Characterization of Progranulin Gene Mutations in Portuguese Patients with Frontotemporal Dementia.

In Portugal, heterozygous loss-of-function mutations in the progranulin (GRN) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the GRN mutation spectrum, investigated in 257 FTD patients and 19 family members from the central/north region of Portugal using sequencing methods. Seven different pathogenic variants were identified in 46 subjects including 40 patients (16%) and 6 relatives (32%). bvFTD was the most common clinical presentation among the GRN mutation patients, who showed a global pattern of moderate-to-severe frontotemporoparietal deficits in the neuropsychological evaluation. Interestingly, two mutations were novel (p.Thr238Profs*18, p.Leu354Profs*16), and five were previously described, although three of them only in the Portuguese population, suggesting a population-specific GRN mutational spectrum. The subjects harboring a GRN mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of GRN and the identification of the underlying GRN mutations provided an accurate genetic counselling and allowed the enrolment of subjects with GRN mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease.

Transthyretin amyloid-related transitory events (TARTEs): Descriptive analysis of clinical, imagiological, and neurophysiological features.

Transthyretin-related familial amyloid polyneuropathy (ATTR-FAP) is a multisystemic disorder inherited as an autosomal dominant trait. Transitory events in ATTR-FAP patients are a feature of this disorder and remain poorly depicted in the literature. We aimed to describe a case series of ATTR-FAP patients who presented to our department with transitory events and document the clinical, neuroimaging and neurophysiological characteristics of the events. We collected data from eight patients carrying the Val30Met ATTR-FAP variant. We registered a total of 23 events. Of the eight patients, seven had been submitted to hepatic transplant. The events were either TIA-like or seizures, often followed by prolonged language, motor or sensory impairment. In 9 (39%) of the events, the patients presented with fever, but an infection was only found in 5 (21%). Cerebrospinal fluid analysis was performed in 5 patients. EEG was abnormal in at least 1 event in 7 of the 8 patients. Brain MRI was performed in 3 patients during the acute stage and showed no acute lesions. Although the etiology of these events remains unclear, brain MRI performed in the acute phase of acute TIA-like events and the EEG abnormalities, argues in favor of regional brain dysfunction due to amyloid deposition. Focal neurological episodes should be considered in long-term duration Val30Met ATTR-FAP patients, who present with acute neurological deficits or seizures.

[Portuguese Consensus on the Diagnosis and Management of Lewy Body Dementia (PORTUCALE)]. / Consenso Português para o Diagnóstico e Gestão Clínica da Demência com Corpos de Lewy (PORTUCALE).

Lewy body dementia is a common cause of dementia leading to the progressive deterioration of cognitive function and motor skills, behavioral changes, and loss of autonomy, impairing the quality of life of patients and their families. Even though it is the second leading cause of neurodegenerative dementia, diagnosis is still challenging, due to its heterogenous clinical presentation, especially in the early stages of the disease. Accordingly, Lewy body dementia is often misdiagnosed and clinically mismanaged. The lack of diagnostic accuracy has important implications for patients, given their increased susceptibility to the adverse effects of certain drugs, such as antipsychotics, which may worsen some symptoms associated with Lewy body dementia. Therefore, a specialist consensus based on the analysis of the most updated and relevant literature, and on clinical experience, is useful to all professionals involved in the care of these patients. This work aims to inform and provide recommendations about the best diagnostic and therapeutic approaches in Lewy body dementia in Portugal. Moreover, we suggest some strategies in order to raise the awareness of physicians, policy makers, and the society at large regarding this disease.

A demência com corpos de Lewy é uma causa comum de demência, provocando a perda progressiva de funções cognitivas e capacidades motoras, alterações comportamentais, e perda de autonomia, com compromisso da qualidade de vida dos doentes e seus familiares. Apesar de ser a segunda causa mais frequente de demência neurodegenerativa, o diagnóstico mantém-se um desafio, devido à sua apresentação clínica heterogénea, sobretudo nas fases iniciais da doença. Por conseguinte, a demência com corpos de Lewy é frequentemente mal diagnosticada e clinicamente gerida de forma insuficiente. A falta de acuidade diagnóstica tem implicações significativas para os doentes, dada a maior suscetibilidade aos efeitos adversos de determinados fármacos, tais como os antipsicóticos, que podem agravar alguns sintomas associados à demência com corpos de Lewy. Por conseguinte, um consenso de especialistas, baseado na análise da literatura mais atual e relevante, e na experiência clínica, é útil para todos os profissionais envolvidos no cuidado destes doentes. O objetivo deste trabalho é informar e gerar recomendações acerca das melhores abordagens diagnóstica e terapêutica da demência com corpos de Lewy em Portugal. Além disso, sugerimos estratégias para aumentar a sensibilização dos médicos, dos decisores políticos e da sociedade em geral em relação a esta doença.

Interferon-beta treated-multiple sclerosis patients exhibit a decreased ratio between immature/transitional B cell subset and plasmablasts.

Our aim was to quantify circulating B cell subsets; immature/transitional, naïve, CD27- and CD27+ memory cells and plasmablasts, in relapsing-remitting multiple sclerosis patients treated with IFN-ß. The most relevant findings were a significant increase of plasmablasts and a decrease of immature/transitional B cells, resulting in a decreased ratio between those cells in relapse RRMS, together with an increase of CD27- and CD27+IgM+ memory B cell subsets in both phases of the disease. These alterations point to an active B cell response, particularly in relapse, and the above referred ratio could constitute a good biomarker of relapse in patients that underwent IFN-ß treatment.

Characterization of circulating gamma-delta T cells in relapsing vs remission multiple sclerosis.

We characterized circulating gamma-delta T cells in relapsing-remitting multiple sclerosis (RRMS) patients, during remission and relapse phases. In relapse, we observed a decrease of circulating CCR5+ γδ TEMRA cell subset, together with a decrease in EOMES and granzyme B mRNA expression in γδ T cells, suggesting a reduction of the cytotoxic potential of this subset. Moreover, we also found a higher frequency of IFNγ+ γδ T cells, which may indicate that these cells are assuming a more regulatory function associated to a Th1 profile. These results suggest a specific release from the periphery of a particular γδ T cell subset, expressing CCR5 and belonging to an effector compartment, supporting the idea that γδ T cells could play a role in MS relapse.

Ictal Magnetic Source Imaging in Presurgical Assessment.

Ictal MEG recordings constitute rare data. The objective of this study was to evaluate ictal magnetic source localization (MSI), using two algorithms: linearly constrained minimum variance (LCMV), a beamforming technique and equivalent current dipole (ECD). Ictal MSI was studied in six patients. Three of them were undergoing post-operative re-evaluation. For all patients, results were validated by the stereoelectroencephalographic (SEEG) definition of the epileptogenic zone (EZ). EZ was quantified using the epileptogenicity index (EI) method, which accounts for both the propensity of a brain area to generate rapid discharges and the time for this area to become involved in the seizure. EI values range from 0 (no epileptogenicity) to 1 (maximal epileptogenicity). Levels of concordance between ictal MSI and EZ were determined as follows: A: ictal MSI localized the site whose value EI = 1, B: MSI localized a part of the EZ (not corresponding to the maximal value of EI = 1), C: a region could be identified on ictal MSI but not on SEEG, D: a region could be identified on SEEG but not on MSI, E: different regions were localized on MSI and SEEG. Ictal MEG pattern consisted of rhythmic activities between 10 and 20 Hz for all patients. For LCMV (first maxima), levels of concordance were A (two cases), B (two cases) and E (two cases). For ECD fitted on each time point separately (location characterized by the best goodness-of-fit value), levels of concordance were A (one case), B (one case), D (three cases) and E (one case). For ECD calculated for the whole time window, levels of concordance were A (two cases) and D (four cases). Source localization methods performed on rhythmic patterns can localize the EZ as validated by SEEG. In terms of concordance, LCMV was superior to ECD. In some cases, LCMV allows extraction of several maxima that could reflect ictal dynamics. In a medial temporal lobe epilepsy case, ictal MSI indicated an area of delayed propagation and was non-contributory to the presurgical assessment.

Multiple cerebral infarcts and intravascular central nervous system lymphoma: a rare but potentially treatable association.

Intravascular large B-cell lymphoma (IVLBCL) is a rare lymphoproliferative disorder characterized by massive intravascular growth of lymphoma cells with a predilection for the central nervous system (CNS). Diagnosis is generally delayed by variable clinical presentation and nonspecific laboratory findings. Brain biopsy is the gold standard diagnostic test. Prognosis is poor with a high mortality rate. We report a case of "in vivo" diagnosis of IVLBCL presenting with rapidly progressive encephalopathy secondary to multiple cerebral infarcts. This case highlights IVLBCL as a possible cause of unexplained multifocal and recurrent strokes. Earlier diagnosis and consequent earlier treatment may be associated with better prognosis.