Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes.

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Lessons learned from a sporadic FUSopathy in a young man: a case report.

BACKGROUND: In frontotemporal dementia (FTD) spectrum, younger patients may correspond to fusopathy cases, and cognitive decline could be rapidly progressive. We present a clinical and neuropathological description of a patient. CASE PRESENTATION: A 37-year-old man, without a family history of neurodegenerative diseases, was brought by his family to consult for dysarthria and behavioural change. Initial exploration showed spastic dysarthria and disinhibition. He progressively worsened with a pseudobulbar syndrome, right-lateralized pyramidal signs, left hemispheric corticobasal syndrome and, finally, lower motor neuron signs in his right arm. He died four years after the initiation of the syndrome from bronchopneumonia. Laboratory tests (including blood and cerebrospinal fluid (CSF)) were normal. Magnetic resonance imaging (MRI) and fluorodeoxyglucose-containing positron emission tomography (PET-18F-FDG) showed left fronto-insular atrophy and hypometabolism. Subsequently, 123I-ioflupane (DaT-SCAN®) single-photon emission computed tomography (SPECT) was pathologic, manifesting bilaterally decreased activity with greater affection on the left side. Only a third electromyogram (EMG) detected denervation in the last year of evolution. No mutations were found in genes such as Tau, progranulin, C9orf72, FUS, TDP-43, CHMP2B, or VCP. In necropsy, severe frontotemporal atrophy with basophilic neuronal cytoplasmic and intranuclear inclusions, negative for tau and TAR DNA binding protein 43 (TDP-43), but positive for fused in sarcoma (FUS) consistent with specifically basophilic inclusions body disease (BIBD) type was found. CONCLUSIONS: In patients affected by FTD, particularly the youngest, with rapidly progressive decline and early motor affection, fusopathy must be suspected. These cases can include motor signs described in the FTD spectrum. Lower motor neuron affection in EMG could be detected late.

Presence of tau astrogliopathy in frontotemporal dementia caused by a novel Grn nonsense (Trp2*) mutation.

Frontotemporal lobar degeneration caused by GRN mutations is mainly associated with a TDP-43 type A proteinopathy. We present a family with autosomal dominant frontotemporal lobar degeneration caused by a novel GRN nonsense mutation (c.5G>A: p.Trp2*) in which the proband's brain also showed prominent glial tauopathy consistent with an aging-related tau astrogliopathy. Astrocytic tauopathy, 4R(+) and 3R(-) immunoreactive, was characterized by thorn-shaped astrocytes present in subpial, subependymal, and perivascular areas, and in gray matter; plus granular or fuzzy tau immunoreactivity in astrocytic processes in gray matter, either solitary or clustered in different regions. Some neurofibrillary tangles and pretangles, both 3R and 4R(+), were present in the medial temporal lobe but did not exhibit the characteristic distribution of Alzheimer's type pathology. This 4R-tau aging-related tau astrogliopathy is likely a co-occurring pathology, although an interaction between progranulin and tau proteins within the neurodegenerative process should not be ruled out.

Inhibition of neurogenesis in a case of Marburg variant multiple sclerosis.

INTRODUCTION: Neural stem cells (NSC) are located essentially in the subventricular zone (SVZ), subgranular zone (SGZ), and along the central canal of the spinal cord. These cells can proliferate in vitro and differentiate into neurons, oligodendrocytes, and astroglia, thus contributing to repair in multiple sclerosis (MS). We conducted a pathological study to analyse neurogenic response in a patient with Marburg variant MS. METHODS: We present the case of a 27-year-old immunocompetent patient with Marburg variant MS, a fulminant form of the disease. The condition lasted 20 days. Diagnosis was based on clinical symptoms and MRI showed demyelinating lesions located in subependymal areas and histopathological findings. Neurogenic niches (SVZ and dentate gyrus) were analysed by confocal microscopy using markers of proliferation (Ki-67, PCNA), neuroblasts (PSA-NCAM, DCX, Tuj1), stem cells (Nestin, GFAPδ, SOX2, PAX6, Musashi), astrocytes (GFAP, AQ4), oligodendrocytes (NG2, Olig), microglia and cell infiltrates (IBA-1, CD68, MHCII), and cell death (TUNEL). RESULTS: Expression of the markers GFAPδ, SOX2, and PAX6 in NSC was found to be very low. Likewise, markers of proliferation (Ki-67) and intermediate precursors (NG2) were also reduced. This lack of markers of the first stages of cell differentiation means that neurogenesis is inhibited even in very early stages of the disease. CONCLUSION: Inhibition of neurogenesis in our patient, which cannot be explained by the fulminant nature of his symptoms, may be related to inflammation and immune response. This finding may further our knowledge of repair mechanisms in MS.

Atypical progressive multifocal leukoencephalopathy in a patient with antisynthetase syndrome.

Antisynthetase syndrome is a disorder belonging to the dermatomyositis/polymyositis group, with high rates of morbidity and mortality. We herein present the case of a 71-year-old man who was diagnosed with antisynthetase syndrome and treated with rituximab. Almost three years later, the patient showed right-sided hemiparesis that ultimately progressed to complete hemiplegia and advancing cognitive deterioration with a poor clinical outcome. The neuropathological diagnosis was progressive multifocal leukoencephalopathy. Treatment with rituximab for antisynthetase syndrome itself plays a fundamental role in the development of infectious complications.

Contribución de la patología vascular a la correlación clínico-patológica en una serie de casos de demencia avanzada / Vascular pathology's contribution to the clinical-pathological correlation in advanced dementia

Fundamento y objetivo: la enfermedad de Alzheimer (EA) se acompaña frecuentemente de patología vascular (PV). La utilización de un sistema de clasificación que combine ambos tipos de patología permitiría realizar un diagnóstico diferencial preciso. En el presente trabajo se aplican de manera conjunta criterios neuropatológicos de EA y PV para clasificar una cohorte de pacientes con demencia avanzada. Material y método: se analizaron los datos neuropatológicos post mórtem de 40 cerebros donados al Banco de Tejidos de la Fundación CIEN. Todos los sujetos eran mayores de 70 años (edad = 85,42 ± 7,06; 75 % mujeres) y residentes del Centro Alzheimer de la Fundación Reina Sofía. Resultados: EA y PV no mostraron ninguna relación entre sí. Las puntuaciones cognitivas correlacionaron de forma inversamente proporcional con la EA, pero no mostraron asociación con la PV. Utilizando una escala de EA y otra de PV, los casos se clasificaron en tres grupos (57,5% EA, 12,5 % demencia vascular y 30 % demencia mixta) y se estudió su rendimiento en los test cognitivos. Conclusiones: el grupo vascular evidenció un rendimiento cognitivo superior a los otros dos. Los resultados apoyan el uso combinado de escalas de EA y PV para clasificar a los pacientes con demencia avanzada (AU)

Introduction and aim: Alzheimer’s (AD) disease is often accompanied by vascular pathology (VP). The use of a classification system combining both types of pathologies would enable a precise differential diagnosis. In this paper neuropathological criteria of AD and VP are applied in order to classify a cohort of patients with advanced dementia. Material and method: Postmortem neuropathological data from 40 brains donated to the CIEN Foundation Bank Tissue were analyzed. All participants were over 70 years old (mean age = 85.42 ± 7.06; 75% women) and they were institutionalized at the Alzheimer Center Reina Sofia Foundation. Results: AD and VP did not show any relation between them. Cognitive scores correlated inversely proportional with AD, but no association with VP was found. Combination of both scales allowed a classification of cases in three groups (57.5% AD, 12.5% vascular dementia, and 30% mixed dementia). Cognitive performance of those groups was studied. Discussion: Vascular group showed a higher cognitive performance than the other two groups. These results support the combination of AD and VP scales to classify a cohort of patients with advanced dementia (AU)

Variante frontal de la enfermedad de Alzheimer. Dos casos confirmados anatomopatológicamente y revisión de la bibliografía / Frontal variant of Alzheimer's disease. Two pathologically confirmed cases and a literature review

Introducción. La enfermedad de Alzheimer (EA) es la causa más frecuente de demencia en nuestro medio. En la mayoría de los pacientes, las manifestaciones iniciales consisten en una afectación selectiva y progresiva de la memoria. Sin embargo, no se trata de un proceso homogéneo y, en algunos casos, el modo de presentación puede ser atípico. La presentación de la EA en forma de alteración precoz de la personalidad, el comportamiento y las funciones ejecutivas se ha denominadovariante frontal de la EA. En nuestro caso, su diagnóstico definitivo sólo fue posible mediante el estudio histológico, pues los criterios clínicos vigentes resultaron entonces insuficientes para el diagnóstico de esta forma atípica de la EA. Casos clínicos. Dos pacientes, una mujer y un hombre de 60 y 52 años respectivamente, presentaron un cuadro progresivo de deterioro cognitivo con afectación inicial de las funciones ejecutivas y cambio de personalidad, junto con alteraciones del estado de ánimo, por lo que se realizó el diagnóstico inicial de probable demencia frontotemporal. No obstante, en ambos casos, la autopsia reveló datos compatibles con el diagnóstico de EA, con una distribución de la patología que afectaba fundamentalmente a los lóbulos frontales. Conclusiones. La EA tiene una forma heterogénea de presentación, lo que puede originar errores en su diagnóstico inicial, dado que los criterios clínicos actuales no recogen de modo suficiente esta variabilidad clínica. Por ello, consideramos importante prestar atención a las formas atípicas de la EA con el objeto de desarrollar nuevos métodos diagnósticos que permitan diferenciar la EA del resto de procesos degenerativos (AU)

Introduction. Alzheimer’s disease (AD) is the most frequent degenerative dementia in our setting. In most patients the initial manifestations of the disease consist in a selective and progressive compromise of memory. Yet, it is not a homogeneous process and in some cases the mode of presentation can be atypical. The presentation of AD in the form of anearly disorder affecting personality, behaviour and the executive functions has been called the frontal variant of AD. In our case, its definitive diagnosis was only possible by means of a histological analysis, given the fact that the applicable clinical criteria were then insufficient to reach a diagnosis of this atypical form of AD. Case reports. We report the cases of two patients, one female and one male aged 60 and 52 respectively, who presented a progressive picture of cognitive impairment with initial involvement of the executive functions and personality changes, together with mood disorders. As a result, the initial diagnosis was one of probable frontotemporal dementia. However, in both cases, the autopsy revealed data consistent with a diagnosis of AD, with a distribution of the pathology that essentially affected the frontal lobes. Conclusions. AD has a heterogeneous form of presentation, which can give rise to errors in its initial diagnosis, since current clinical criteria do not take this clinical variability sufficiently into account. We therefore consider it important to pay attention to the atypical forms of AD with the aim of developing new diagnostic methods that allow AD to be distinguished from other degenerative processes (AU)

[Frontal variant of Alzheimer's disease. Two pathologically confirmed cases and a literature review]. / Variante frontal de la enfermedad de Alzheimer. Dos casos confirmados anatomopatologicamente y revision de la bibliografia.

INTRODUCTION: Alzheimer's disease (AD) is the most frequent degenerative dementia in our setting. In most patients the initial manifestations of the disease consist in a selective and progressive compromise of memory. Yet, it is not a homogeneous process and in some cases the mode of presentation can be atypical. The presentation of AD in the form of an early disorder affecting personality, behaviour and the executive functions has been called the frontal variant of AD. In our case, its definitive diagnosis was only possible by means of a histological analysis, given the fact that the applicable clinical criteria were then insufficient to reach a diagnosis of this atypical form of AD. CASE REPORTS: We report the cases of two patients, one female and one male aged 60 and 52 respectively, who presented a progressive picture of cognitive impairment with initial involvement of the executive functions and personality changes, together with mood disorders. As a result, the initial diagnosis was one of probable frontotemporal dementia. However, in both cases, the autopsy revealed data consistent with a diagnosis of AD, with a distribution of the pathology that essentially affected the frontal lobes. CONCLUSIONS: AD has a heterogeneous form of presentation, which can give rise to errors in its initial diagnosis, since current clinical criteria do not take this clinical variability sufficiently into account. We therefore consider it important to pay attention to the atypical forms of AD with the aim of developing new diagnostic methods that allow AD to be distinguished from other degenerative processes.

TITLE: Variante frontal de la enfermedad de Alzheimer. Dos casos confirmados anatomopatologicamente y revision de la bibliografia.Introduccion. La enfermedad de Alzheimer (EA) es la causa mas frecuente de demencia en nuestro medio. En la mayoria de los pacientes, las manifestaciones iniciales consisten en una afectacion selectiva y progresiva de la memoria. Sin embargo, no se trata de un proceso homogeneo y, en algunos casos, el modo de presentacion puede ser atipico. La presentacion de la EA en forma de alteracion precoz de la personalidad, el comportamiento y las funciones ejecutivas se ha denominado variante frontal de la EA. En nuestro caso, su diagnostico definitivo solo fue posible mediante el estudio histologico, pues los criterios clinicos vigentes resultaron entonces insuficientes para el diagnostico de esta forma atipica de la EA. Casos clinicos. Dos pacientes, una mujer y un hombre de 60 y 52 años respectivamente, presentaron un cuadro progresivo de deterioro cognitivo con afectacion inicial de las funciones ejecutivas y cambio de personalidad, junto con alteraciones del estado de animo, por lo que se realizo el diagnostico inicial de probable demencia frontotemporal. No obstante, en ambos casos, la autopsia revelo datos compatibles con el diagnostico de EA, con una distribucion de la patologia que afectaba fundamentalmente a los lobulos frontales. Conclusiones. La EA tiene una forma heterogenea de presentacion, lo que puede originar errores en su diagnostico inicial, dado que los criterios clinicos actuales no recogen de modo suficiente esta variabilidad clinica. Por ello, consideramos importante prestar atencion a las formas atipicas de la EA con el objeto de desarrollar nuevos metodos diagnosticos que permitan diferenciar la EA del resto de procesos degenerativos.

Efectos del alcohol etílico sobre el sistema nervioso / No disponible

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