Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy.

Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.

[Functions and organisation of a neuro-oncology committee in hospitals with a neurosurgery service]. / Funciones y organización de un comité de neurooncología en un hospital con servicio de neurocirugía.

The Neuro-Oncology Study Group (NOSG) at SENEC has commissioned the elaboration of the present document to the Neuro-Oncology Committee at Donostia University Hospital. It is intended to serve as a NOSG Consensus Guide and a proposed recommendation for the management of this pathological condition at all Spanish Hospitals, both public and private. Neuro-Oncology Committees must be established and active at all centres with a Neurosurgery Service, taking into account the specific diagnostic and therapeutic capacity available. The work presents an example of the constitution, functioning and experience of such a Committee, drawing on 8 years of multidisciplinary work with brain tumour patients.

Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders.

Olfactory dysfunction is a frequent and early feature of patients with neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) and is very uncommon in patients with frontotemporal dementia (FTD). Mechanisms underlying this clinical manifestation are poorly understood but the premature deposition of protein aggregates in the olfactory bulb (OB) of these patients might impair its synaptic organization, thus accounting for the smell deficits. Tau, ß-amyloid and alpha-synuclein deposits were studied in 41 human OBs with histological diagnosis of AD (n = 24), PD (n = 6), FTD (n = 11) and compared with the OB of 15 control subjects. Tau pathology was present in the OB of all patients, irrespective of the histological diagnosis, while ß-amyloid and alpha-synuclein protein deposit were frequently observed in AD and PD, respectively. Using stereological techniques we found an increased number of dopaminergic periglomerular neurons in the OB of AD, PD and FTD patients when compared with age-matched controls. Moreover, volumetric measurements of OBs showed a significant decrease only in AD patients, while the OB volume was similar to control in PD or FTD cases. The increased dopaminergic tone created in the OBs of these patients could reflect a compensatory mechanism created by the early degeneration of other neurotransmitter systems and might contribute to the olfactory dysfunction exhibited by patients with neurodegenerative disorders.

Mixed pathologies in pancreatic ß cells from subjects with neurodegenerative diseases and their interaction with prion protein.

Protein misfolding diseases refer to a variety of disorders that develop as a consequence of the misfolding of proteins in various organs. The etiologies of Parkinson's and Alzheimer's disease remain unclear, but it seems that type two diabetes and other prediabetic states could contribute to the appearance of the sporadic forms of these diseases. In addition to amylin deposition, other amyloidogenic proteins implicated in the pathophysiology of neurodegenerative diseases could have important roles in the pathogenesis of this disease. As we have previously demonstrated the presence of α-synuclein deposits in the pancreas of patients with synucleinopathies, as well as tau and Aß deposits in the pancreatic tissue of Alzheimer's disease patients, we studied the immunoreactivity of amylin, tau and α-synuclein in the pancreas of 138 subjects with neurodegenerative diseases or type two diabetes and assessed whether the pancreatic ß-cells of these subjects present cooccurrence of misfolded proteins. Furthermore, we also assessed the pancreatic expression of prion protein (PrP) in these subjects and its interaction, both in the pancreas and brain, with α-synuclein, tau, Aß and amylin. Our study shows, for the first time, that along with amylin, pancreatic α-synuclein, Aß, PrP and tau may contribute together to the complex pathophysiology of type two diabetes and in the appearance of insulin resistance in Alzheimer's and Parkinson's disease. Furthermore, we show that the same mixed pathologies that are observed in the brains of patients with neurodegenerative diseases are also present outside the nervous system. Finally, we provide the first histological evidence of an interaction between PrP and Aß, α-synuclein, amylin or tau in the pancreas and locus coeruleus. These findings will shed more light on the common pathological pathways shared by neurodegenerative diseases and type two diabetes, benefiting the exploration of common therapeutic strategies to prevent or treat these devastating amyloid diseases.

The unexpected co-occurrence of GRN and MAPT p.A152T in Basque families: Clinical and pathological characteristics.

BACKGROUND: The co-occurrence of the c.709-1G>A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. METHODS AND FINDINGS: We compared clinical characteristics of 14 patients who carried the c.709-1G>A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G>A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T- patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked ß-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability). CONCLUSIONS: In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question.

[Association between microsatellite instability and clinico-pathological characteristics in sporadic colon cancer]. / Asociación entre la inestabilidad de microsatélites y las características clínicas y anatomopatológicas en pacientes con cáncer de colon esporádico.

BACKGROUND AND OBJECTIVE: Currently, colon cancer is a leading cause of cancer death world-wide. It progresses according to three molecular pathways, named suppressor, mutador and methylator. Microsatellite instability is a hallmark of the lack of reparation, of DNA mismatches and it characterizes a subset of colon tumors (unstable tumors, MSI). MSI-H patients (high degree of microsatellite instability) seem to share clinico-pathological differences with MSS (microsatellite stable) and MSI-L (low degree of microsatellite instability) patients. In this study, associations between high degree of microsatellite instability and pathological (location, mucinous content, differentiation grade, stages T3N0, stages II and III) and clinical features (response to chemotherapy, disease-free survival and overall survival) were evaluated. PATIENTS AND METHOD: 117 patients with sporadic colon cancer were classified into two populations (MSS/MSI-L and MSI-H) by using PCR and electrophoresis of seven microsatellites, according to the National Cancer Institute recommendations. RESULTS: MSI-H tumors tended to be located in the right colon (p = 0.022) and were of mucinous histologic type (p = 0.04). No differences in disease-free survival and overall survival between group of stage II and III patients with MSS/ MSI-L and corresponding ones with MSI-H colon cancer were found (p = 0.54, p = 0.37, respectively). Conversely, MSI-H patients with stage II colon cancer had a favourable prognosis (p = 0.027). Nevertheless, response to 5-fluorouracil (5-FU) and leucovorin was similar in MSS/ MSI-L and MSI-H groups (p = 0.38). CONCLUSIONS: MSI-H patients are characterized by certain pathological features; those MSI-H patients with a stage II seem to have a better prognosis than MSS/ MSI-L patients.

Co-occurrence of different pathologies in dementia: implications for dementia diagnosis.

The standard for differentiating between dementia subtypes is currently based on neuropathological changes and follows traditional nosological classifications. However, the high incidence of comorbid neuropathologies complicates the differentiation between dementia diagnoses in the clinic. The aim of this study was to investigate the grades of agreement between clinical and neuropathological diagnoses in neurodegenerative disorders, to compare them with rates found in previous studies, and to propose implications for dementia diagnostics. Patients, who donated their brains to the Brain Bank of Navarre (Pamplona, Spain), had been diagnosed with a neurodegenerative disorder during life (clinical diagnosis) and postmortem (neuropathological diagnosis). We studied a sample of patients with a short average time interval between the last clinical assessment and death (4.6 months). Overall, there was a mean grade of agreement of 44.0% between the clinical diagnosis and the pure neuropathological diagnosis (i.e., without co-morbid neuropathological disorders). This grade of agreement differed between dementia subtypes: e.g., 85% for prion disease, 49% for Alzheimer's disease, and 0% for Lewy body dementia. Our data confirm that co-occurrence of multiple neuropathological disorders is very common in individuals with dementia, and that the underlying neuropathology often differs from the neuropathology implied by the clinical diagnosis. These findings support a multidimensional approach to diagnosing dementia, in which dementia syndromes are not categorized into diagnostic subtypes, but are seen as syndromes characterized by a combination of various neuropathological dimensions.

Funciones y organización de un comité de neurooncología en un hospital con servicio de neurocirugía / Functions and organisation of a neuro-oncology committee in hospitals with a neurosurgery service

El Grupo de Trabajo de Neurooncología (GTNO) de la SENEC ha encargado a los miembros del comité de neurooncología del Hospital Universitario Donostia de San Sebastián (España) la elaboración del presente documento, para que sirva como Guía del consenso establecido en el seno del GTNO y recomendación propuesta en todos los hospitales, públicos o privados, que manejan esta patología. Es obligado la constitución y funcionamiento normalizado de comités de neurooncología en todos los centros con servicio de neurocirugía, y lo expuesto a continuación debe contemplarse a la luz de las condiciones particulares de los mismos, con las variaciones pertinentes según los recursos diagnósticos y terapéuticos. Nos presentan a continuación el ejemplo de la constitución, funcionamiento y experiencia que han contraído en más de 8 años de trabajo multidisciplinar en pacientes con tumores cerebrales (AU)

The Neuro-Oncology Study Group (NOSG) at SENEC has commissioned the elaboration of the present document to the Neuro-Oncology Committee at Donostia University Hospital. It is intended to serve as a NOSG Consensus Guide and a proposed recommendation for the management of his pathological conditionatallSpanishHospitals,bothpublicandprivate.Neuro-Oncology Committees must be established and active at all centres with a Neurosurgery Service, taking into account the specific diagnostic and therapeutic capacity available. The work presents an example of the constitution, functioning and experience of such a Committee, drawing on 8 years of multidisciplinary work with brain tumour patients (AU)

Asociación entre la inestabilidad de microsatélites y las características clínicas y anatomopatológicas en pacientes con cáncer de colon esporádico / Association between microsatellite instability and clinico-pathological characteristics in sporadic colon cancer

FUNDAMENTO Y OBJETIVO: La inestabilidad de microsatélites derivada del fallo en la reparación delos falsos emparejamientos del ADN es la alteración característica de los tumores de la vía mutadorao inestables (MSI). Tales casos parecen presentar diferencias desde el punto de vista clinicopatológicocon los tumores de la vía supresora o estables (MSS). Los tumores con alto gradode inestabilidad (MSI-H) parecen constituir una nueva entidad de tumores con diferencias endeterminadas características anatomopatológicas y clínicas con respecto a los tumores estables(MSS) e inestables de bajo grado (MSI-L). En el presente estudio se valora la posible asociaciónentre el alto grado de inestabilidad de microsatélites con la localización, contenido mucinoso,grado de diferenciación, estadio, así como el intervalo libre de enfermedad y supervivencia.PACIENTES Y MÉTODO: Se clasifica a 117 pacientes con cáncer de colon esporádico en las poblacionesMSS/MSI-L y MSI-H (siguiendo las recomendaciones del National Cancer Institute) mediantereacción en cadena de la polimerasa y electroforesis de 7 microsatélites.RESULTADOS: Los tumores MSI-H tendieron a localizarse en el colon derecho (p = 0,022) y a presentarcontenido mucinoso (p = 0,04). El conjunto de pacientes MSI-H de estadios II y III no presentóintervalos libres de enfermedad ni períodos de supervivencia más prolongados (p = 0,54, p= 0,37, respectivamente). Los tumores MSI-H de estadio II presentaron períodos de supervivenciamás prolongados que los tumores MSS/MSI-L (p = 0,027). No observamos diferencias en la respuestaa quimioterapia con 5-fluorouracilo y leucovorín entre los grupos MSS/MSI-L y MSI-H (p =0,38).CONCLUSIONES: El alto grado de inestabilidad de microsatélites se asocia con determinadas característicaspatológicas, así como con períodos de supervivencia más prolongados para los tumoresde estadios II

BACKGROUND AND OBJECTIVE: Currently, colon cancer is a leading cause of cancer death worldwide.It progresses according to three molecular pathways, named suppressor, mutador andmethylator. Microsatellite instability is a hallmark of the lack of reparation, of DNA mismatchesand it characterizes a subset of colon tumors (unstable tumors, MSI). MSI-H patients (high degreeof microsatellite instability) seem to share clinico-pathological differences with MSS (microsatellitestable) and MSI-L (low degree of microsatellite instability) patients. In this study,associations between high degree of microsatellite instability and pathological (location, mucinouscontent, differentiation grade, stages T3N0, stages II and III) and clinical features (responseto chemotherapy, disease-free survival and overall survival) were evaluated.PATIENTS AND METHOD: 117 patients with sporadic colon cancer were classified into two populations(MSS/MSI-L and MSI-H) by using PCR and electrophoresis of seven microsatellites, accordingto the National Cancer Institute recommendations.RESULTS: MSI-H tumors tended to be located in the right colon (p = 0.022) and were of mucinoushistologic type (p = 0.04). No differences in disease-free survival and overall survival betweengroup of stage II and III patients with MSS/ MSI-L and corresponding ones with MSI-Hcolon cancer were found (p = 0.54, p = 0.37, respectively). Conversely, MSI-H patients withstage II colon cancer had a favourable prognosis (p = 0.027). Nevertheless, response to 5-fluorouracil(5-FU) and leucovorin was similar in MSS/ MSI-L and MSI-H groups (p = 0.38).CONCLUSIONS: MSI-H patients are characterized by certain pathological features; those MSI-Hpatients with a stage II seem to have a better prognosis than MSS/ MSI-L patients