Midbrain and pons MRI shape analysis and its clinical and CSF correlates in degenerative parkinsonisms: a pilot study

Multiple system atrophy; Neurofilament protein; Parkinsonian disordersAtròfia de sistemes múltiples; Proteïna del neurofilament; Trastorns de ParkinsonAtrofia multisistémica; Proteína de neurofilamento; Trastornos parkinsonianosObjectives: To conduct brainstem MRI shape analysis across neurodegenerative parkinsonisms and control subjects (CS), along with its association with clinical and cerebrospinal fluid (CSF) correlates. Methodology: We collected demographic and clinical variables, performed planimetric and shape MRI analyses, and determined CSF neurofilament-light chain (NfL) levels in 84 participants: 11 CS, 12 with Parkinson's disease (PD), 26 with multiple system atrophy (MSA), 21 with progressive supranuclear palsy (PSP), and 14 with corticobasal degeneration (CBD). Results: MSA featured the most extensive and significant brainstem shape narrowing (that is, atrophy), mostly in the pons. CBD presented local atrophy in several small areas in the pons and midbrain compared to PD and CS. PSP presented local atrophy in small areas in the posterior and upper midbrain as well as the rostral pons compared to MSA. Our findings of planimetric MRI measurements and CSF NfL levels replicated those from previous literature. Brainstem shape atrophy correlated with worse motor state in all parkinsonisms and with higher NfL levels in MSA, PSP, and PD. Conclusion: Atypical parkinsonisms present different brainstem shape patterns which correlate with clinical severity and neuronal degeneration. In MSA, shape analysis could be further explored as a potential diagnostic biomarker. By contrast, shape analysis appears to have a rather limited discriminant value in PSP

Noves aproximacions diagnòstiques a la paràlisi supranuclear progressiva: biomarcadors clínics, en líquid cefaloraquidi i de ressonància magnètica

[cat] La paràlisi supranuclear progressiva (PSP) és un parkinsonisme neurodegeneratiu caracteritzat patològicament pel dipòsit neuronal i glial de la proteïna tau de 4 repeticions (4R-tau) a diferència de la malaltia de Parkinson (MP) on la proteïna de dipòsit es l’alfa-sinucleïna (aS). Degut a que comparteix signes i símptomes amb altres parkinsonismes neurodegeneratius, el diagnòstic diferencial pot ésser difícil sobretot en les fases inicials de la malaltia. A hores d’ara no disposem de biomarcadors fiables i el diagnòstic definitiu de la PSP és patològic. In vivo només es pot arribar a un diagnòstic de PSP suggestiva (certesa baixa), possible (certesa intermèdia) o probable (certesa alta però incompleta) mitjançant criteris clínics. Per tant, l’estudi de biomarcadors que ajudin a realitzar un diagnòstic més precís i en una fase precoç de la malaltia és essencial. Així doncs, aquesta tesi vol profunditzar en el coneixement dels biomarcadors diagnòstics a la PSP. Hem formulat les següents hipòtesis: 1) existeixen símptomes prediagnòstics a la PSP que difereixen de la fase prediagnòstica de la MP; 2) la combinació de biomarcadors permet diferenciar la PSP d’altres parkinsonismes; 3) la morfologia o forma (“shape”) per ressonància magnètica (RM) del tronc de l’encèfal també difereix entre PSP i altres parkinsonismes i es correlaciona amb indicadors clínics i bioquímics de gravetat de la malaltia. En conseqüència hem plantejat els següents objectius: 1) avaluar els símptomes que precedeixen el diagnòstic per a definir-ne la fase prediagnòstica i comparar-los amb la MP; 2) avaluar el rendiment de la combinació de diferents biomarcadors proteics en líquid cefaloraquidi (LCR) i radiològics per RM en comparació a d’altres parkinsonismes neurodegeneratius incloent la nova tècnica d’agregació RT-QuIC; 3) avaluar les diferències entre PSP i altres parkinsonismes amb la nova aproximació de RM anomenada shape analysis i els seus correlats clínics i en LCR. El primer objectiu es tracta en el primer article d’aquesta tesi on s’analitzen de forma restrospectiva els símptomes que poden presentar els pacients amb PSP anys abans de rebre el diagnòstic (prediagnòstics) i es comparen les troballes amb dos grups controls (un format per pacients amb MP i l’altre per subjectes control sense malaltia neurològica (SC)). En la nostra cohort, els pacients amb PSP presenten una major prevalença d’alguns símptomes motors i no motors que poden estar presents fins a 10 anys abans del diagnòstic. La presència d’aquests símptomes combinada amb l’absència d’altres símptomes prediagnòstics més propis de la MP proporciona una alta capacitat predictiva per a diferenciar PSP de MP. El segon objectiu es recull al segon estudi, centrat en la capacitat diagnòstica de la combinació de diferents biomarcadors en LCR i radiològics. En la nostra cohort, la combinació d’una àrea mesencefàlica reduïda a la RM, nivells elevats de neurofilament (NFL) i la negativitat d’agregació d’aS per RT-QuIC, mostra una excel·lent capacitat discriminant entre taupaties (PSP i degeneració corticobasal (DCB)) i altres tipus de parkinsonismes. Per últim, al tercer article s’explora el tercer objectiu: valorar si els diferents parkinsonismes presenten patrons de shape analysis (estudi de forma més que de superfície o voulm) diferencials a nivell del tronc encefàlic. Tot i que aquesta tècnica mostra resultats menys significatius a la PSP que a d’altres parkinsonismes neurodegeneratius, sí que mostra correlacions significatives amb indicadors clínics de gravetat i amb el biomarcador d’agressivitat de la neurodegeneració (nivells elevats de NFL en LCR). En resum, aquesta tesi aporta nou coneixement sobre biomarcadors diagnòstics en una malaltia de difícil i complex diagnòstic. Els símptomes prediagnòstics poden ser d’utilitat per a realitzar un diagnòstic precoç de la PSP, i la combinació de biomarcadors ens pot ajudar en el diagnòstic diferencial amb d’altres parkinsonismes. Les troballes d’aquesta investigació són doncs de potencial rellevància clínica, i obren noves i interessants línies d’investigació.[eng] Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonism pathologically characterized by neuronal and glial deposition of 4-repeat tau protein (4R-tau). Due to the overlap of signs and symptoms with other neurodegenerative parkinsonisms, the differential diagnosis of PSP can be challenging, particularly during the early stages of the disease. Currently, there are no reliable biomarkers available and the definite diagnosis of PSP is pathological. The research of biomarkers in order to do a more precise diagnosis and in an earlier phase of the disease is essential. Therefore, this thesis aims to deepen the knowledge of diagnostic biomarkers in PSP. We formulated the following hypotheses: 1) prediagnostic symptoms in PSP differ from the ones present in the prediagnostic phase of Parkinson’s disease; 2) the combination of CSF and neuroradiological biomarkers allow to differentiate PSP from the other parkinsonisms; 3) brainstem shape analysis differs between PSP and the other parkinsonisms and, correlates with clinical and biochemical markers of disease severity. Accordingly, we have proposed the following objectives 1) to evaluate the symptoms preceding the diagnosis of PSP and compare them with the prediagnostic symptoms of PD; 2) to explore the combined biomarkers discriminant ability across PSP and other degenerative parkinsonisms; 3) to compare brainstem shape patterns across degenerative parkinsonisms, as well as analyzing the clinical and biological correlates of shape changes. The first objective was addressed in the first study. We performed a retrospective case-control study and found that PSP patients presented a broad variety of motor and non-motor symptoms several years before the diagnosis. The second objective was evaluated in the second study. We performed a cross-sectional study and found that the combination of CSF neurofilament, CSF RT-QuIC alpha-synuclein and midbrain MRI measures showed high discriminant ability between PSP and the other parkinsonisms. Finally, the third objective was addressed in the third study where we found that although shape analysis appeared to be of rather limited discriminant value in PSP, it showed significant correlations with clinical disease severity markers and also with biomarkers of neurodegeneration. These studies delve into and provide new data on diagnostic biomarkers in PSP

Diagnostic Accuracy of Magnetic Resonance Imaging Measures of Brain Atrophy Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Degeneration

Altres ajuts: Global Brain Health Institute (GBHI), Alzheimer's Association, and Alzheimer's Society (GBHI ALZ UK-21-720973, AACSF-21-850193); NIH grants (AG019724, AG032306, AG045390, NS092089, AG045333, AG056749, AG062422, K24AG053435, K08AG052648, R01AG059794, R01AG056850-01A1, R21AG056974, R01AG061566, K23AG059888); Fondo de Investigaciones Sanitario; Centro de Investigación en Red-Enfermedades Neurodegenerativas program (Program 1, Alzheimer Disease); Fondo Europeo de Desarrollo Regional, Unión Europea, una manera de hacer Europa; La Marató de TV3 (20141210); Generalitat de Catalunya; Banco Bilbao Vizcaya Argentaria foundation.Importance: The accurate diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is hampered by imperfect clinical-pathological correlations. Objective: To assess and compare the diagnostic value of the magnetic resonance parkinsonism index (MRPI) and other magnetic resonance imaging-based measures of cerebral atrophy to differentiate between PSP, CBD, and other neurodegenerative diseases. Design, Setting, and Participants: This prospective diagnostic study included participants with 4-repeat tauopathies (4RT), PSP, CBD, other neurodegenerative diseases and available MRI who appeared in the University of California, San Francisco, Memory and Aging Center database. Data were collected from October 27, 1994, to September 29, 2019. Data were analyzed from March 1 to September 14, 2021. Main Outcomes and Measures: The main outcome of this study was the neuropathological diagnosis of PSP or CBD. The clinical diagnosis at the time of the MRI acquisition was noted. The imaging measures included the MRPI, cortical thickness, subcortical volumes, including the midbrain, pons, and superior cerebellar peduncle volumes. Multinomial logistic regression models (MLRM) combining different cortical and subcortical regions were defined to discriminate between PSP, CBD, and other pathologies. The areas under the receiver operating characteristic curves (AUROC) and cutoffs were calculated to differentiate between PSP, CBD, and other diseases. Results: Of the 326 included participants, 176 (54%) were male, and the mean (SD) age at MRI was 64.1 (8.0) years. The MRPI showed good diagnostic accuracy for the differentiation between PSP and all other pathologies (accuracy, 87%; AUROC, 0.90; 95% CI, 0.86-0.95) and between 4RT and other pathologies (accuracy, 80%; AUROC, 0.82; 95% CI, 0.76-0.87), but did not allow the discrimination of participants with CBD. Its diagnostic accuracy was lower in the subgroup of patients without the canonical PSP-Richardson syndrome (PSP-RS) or probable corticobasal syndrome (CBS) at MRI. MLRM combining cortical and subcortical measurements showed the highest accuracy for the differentiation between PSP and other pathologies (accuracy, 95%; AUROC, 0.98; 95% CI, 0.97-0.99), CBD and other pathologies (accuracy, 83%; AUROC, 0.86; 95% CI, 0.81-0.91), 4RT and other pathologies (accuracy, 89%; AUROC, 0.94; 95% CI, 0.92-0.97), and PSP and CBD (accuracy, 91%; AUROC, 0.95; 95% CI, 0.91-0.99), even in participants without PSP-RS or CBS at MRI. Conclusions and Relevance: In this study, the combination of widely available cortical and subcortical measures of atrophy on MRI discriminated between PSP, CBD, and other pathologies and could be used to support the diagnosis of 4RT in clinical practice

Cerebrospinal fluid cytokines in multiple system atrophy: A cross-sectional Catalan MSA registry study

Introduction: Neuroinflammation is a potential player in neurodegenerative conditions, particularly the aggressive ones, such as multiple system atrophy (MSA). Previous reports on cytokine levels in MSA using serum or cerebrospinal fluid (CSF) have been inconsistent, including small samples and a limited number of cytokines, often without comparison to Parkinson's disease (PD), a main MSA differential diagnosis. Methods: Cross-sectional study of CSF levels of 38 cytokines using a multiplex assay in 73 participants: 39 MSA patients (19 with parkinsonian type [MSAp], 20 with cerebellar type [MSAc]; 31 probable, 8 possible), 19 PD patients and 15 neurologically unimpaired controls. None of the participants was under non-steroidal anti-inflammatory drugs at the time of the lumbar puncture. Results: There were not significant differences in sex and age among participants. In global non-parametric comparisons FDR-corrected for multiple comparisons, CSF levels of 5 cytokines (FGF-2, IL-10, MCP-3, IL-12p40, MDC) differed among the three groups. In pair-wise FDR-corrected non-parametric comparisons 12 cytokines (FGF-2, eotaxin, fractalkine, IFN-α2, IL-10, MCP-3, IL-12p40, MDC, IL-17, IL-7, MIP-1β, TNF-α) were significantly higher in MSA vs. non-MSA cases (PD + controls pooled together). Of these, MCP-3 and MDC were the most significant ones, also differed in MSA vs. PD, and were significant MSA-predictors in binary logistic regression models and ROC curves adjusted for age. CSF levels of fractalkine and MIP-1α showed a strong and significant positive correlation with UMSARS-2 scores. Conclusion: Increased CSF levels of cytokines such as MCP-3, MDC, fractalkine and MIP-1α deserve consideration as potential diagnostic or severity biomarkers of MSA

Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España

Introduction: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. Patients and methods: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. Results: We gathered data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. Conclusions: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials. (c) 2021 Sociedad Espanola de Neurologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/)