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.

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.

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.

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.

Beneficial effects of omega-3 fatty acid supplementation in schizophrenia: possible mechanisms.

BACKGROUND: Schizophrenia is a serious long-term psychotic disorder marked by positive and negative symptoms, severe behavioral problems and cognitive function deficits. The cause of this disorder is not completely clear, but is suggested to be multifactorial, involving both inherited and environmental factors. Since human brain regulates all behaviour, studies have focused on identifying changes in neurobiology and biochemistry of brain in schizophrenia. Brain is the most lipid rich organ (approximately 50% of brain dry weight). Total brain lipids is constituted of more than 60% of phospholipids, in which docosahexaenoic acid (DHA, 22:6n-3) is the most abundant (more than 40%) polyunsaturated fatty acid (PUFA) in brain membrane phospholipids. Results from numerous studies have shown significant decreases of PUFAs, in particular, DHA in peripheral blood (plasma and erythrocyte membranes) as well as brain of schizophrenia patients at different developmental phases of the disorder. PUFA deficiency has been associated to psychotic symptoms and cognitive deficits in schizophrenia. These findings have led to a number of clinical trials examining whether dietary omega-3 fatty acid supplementation could improve the course of illness in patients with schizophrenia. Results are inconsistent. Some report beneficial whereas others show not effective. The discrepancy can be attributed to the heterogeneity of patient population. METHODS: In this review, results from recent experimental and clinical studies, which focus on illustrating the role of PUFAs in the development of schizophrenia were examined. The rationale why omega-3 supplementation was beneficial on symptoms (presented by subscales of the positive and negative symptom scale (PANSS), and cognitive functions in certain patients but not others was reviewed. The potential mechanisms underlying the beneficial effects were discussed. RESULTS: Omega-3 fatty acid supplementation reduced the conversion rate to psychosis and improved both positive and negative symptoms and global functions in adolescents at ultra-high risk for psychosis. Omega-3 fatty acid supplementation could also improve negative symptoms and global functions in the first-episode patients with schizophrenia, but improve mainly total or general PANSS subscales in chronic patients. Patients with low PUFA (particularly DHA) baseline in blood were more responsive to the omega-3 fatty acid intervention. CONCLUSION: Omega-3 supplementation is more effective in reducing psychotic symptom severity in young adults or adolescents in the prodromal phase of schizophrenia who have low omega-3 baseline. Omega-3 supplementation was more effective in patients with low PUFA baseline. It suggests that patients with predefined lipid levels might benefit from lipid treatments, but more controlled clinical trials are warranted.

Patient's perception: shorter and more severe prodromal phase in GBA-associated PD.

BACKGROUND: Prevalence and time of occurrence of prodromal symptoms of Parkinson's disease (PD) in relation to the onset of classical motor manifestation varies between patients. Possible modifying factors might be different genetic architectures predisposing to varying burden of manifestations. OBJECTIVES: To characterize the prodromal phase in PD patients with heterozygous mutations in the GBA gene compared to PD patients without GBA mutation. METHODS: In a retrospective design, 151 participants [47 PD patients carrying a GBA mutation (PDGBA ), 52 idiopathic PD patients (PDidiopathic ), 52 healthy elderly (CON)] underwent a validated structured interview designed to assess prevalence and time of occurrence of prodromal symptoms. RESULTS: PDGBA showed a higher prevalence of prodromal symptoms and almost simultaneous occurrence of non-motor and early motor symptoms shortly before PD diagnosis whereas PDidiopathic reported a longer prodromal phase starting with non-motor symptoms. CONCLUSION: The short and severe prodromal phase in PDGBA might call for shorter assessment intervals in yet premanifest GBA mutation carriers.

[Biomarker-based diagnostics of Alzheimer's disease : Concept of suspected non-Alzheimer pathology]. / Biomarker-basierte Diagnostik der Alzheimer-Krankheit : Konzept der "suspected non-Alzheimer pathology".

In the field of prodromal Alzheimer's disease biomarker-based diagnostics are becoming increasingly more important. Unclear biomarker constellations, such as suspected non-Alzheimer pathology (SNAP) can lead to diagnostic and prognostic uncertainty. The use of biomarker-based research criteria in the clinical routine is therefore not without problems. Despite sometimes contradictory findings it appears to be nearly certain that the biomarker constellation of SNAP indicates an increased risk of progression to dementia, at least in patients with mild cognitive deficits (MCI). This article discusses the prognostic implications of a SNAP result and the diagnostic and prognostic problems of biomarker-based diagnostic criteria are presented based on the SNAP.

Cognitive changes in prodromal Parkinson's disease: A review.

Although other nonmotor phenomena representing possible prodromal symptoms of Parkinson's disease have been described in some detail, the occurrence and characteristics of cognitive decline in this early phase of the disease are less well understood. The aim of this review is to summarize the current state of research on cognitive changes in prodromal PD. Only a small number of longitudinal studies have been conducted that examined cognitive function in individuals with a subsequent PD diagnosis. However, when we consider data from at-risk groups, the evidence suggests that cognitive decline may occur in a substantial number of individuals who have the potential for developing PD. In terms of specific cognitive domains, executive function in particular and, less frequently, memory scores are reduced. Prospective longitudinal studies are thus needed to clarify whether cognitive, and specifically executive, decline might be added to the prodromal nonmotor symptom complex that may precede motor manifestations of PD by years and may help to update the risk scores used for early identification of PD. © 2017 International Parkinson and Movement Disorder Society.

The prodromal phase of leucine-rich repeat kinase 2-associated Parkinson disease: Clinical and imaging Studies.

BACKGROUND: Asymptomatic, nonmanifesting carriers of leucine-rich repeat kinase 2 mutations are at increased risk of developing PD. Clinical and neuroimaging features may be associated with gene carriage and/or may demarcate individuals at greater risk for phenoconversion to PD. OBJECTIVES: To investigate clinical and dopamine transporter single-photon emission computed tomography imaging characteristics of leucine-rich repeat kinase 2 asymptomatic carriers. METHODS: A total of 342 carriers' and 259 noncarriers' relatives of G2019S leucine-rich repeat kinase 2/PD patients and 39 carriers' and 31 noncarriers' relatives of R1441G leucine-rich repeat kinase 2/PD patients were evaluated. Motor and nonmotor symptoms were assessed using specific scales and questionnaires. Neuroimaging quantitative data were obtained in 81 carriers and compared with 41 noncarriers. RESULTS: G2019S carriers scored higher in motor scores and had lower radioligand uptake compared to noncarriers, but no differences in nonmotor symptoms scores were observed. R1441G carriers scored higher in motor scores, had lower radioligand uptake, and had higher scores in depression, dysautonomia, and Rapid Eye Movements Sleep Behavior Disorder Screening Questionnaire scores, but had better cognition scores than noncarriers. Among G2019S carriers, a group with "mild motor signs" was identified, and was significantly older, with worse olfaction and lower radioligand uptake. CONCLUSIONS: G2019S and R1441G carriers differ from their noncarriers' relatives in higher motor scores and slightly lower radioligand uptake. Nonmotor symptoms were mild, and different nonmotor profiles were observed in G2019S carriers compared to R1441G carriers. A group of G2019S carriers with known prodromal features was identified. Longitudinal studies are required to determine whether such individuals are at short-term risk of developing overt parkinsonism. © 2017 International Parkinson and Movement Disorder Society.

Relation between duration of the prodromal phase and renal damage in ANCA-associated vasculitis.

BACKGROUND: In ANCA-associated vasculitis the acute phase of the disease is often preceded by prodromal symptoms. The aim of the present study was to analyze the relation between the duration of the prodromal phase and renal damage. METHODS: Patients with ANCA-associated vasculitis and renal involvement from a retrospective single-center cohort were divided into two equal groups based on the duration of the prodromal phase. The prodromal phase was defined as the time between first vasculitis related symptoms and the date of diagnosis. Clinical characteristics at diagnosis and renal items on the vasculitis damage index at 6 months were compared between the two groups. In addition, the relation between a long prodromal phase and 3-year end-stage renal disease and mortality as a composite outcome was studied. RESULTS: A total of 72 patients were included (age 64 ± 12 years; 74% male; 96% Caucasian). At diagnosis, in patients with a prodromal phase ≤22 weeks versus >22 weeks estimated glomerular filtration rate and proteinuria did not differ significantly (35 (interquartile range 50) versus 30 (50) ml/min p = 0.84; 75% versus 87%, p = 0.21 respectively). Furthermore, Birmingham Vasculitis Activity Scores were comparable (7 (3), p = 0.71). At 6 months, a long prodromal phase was associated with proteinuria (odds ratio 5.38, 95% confidence interval (CI) 1.47-19.62), but not with an estimated glomerular filtration rate ≤ 50 ml/min (odds ratio 0.89, 95% CI 0.33-2.37) in multivariable analyses. In addition, a long prodromal phase was associated with end-stage renal disease/mortality (hazard ratio 5.22, 95% CI 1.13-24.20). CONCLUSIONS: A long prodromal phase was associated with proteinuria and 3-year end-stage renal disease/mortality, but not with a reduced renal function at 6 months. These results underline the importance of an early diagnosis in ANCA-associated vasculitis patients in order to improve renal outcomes.

Prodromal features for Parkinson's disease--baseline data from the TREND study.

BACKGROUND AND PURPOSE: A number of non-motor features are known to precede motor manifestations of Parkinson's disease (PD). They are supposed to already represent the prodromal neurodegenerative state in those who later develop PD and are thus called prodromal markers. In this study, three prodromal markers, depression, rapid eye movement behaviour disorder (RBD) and hyposmia, were selected and were related to other prodromal features in elderly individuals without PD. METHODS: From the Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration (TREND) study, 698 healthy individuals aged 50-80 years reporting one or more of the selected prodromal markers (SPMs), but without neurodegenerative disorders, were evaluated and classified according to the status of prodromal markers. Other prodromal PD-related features were assessed with a 23-item questionnaire and compared between participants with and without the three SPMs. RESULTS: Individuals with the SPMs for PD endorsed more of the additional possible prodromal features of PD than those without; of 23 possible prodromal features, the median number identified amongst participants with no SPMs was two, compared with four with one marker, five with two and seven with three (P < 0.001). Regarding individual SPMs, participants with depression and RBD endorsed five of 23 markers, compared with three for those with hyposmia (P = 0.001). There was no significant increase in the number of prodromal features amongst those with two SPMs compared with those with only one marker. CONCLUSIONS: Individuals with the SPMs for PD report a higher prevalence of other prodromal PD symptoms. This may indicate that these markers can identify individuals at risk for PD.

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.

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.

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.

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.

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.