. After 4 years, the mean MMSE was 26.1, and only one patient had an MMSE below 23. FAB improved to 15.2 after 1 year and then declined slowly at 0.85/year. Ten patients (83%) maintained a high capacity for social participation postoperatively. The preoperative tendency to fall and IGD in 9 (75%) and 8 (67%) patients, respectively, completely disappeared postoperatively, resulting in improved mobility. Shunt malfunction associated with four weight fluctuations and one catheter rupture caused temporary worsening of symptoms, which were recovered by valve re-setting and catheter revision, respectively. Conclusion: Early intervention in the prodromal phase of iNPH patients maintained good cognitive and mobility function and social participation ability in the long term. The maintenance of long-term cognitive function suggests its preventive effect on dementia. To realize early intervention for iNPH, it is desirable to establish an early diagnosis system for iNPH.

The Clinical Concept of LTDpathy: Is Dysregulated LTD Responsible for Prodromal Cerebellar Symptoms?

Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) induce dysfunction of PF-PC LTD, resulting in the development of cerebellar ataxias (CAs). These disorders show a good response to immunotherapies in non-paraneoplastic conditions but are sometimes followed by cell death in paraneoplastic conditions. On the other hand, in some types of spinocerebellar ataxia (SCA), dysfunction in PF-PC LTD, and impairments of PF-PC LTD-related adaptive behaviors (including vestibulo-ocular reflex (VOR) and prism adaptation) appear during the prodromal stage, well before the manifestations of obvious CAs and cerebellar atrophy. Based on these findings and taking into account the findings of animal studies, we re-assessed the clinical concept of LTDpathy. LTDpathy can be defined as a clinical spectrum comprising etiologies associated with a functional disturbance of PF-PC LTD with concomitant impairment of related adaptative behaviors, including VOR, blink reflex, and prism adaptation. In IMCAs or degenerative CAs characterized by persistent impairment of a wide range of molecular mechanisms, these disorders are initially functional and are followed subsequently by degenerative cell processes. In such cases, adaptive disorders associated with PF-PC LTD manifest clinically with subtle symptoms and can be prodromal. Our hypothesis underlines for the first time a potential role of LTD dysfunction in the pathogenesis of the prodromal symptoms of CAs. This hypothesis opens perspectives to block the course of CAs at a very early stage.

Significance of Cortical Ribboning as a Biomarker in the Prodromal Phase of Sporadic Creutzfeldt-Jakob Disease.

A 63-year-old woman who presented for orofacial dystonia showed cortical ribboning, a typical MRI finding in sporadic Creutzfeldt-Jakob disease (sCJD). However, real-time quaking-induced conversion (RT-QuIC), the most sensitive method for an early diagnosis of sCJD, was negative. She developed sCJD six months later, at which time RT-QuIC became positive. The cerebral blood flow showed a decrease in the cerebral cortex (especially in the supramarginal gyrus) consistent with cortical ribboning, but an increase in the basal ganglia, probably involved in orofacial dystonia. Cortical ribboning on MRI might be a better biomarker than RT-QuIC in the prodromal phase of sCJD.

Unfolded p53 as a Marker of Oxidative Stress in Mild Cognitive Impairment, Alzheimer's and Parkinson's Disease.

AIMS: There are several candidate biomarkers for AD and PD which differ in sensitivity, specificity, cost-effectiveness, invasiveness, logistical and technical demands. This study is aimed to test whether plasma concentration of unfolded p53 may help to discriminate among the neurodegenerative processes occurring in Mild Cognitive Impairment, Alzheimer's disease and Parkinson's disease. METHODS: An electrochemical immunosensor was used to measure unfolded p53 in plasma samples of 20 Mild Cognitive Impairment (13 males/7 females; mean age 74.95±5.31), 20 Alzheimer's (11 males/9 females; mean age: 77.25±7.79), 15 Parkinson's disease patients (12 males/3 females; mean age: 68.60 ± 7.36) and its respective age/sex/studies-matched controls. RESULTS: We observed a significantly higher concentration of unfolded p53 in the plasma of patients of each of the three pathologies with respect to their control groups (p=0.000). Furthermore, the plasma concentration of unfolded p53 was significantly higher in Alzheimer's disease patients in comparison with Mild Cognitive Impairment patients (p=0.000) and Parkinson's disease patients (p=0.006). No significant difference between Mild Cognitive Impairment and Parkinson's disease patients was observed (p=0.524). CONCLUSION: Our results suggest that unfolded p53 concentration in the plasma may be a useful biomarker for an undergoing neuropathological process that may be common, albeit with different intensity, to different diseases.

Defining the prodromal phase of multiple sclerosis based on healthcare access in a Portuguese population - ProdMS study.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. Prodromal symptoms and higher healthcare use have been suggested in patients who later develop MS. OBJECTIVES: Assess the healthcare utilization pattern of relapsing-remitting MS (RRMS) patients in the five years prior to MS diagnosis. METHODS: Retrospective, multicentric study. Demographic and clinical data, drug prescriptions and diagnostic tests were collected from electronic health records five-years previous to MS diagnosis and compared with national data. RESULTS: Included 168 patients, 112 (66.7%) female, median age 34±11 years. The mean number of healthcare use per patient per year was 3.14±2,69, most of them in primary healthcare (47%). Most frequent symptoms were musculoskeletal (22%), gastrointestinal (17%), sensitive (14%) and sensory organs (14%). Median number of diagnostic tests per patient was 6 (IQR 7), and drug prescriptions per patient was 6 (IQR 9). Most frequently prescribed drugs were analgesic/anti-inflammatories, antibiotics and anxiolytics and there was a high request rate of MRIs. CONCLUSION: RRMS patients had a high frequency of healthcare utilization when compared to national data. This supports the current evidence showing a prodromal phase in MS.

No significant differences in absenteeism or academic achievements in a Norwegian multiple sclerosis case control study.

BACKGROUND: The duration and features of the multiple sclerosis (MS) prodrome are not well defined. We aimed to ascertain whether people with a future MS diagnosis have more days of absence and perform worse in upper secondary school than age, gender and county-matched controls. METHODS: Using registry data from the southeast of Norway, we identified people with MS born ≥1978. Statistics Norway provided information on grades and days of absence in cases and matched controls. We looked at absence in the three years of upper secondary school and grades in the compulsory subjects Norwegian, English, mathematics and physical education. RESULTS: We identified 107 cases with disease onset one year or more after graduation and 626 controls. There were no significant differences in absence or grades achieved in the population as a whole or in those with disease onset within four years of diagnosis, and no association between time to disease onset and days of absence or grades. CONCLUSION: There was no difference in days of absence or grades achieved in upper secondary school in the four years leading up to disease onset in cases compared to controls. A potential prodrome may not affect cognition enough to impact school achievements.

α-Synuclein Responses in the Laterodorsal Tegmentum, the Pedunculopontine Tegmentum, and the Substantia Nigra: Implications for Early Appearance of Sleep Disorders in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder associated with insoluble pathological aggregates of the protein α-synuclein. While PD is diagnosed by motor symptoms putatively due to aggregated α-synuclein-mediated damage to substantia nigra (SN) neurons, up to a decade before motor symptom appearance, patients exhibit sleep disorders (SDs). Therefore, we hypothesized that α-synuclein, which can be present in monomeric, fibril, and other forms, has deleterious cellular actions on sleep-control nuclei. OBJECTIVE: We investigated whether native monomer and fibril forms of α-synuclein have effects on neuronal function, calcium dynamics, and cell-death-induction in two sleep-controlling nuclei: the laterodorsal tegmentum (LDT), and the pedunculopontine tegmentum (PPT), as well as the motor-controlling SN. METHODS: Size exclusion chromatography, Thioflavin T fluorescence assays, and circular dichroism spectroscopy were used to isolate structurally defined forms of recombinant, human α-synuclein. Neuronal and viability effects of characterized monomeric and fibril forms of α-synuclein were determined on LDT, PPT, and SN neurons using electrophysiology, calcium imaging, and neurotoxicity assays. RESULTS: In LDT and PPT neurons, both forms of α-synuclein induced excitation and increased calcium, and the monomeric form heightened putatively excitotoxic neuronal death, whereas, in the SN, we saw inhibition, decreased intracellular calcium, and monomeric α-synuclein was not associated with heightened cell death. CONCLUSION: Nucleus-specific differential effects suggest mechanistic underpinnings of SDs' prodromal appearance in PD. While speculative, we hypothesize that the monomeric form of α-synuclein compromises functionality of sleep-control neurons, leading to the presence of SDs decades prior to motor dysfunction.

Multiple sclerosis and subclinical neuropathology in healthy individuals with familial risk: A scoping review of MRI studies.

Multiple genetic and non-heritable factors have been linked to the risk of multiple sclerosis (MS). These factors seem to contribute to disease pathogenesis before the onset of clinical symptoms, as suggested by incidental MRI evidence of subclinical MS neuropathology in individuals without clinical symptoms. Individuals with high familial risk for MS, such as first-degree relatives of patients with MS, can be studied by MRI to characterize the neuropathology during a subclinical period of MS. 16 studies published in English, which performed brain MRI on healthy individuals with high familial risk of MS were included in this scoping review. Studies suggest either no conclusive (5), or inconclusive yet considerable (4), or conclusive evidence (7) for the incidence of subclinical neuropathology, including focal and diffuse tissue damage. Across all studies, white matter lesions fulfilling MS criteria were observed in 86 of 613 individuals (14%). Future research is needed to evaluate the longitudinal dynamics and clinical relevance of preclinical imaging abnormalities in MS.

Monitoring the Motor Phenotype in Huntington's Disease by Analysis of Keyboard Typing During Real Life Computer Use.

BACKGROUND: Besides cognitive and psychiatric abnormalities, motor symptoms are the most prominent in Huntington's disease. The manifest disease is preceded by a prodromal phase with subtle changes such as fine motor disturbances or concentration problems. OBJECTIVE: Movement disorders show a high variation in their clinical manifestation depending on condition and external influences. Therefore, devices for continuous measurements, which patients use in their daily life and which can monitor motor abnormalities, in addition to the medical examination, might be useful. The aim of current scientific efforts is to find markers that reflect the prodromal phase in gene carriers. This is important for future interventional studies, as future therapies should be applied at the stage of neuronal dysfunction, i.e., before the clinical manifestation. METHODS: We performed a software-supported, continuous monitoring of keyboard typing on the participants' own computer to evaluate this method as a tool to assess the motor phenotype in HD. We included 40 participants and obtained sufficient data from 25 participants, 12 of whom were manifest HD patients, 7 HD gene expansion carriers (HDGEC) and 6 healthy controls. RESULTS: In a cross-sectional analysis we found statistically significant higher typing inconsistency in HD patients compared to controls. Typing inconsistency compared between HDGEC and healthy controls showed a trend to higher inconsistency levels in HDGEC. We found correlations between typing cadence and clinical scores: the UHDRS finger tapping item, the composite UHDRS and the CAP score. CONCLUSION: The typing cadence inconsistency is an appropriate marker to evaluate fine motor skills of HD patients and HDGEC and is correlated to established clinical measurements.

The motor prodromes of parkinson's disease: from bedside observation to large-scale application.

There is sufficient evidence that the pathological process that causes Parkinson's disease begins years before the clinical diagnosis is made. Over the last 15 years, there has been much interest in the existence of a prodrome in some patients, with a particular focus on non-motor symptoms such as reduced sense of smell, REM-sleep disorder, depression, and constipation. Given that the diagnostic criteria for Parkinson's disease depends on the presence of bradykinesia, it is somewhat surprising that there has been much less research into the possibility of subtle motor dysfunction as a pre-diagnostic pointer. This review will focus on early motor features and provide some advice on how to detect and measure them.

The multiple sclerosis prodrome: Emerging evidence, challenges, and opportunities.

A prodrome is considered an early set of signs or symptoms indicating the onset of a disease or illness. In multiple sclerosis (MS), the prodromal period is the months or years before our current, classic understanding of "MS symptom onset." Prodromal periods are well recognized in other neurodegenerative conditions and more recently have been shown in MS. In this Viewpoint, we reflect on the emerging evidence surrounding the MS prodrome, including features that may be common across chronic inflammatory and neurodegenerative diseases. Finally, we discuss the implications for future disease prevention in MS.