Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

People with Early Onset Parkinson's Disease: Empowered to Improve Care.

Patient organizations play an ever-growing role in modern societies by providing organized resources for patients and care partners. Importantly, patient organizations enable patients to define and share their needs and views. In Parkinson's disease (PD), patient organizations play significant roles in different countries. However, there is limited support and resources tailored for people with early onset Parkinson's disease (EOPD). These individuals face unique social, professional, and personal challenges that are often not accounted for by general PD organizations, which play very important roles for a significant proportion of individuals with PD. In Portugal, this was the situation until 2022, when Young Parkies Portugal (YPP) was founded to allow people with EOPD and various stakeholders to join forces to cover their specific needs. In this manuscript, we aim to share our experience in building an association for people with EOPD, reflecting on the reasons for this need, the activities developed thus far, challenges in implementation, and future directions. In summary, we believe that nonprofit organizations like YPP play an essential role in shaping the care and support of people with PD care and should be considered key partners of care alongside the larger multidisciplinary team. We are confident that sharing our experience can inspire and guide the implementation of similar initiatives in other countries.

Aberrant Splicing Caused by a Novel VPS16 Variant Linked to Dystonia Type 30.

Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent involuntary muscle contractions, causing abnormal postures and/or repetitive movements. In this report, we identified a novel heterozygous splice-site variant in VPS16 (NM_022575.4:c.240+3G>C) in a patient with cervical and upper limb dystonia without other neurological or extra-neurological features. Analysis of patient's blood mRNA showed disruption of exon 3/intron 3 donor splice-site, leading to exon 3 skipping, which predictably results in a frameshift [p.(Ala48Valfs*14)]. Despite the scarcity of splice-affecting variants described in VPS16-related dystonia, our report contributes with the first fully characterized variant at the mRNA level.

Blood Biomarkers for the Diagnosis of Neurodegenerative Dementia: A Systematic Review.

IMPORTANCE: Accurately diagnosing neurodegenerative dementia is often challenging due to overlapping clinical features. Disease specific biomarkers could enhance diagnostic accuracy. However, CSF analysis procedures and advanced imaging modalities are either invasive or high-priced, and routinely unavailable. Easily accessible disease biomarkers would be of utmost value for accurate differential diagnosis of dementia subtypes. OBJECTIVE: To assess the diagnostic accuracy of blood-based biomarkers for the differential diagnosis of AD from Frontotemporal Lobar Degeneration (FTLD), or AD from Dementia with Lewy Bodies (DLB). METHODS: Systematic review. Three databases (PubMed, Scopus, and Web of Science) were searched. Studies assessing blood-based biomarkers levels in AD versus FTLD, or AD versus DLB, and its diagnostic accuracy, were selected. When the same biomarker was assessed in three or more studies, a meta-analysis was performed. QUADAS-2 criteria were used for quality assessment. RESULTS: Twenty studies were included in this analysis. Collectively, 905 AD patients were compared to 1262 FTLD patients, and 209 AD patients were compared to 246 DLB patients. Regarding biomarkers for AD versus FTLD, excellent discriminative accuracy (AUC >0.9) was found for p-tau181, p-tau217, synaptophysin, synaptopodin, GAP43 and calmodulin. Other biomarkers also demonstrated good accuracy (AUC = 0.8-0.9). For AD versus DLB distinction, only miR-21-5p and miR-451a achieved excellent accuracy (AUC >0.9). CONCLUSION: Encouraging results were found for several biomarkers, alone or in combination. Prospective longitudinal designs and consensual protocols, comprising larger cohorts and homogeneous testing modalities across centres, are essential to validate the clinical value of blood biomarkers for the precise etiological diagnosis of dementia.

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.

Community Exercise: A New Tool for Personalized Parkinson's Care or Just an Addition to Formal Care?

Physiotherapy and exercise are associated with motor and non-motor benefits in Parkinson's disease (PD). Community exercise programs may increase ongoing exercise participation and help people with Parkinson's disease actively participate in their health management. But there is still limited knowledge about these programs regarding their benefits, safety, implications over the long-term, and effective implementation. These questions could hold relevant clinical implications. In this perspective article, we identify the current challenges and reflect upon potential solutions to help community exercise to be implemented as an additional anchor to personalize management models for Parkinson's 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.

Another Twist in the Tale: Intrafamilial Phenotypic Heterogeneity in ANO3-Related Dystonia.

BACKGROUND: Mutations in the anoctamin 3 (ANO3) gene cause autosomal dominant craniocervical dystonia (DYT24), presenting from childhood to mid-life. However, in the past years, the clinical spectrum of this disorder has widened. We present a family with heterogeneous presentation, exemplifying phenotypic diversity in DYT24. CASES: The index case presented with myoclonic dystonia at age 10. His family history was remarkable for cervical dystonia with myoclonus in his grandfather, cervical and upper limb dystonia along with dopa-responsive parkinsonism in his father and lower-limb dystonia in his teenage sister. Magnetic resonance imaging and blood work-ups of all the affected family members were normal. The genetic panel for inherited forms of dystonia disclosed a point mutation c.1787C > A (p.Ser596Tyr) segregated in all affected family members. CONCLUSIONS: ANO3 mutations usually present with craniocervical dystonia and rarely generalized or leg dystonia. This family exemplifies the heterogeneous presentation of this disorder as well as a wide phenotypic variability within the same family.

From Kidney to Brain: An Uncommon Severe Relapse of Myeloperoxidase Anti-Neutrophil Cytoplasmic Antibody (MPO-ANCA) Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare autoimmune diseases that affect medium and small blood vessels, with uncommon, variable central nervous system (CNS) involvement. It poses diagnosis challenges due to the limited accuracy of conventional imaging and vast differential diagnosis. We describe the case of a 76-year-old man with a previously diagnosed myeloperoxidase (MPO)-positive AAV with exclusive renal involvement. The patient presented to our emergency department (ED) with sudden-onset weakness of the right side of the body, difficulty speaking, fever, and a history of progressive cognitive impairment in the previous three months (loss of memory, time and space disorientation, acalculia). Brain imaging showed multiple acute and subacute ischemic lesions, suggesting CNS vasculitic involvement. The patient was treated with methylprednisolone pulses, followed by rituximab, with motor and cognitive improvement. Timely diagnosis and adequate treatment of AAV as a cause for new-onset neurological symptoms are crucial to improve outcomes. Otherwise, a higher risk of relapse remains, and extensive neurological deficits may become permanent. Evidence regarding the best treatment options in these patients is scarce and case reports provide further data on this topic.

Imaging Evidence of Nigrostriatal Degeneration in DYT-PRKRA.

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312941-sup-v001.htm.

[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.

Encefalitis sensible a esteroides asociada con tiroiditis autoinmune como paradigma del diagnóstico diferencial neuropsiquiátrico: informe de caso y revisión / Steroid-responsive auto-immune encephalitis as a paradigm of neuropsychiatric differential diagnosis: case report and review

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[Parkinson's Disease: Clinical Review and Update]. / Doença de Parkinson: Revisão Clínica e Atualização.

Parkinson's disease is the second most common neurodegenerative disorder, and a significant increase in its prevalence in the past three decades has been documented. Environmental and genetic factors contribute to the pathophysiology of this disease, and 5% - 10% of cases have a monogenic cause. The diagnosis relies on clinical findings, supported by adequate testing. There is no absolute method to diagnose Parkinson's disease in vivo, except for genetic testing in specific circumstances, whose usefulness is limited to a minority of cases. New diagnostic criteria have been recently proposed with the aim of improving diagnostic accuracy, emphasizing findings that might point to other causes of parkinsonism. The available therapeutic options are clinically useful, as they improve the symptoms as well as the quality of life of patients. After the introduction of levodopa, deep brain stimulation emerged as the second therapy with an important symptomatic impact in the treatment of Parkinson's disease. Non-motor symptoms and motor complications are responsible for a large proportion of disability, so these should be identified and treated. Current scientific research is focused on the identification of disease biomarkers allowing correct and timely diagnosis, and on creating more effective therapies, thus fulfilling current clinical unmet needs. This paper presents an updated review on Parkinson's disease, guiding the readership through current concepts, and allowing their application to daily clinical practice.

A doença de Parkinson é a segunda doença neurodegenerativa mais comum, tendo sido documentado um aumento significativo da sua prevalência nas últimas três décadas. A fisiopatologia da doença assenta numa interação genética-ambiente, estimando-se que cerca de 5% ­ 10% dos casos tenham causa genética monogénica. O diagnóstico é clínico, apoiado por investigação complementar adequada. Não dispomos ainda de uma forma de diagnosticar com certeza a doença de Parkinson in vivo, à exceção de testes genéticos em circunstâncias específicas, cuja utilidade é limitada a uma minoria de casos. Recentemente foram propostos novos critérios de diagnóstico, com o objetivo de melhorar a acuidade diagnóstica, com ênfase nas características que apontam para outras causas de parkinsonismo. As opções terapêuticas atualmente disponíveis são clinicamente úteis, pois têm a capacidade de melhorar os sintomas da doença e a qualidade de vida dos doentes. Após a introdução da levodopa, a estimulação cerebral profunda surgiu, mais recentemente, como a segunda intervenção terapêutica com importante impacto sintomático no tratamento desta doença. Os sintomas não motores e as complicações motoras são responsáveis por uma parte considerável da incapacidade na doença de Parkinson, pelo que devem ser identificados e tratados. A investigação científica atual foca-se na identificação de potenciais biomarcadores da doença, que permitam alcançar um diagnóstico certeiro e atempado, e na criação de terapêuticas mais eficazes, de modo a preencher as necessidades clínicas atualmente não satisfeitas. Este artigo apresenta uma revisão atualizada sobre a doença de Parkinson, guiando o leitor através dos conceitos mais atualizados nesta temática, de forma a permitir a sua aplicação na prática clínica diária.

Intraoperative microelectrode recording in Parkinson's disease subthalamic deep brain stimulation: Analysis of clinical utility.

This retrospective study aims to explore the clinical utility of microelectrode recording (MER) during subthalamic deep brain stimulation (DBS) surgery in patients with Parkinson's disease (PD). We analyzed the data from 103 PD patients, who consecutively received bilateral subthalamic nucleus (STN) DBS at an experienced academic medical center. We collected demographic, clinical, and DBS related data, including intraoperative microelectrode recording data, electrode positioning, and clinical effects provided by intraoperative microstimulation. The 2 brain sides were independently analyzed and are described as first and second side (to be operated on); the first side is contralateral to motor symptoms onset. Patients were mostly men (64.1%). In both sides of the brain, percentage of agreement with the electrode final position was higher with clinical results than with intraoperative microelectrode recordings (98% vs 57% on the first implantation side, and 97% vs 58% on the second implantation side, respectively). Regarding electrode final implantation depth, 86% of electrodes were implanted between 0 mm and +2 mm in relation to anatomical target, and 95% of electrodes were implanted from -2 mm to +2 mm. Our study suggests that MER might not be necessary to achieve good clinical outcomes in PD patients undergoing STN DBS. These results support and inform the design of future prospective controlled research studies.