Suicide attempt in a dopamine agonist withdrawal syndrome in Parkinson's disease.

Dopamine agonist withdrawal syndrome (DAWS) results from the reduction or suspension of dopamine agonist medications; it encompasses mainly psychiatric symptoms, including suicidal behaviors. In patients with Parkinson's disease (PD), the impact of DAWS can be significant in terms of distress and disability; however, we must take this syndrome into account as a threatening condition because suicidal behaviors could be developing in the context of DAWS. Here we present a brief case of DAWS affecting a young man with PD, whom abruptly discontinued DA treatment and developed psychiatric symptoms within two weeks which led to a suicidal attempt.

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions.

Several epidemiological studies support low cancer rates in patients with neurodegenerative disorders, including Parkinson's disease, Huntington's disease, and Alzheimer's disease. Different mechanisms were raised as possible causes, from mutated tumor suppressor genes (PARKIN, PINK1) to small interfering RNA based on the CAG trinucleotide repeat expansions located in introns or untranslated regions. However, as every rule has an exception, some tumors have an increased incidence in these neurodegenerative diseases such as breast and skin cancer (melanoma). This mini-review aims to establish the epidemiology between these neurodegenerative disorders and cancer to determine the possible mechanisms involved and therefore set eventual therapeutic applications. According to our findings, we conclude the presence of an inverse relationship among most cancers and the aforementioned neurodegenerative disorders. However, this concept needs to be considered cautiously considering specific genetic and extra-genetic linkage factors for particular tumors.

Huntington disease: Advances in the understanding of its mechanisms.

Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unraveling mechanisms are still unknown. This practical and brief review summarizes some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis.

Late Onset Huntington Disease: Phenotypic and Genotypic Characteristics of 10 Cases in Argentina.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder that includes motor, psychiatric and cognitive manifestations with typical onset of symptoms is in the forties. A percentage of patients (4.4% - 11.5%) may be exceptions to this and manifest symptoms later (>60 years old). Diagnosis of Late onset HD (LoHD) can be a challenge, due to the low suspicion of the disease at this age. OBJECTIVE: To review the genotype and phenotype of LoHD in an Argentinian cohort. METHODS: We reviewed the medical records and genetic testing of a total of 95 individuals with clinical and molecular diagnosis of Huntington's disease, based on 2 institution's registry. RESULTS: Among our HD cohort, 10 patients (10.52%) had LoHD, with variable results regarding family history. The average of repetitions of the expanded allele was 40 (range 38-44). All cases had mild motor symptoms at onset. CONCLUSIONS: Late onset HD can be a diagnostic challenge, due to its slow progression, unawareness of manifestations among patients and in many cases, mild symptomatology that does not warrant medical attention.

Parkinsonisms and Glucocerebrosidase Deficiency: A Comprehensive Review for Molecular and Cellular Mechanism of Glucocerebrosidase Deficiency.

In the last years, lysosomal storage diseases appear as a bridge of knowledge between rare genetic inborn metabolic disorders and neurodegenerative diseases such as Parkinson's disease (PD) or frontotemporal dementia. Epidemiological studies helped promote research in the field that continues to improve our understanding of the link between mutations in the glucocerebrosidase (GBA) gene and PD. We conducted a review of this link, highlighting the association in GBA mutation carriers and in Gaucher disease type 1 patients (GD type 1). A comprehensive review of the literature from January 2008 to December 2018 was undertaken. Relevance findings include: (1) There is a bidirectional interaction between GBA and α- synuclein in protein homeostasis regulatory pathways involving the clearance of aggregated proteins. (2) The link between GBA deficiency and PD appears not to be restricted to α⁻synuclein aggregates but also involves Parkin and PINK1 mutations. (3) Other factors help explain this association, including early and later endosomes and the lysosomal-associated membrane protein 2A (LAMP-2A) involved in the chaperone-mediated autophagy (CMA). (4) The best knowledge allows researchers to explore new therapeutic pathways alongside substrate reduction or enzyme replacement therapies.

Biological and clinical manifestations of juvenile Huntington's disease: a retrospective analysis.

BACKGROUND: Huntington's disease is a rare, neurodegenerative disease caused by an expanded CAG repeat mutation in the huntingtin gene. Compared with adult-onset Huntington's disease, juvenile Huntington's disease (onset ≤20 years) is even rarer and has not been studied extensively. We aimed to further characterise juvenile Huntington's disease by examining the effect of CAG repeat size on disease presentation, progression, and survival. METHODS: We did a retrospective analysis of patients with juvenile Huntington's disease aged 20 years or younger, according to the length of their CAG repeat and who had disabling psychiatric symptoms (with motor symptoms) or motor symptoms alone, and of patients with adult-onset Huntington's disease manifesting aged 30-60 years with 40 or more CAG repeats, from the REGISTRY and ENROLL-HD platforms and from two institutional databases (Lega Italiana Ricerca Huntington Foundation and the Instituto Neurociencias de Buenos Aires and the Sanatorio de la Trinidad Mitre). Patients with psychiatric but no motor symptoms were excluded. We compared symptoms at onset and longitudinally in patients with juvenile Huntington's disease with highly expanded (HE subgroup) or low expansion (LE subgroup) mutations, grouped by hierarchical clustering analysis. We also compared disease progression (longitudinal change in Unified Huntington's Disease Rating Scale-Total Motor Score) and survival of patients with juvenile and adult-onset Huntington's disease. FINDINGS: We extracted medical records from 580 patients entered into the studies or databases between June 23, 2004, and March 31, 2018, of whom 36 patients met our definition of juvenile Huntington's disease and 197 for adult-onset Huntington's disease. According to caregiver reports, gait disturbance was more often a first presenting symptom in the HE subgroup (eight [80%] of 10 patients) than in the LE subgroup (seven [27%] of 26 patients; p=0·0071), whereas loss of hand dexterity was more common in the LE subgroup (11 [42%] of 26 patients) than in the HE subgroup (0 [0%] of 10 patients; p=0·0160). Compared with the LE subgroup, development delay (0 [0%] in the LE subgroup vs nine [90%] in the HE subgroup; p<0·0001), severe gait impairment (nine [35%] in the LE subgroup vs nine [90%] in the HE subgroup; p=0·0072), and seizures (three [11%] in the LE subgroup vs eight [80%] in the HE subgroup; p<0·0001) prevailed over time in the HE subgroup. Disease progression was more rapid in juvenile Huntington's disease (n=14) than in adult-onset Huntington's disease (n=52; generalised estimating equation model, p=0·0003). Of 121 deceased patients, median survival was shorter in the juvenile Huntington's disease (n=17) cohort than in adult-onset Huntington's disease (n=104) cohort (hazard ratio 2·18 [95% CI 1·08-4·40]; p=0·002). INTERPRETATION: Patients with HE juvenile Huntington's disease differ clinically from patients with LE juvenile Huntington's disease or adult-onset Huntington's disease, suggesting reclassification of this particularly aggressive form of Huntington's disease might be required. FUNDING: Lega Italiana Ricerca Huntington Foundation and IRCCS Ospedale Casa Sollievo della Sofferenza.

Holmes Tremor Partially Responsive to Topiramate: A Case Report.

Background: Holmes tremor is a rare symptomatic movement disorder, characterized by a combination of resting, postural, and intention tremor. It is usually caused by lesions in the brainstem, thalamus, and cerebellum. Despite pharmacological advances, its treatment remains a challenge; many medications have been used with various degrees of effectiveness. Stereotactic thalamotomy and deep brain stimulation in the ventralis intermedius nucleus have been effective surgical procedures in cases refractory to medical treatment. Case Report: Here we report a young woman with topiramate-responsive Holmes tremor secondary to a brainstem cavernoma. Discussion: Herein we report a Holmes tremor responsive to Topiramate.

Prodromal Clinical Markers of Parkinson disease in Gaucher Disease Individuals.

Heterozygous mutations in the glucocerebrosidase (GBA) gene have been reported as a common risk factor for the development of Parkinson's disease (PD) in Gaucher disease (GD) patients and in heterozygous GBA mutation positive carriers. In this study, we analyzed the occurrence of prodromal markers of PD in an Argentinean cohort with type 1 GD. After signed informed consent, we evaluated 26 patients with type 1 GD under enzymatic replacement therapy from a cohort of the Hospital Ricardo Gutierrez GD Study Group in Buenos Aires City, Argentina. We performed an extensive neurological examination, including cognitive assessment by Montreal Cognitive Assessment (MoCA) and a questionnaire performed ad hoc, to identify non-motor PD symptoms. Parasomnias were reported by 7 patients (26.92%), rapid eye movement behavior disorders in 2 (7.69%), constipation in 2 (7.69%), hyposmia in 1 (3.84%), tremor in 1 (3.84%), and depression in 3 cases (11.53%). MoCA assessment was abnormal in 44.44% of patients. No patient fulfilled PD diagnostic criteria (Queen Square Brain Bank criteria). The identification of prodromal markers of PD in type 1 GD suggests that this population represents a very interesting cohort for identifying potential biomarkers and neuroprotective therapies for PD.

Juvenile Huntington disease in Argentina / Doença de Huntington juvenil na Argentina

ABSTRACT We analyzed demographic, clinical and genetic characteristics of juvenile Huntington disease (JHD) and it frequency in an Argentinean cohort. Age at onset was defined as the age at which behavioral, cognitive, psychiatric or motor abnormalities suggestive of JHD were first reported. Clinical and genetic data were similar to other international series, however, in this context we identified the highest JHD frequency reported so far (19.72%; 14/71). Age at onset of JHD is challenging and still under discussion. Our findings reinforce the hypothesis that clinical manifestations, other than the typical movement disorder, may anticipate age at onset of even many years. Analyses of JHD cohorts are required to explore it frequency in populations with different backgrounds to avoid an underestimation of this rare phenotype. Moreover, data from selected populations may open new pathways in therapeutic approaches and may explain new potential correlations between HD presentations and environmental or biological factors.

RESUMO Foram analisadas as características demográficas, clínicas e genéticas de doença de Huntington juvenil (JHD) e na freqüência em uma coorte argentino. A idade de início foi definida como a idade em que distúrbios comportamentais, cognitivos, psiquiátricos ou anormalidades motoras sugestivas de JHD foram relatada pela primeira vez. Os dados clínicos e genéticos foram semelhantes aos de outras séries internacionais, no entanto, neste contexto identificamos a maior freqüência de JHD relatados até agora (19,72%; 14/71). A idade de início de JHD é um desafio ainda em discussão. Nossos resultados reforçam a hipótese de que as manifestações clínicas, além do transtorno de movimento típico, pode antecipar a idade de início em muitos anos. As análises de coortes de JHD são obrigados a explorar frequências em populações com diferentes formações, para evitar uma subestimação deste fenótipo raro. Além disso, os dados de populações selecionadas podem abrir novos caminhos em abordagens terapêuticas e pode explicar novas correlações potenciais entre apresentações de HD e fatores ambientais ou biológicas.

Juvenile Huntington disease in Argentina.

We analyzed demographic, clinical and genetic characteristics of juvenile Huntington disease (JHD) and it frequency in an Argentinean cohort. Age at onset was defined as the age at which behavioral, cognitive, psychiatric or motor abnormalities suggestive of JHD were first reported. Clinical and genetic data were similar to other international series, however, in this context we identified the highest JHD frequency reported so far (19.72%; 14/71). Age at onset of JHD is challenging and still under discussion. Our findings reinforce the hypothesis that clinical manifestations, other than the typical movement disorder, may anticipate age at onset of even many years. Analyses of JHD cohorts are required to explore it frequency in populations with different backgrounds to avoid an underestimation of this rare phenotype. Moreover, data from selected populations may open new pathways in therapeutic approaches and may explain new potential correlations between HD presentations and environmental or biological factors.

Cognition in a multiple system atrophy series of cases from Argentina.

UNLABELLED: Cognitive dysfunction may occur in 17-40% of patients with multiple system atrophy (MSA). It has been suggested a milder cognitive impairment in cerebellar (MSA-C) than in parkinsonian variant (MSA-P). However, differences in cognitive profiles remain under discussion. OBJECTIVE: To evaluate cognitive features in a series of patients with "probable MSA" from Argentina. METHOD: After informed consent was obtained, an extensive cognitive tests battery was administered. Nine patients (6 MSA-P and 3 MSA-C) composed the sample. RESULTS: Depression was detected in 43% of patients. Seven patients showed at least one cognitive domain impairment. Temporospatial orientation, visuospatial abilities, executive and attentional functions, episodic memory and language were compromised in MSA-P, while MSA-C dysfunction was restricted to attentional and executive domains. CONCLUSION: Despite the small sample size, our findings could suggest a more widespread cognitive impairment in MSA-P than MSA-C.

Cognition in a multiple system atrophy series of cases from Argentina / Cognição em uma série dos casos de atrofia de múltiplos sistemas da Argentina

Cognitive dysfunction may occur in 17-40% of patients with multiple system atrophy (MSA). It has been suggested a milder cognitive impairment in cerebellar (MSA-C) than in parkinsonian variant (MSA-P). However, differences in cognitive profiles remain under discussion. Objective To evaluate cognitive features in a series of patients with “probable MSA” from Argentina. Method After informed consent was obtained, an extensive cognitive tests battery was administered. Nine patients (6 MSA-P and 3 MSA-C) composed the sample. Results Depression was detected in 43% of patients. Seven patients showed at least one cognitive domain impairment. Temporospatial orientation, visuospatial abilities, executive and attentional functions, episodic memory and language were compromised in MSA-P, while MSA-C dysfunction was restricted to attentional and executive domains. Conclusion Despite the small sample size, our findings could suggest a more widespread cognitive impairment in MSA-P than MSA-C. .

Disfunção cognitiva pode ocorrer em 17-40 % dos pacientes com atrofia de múltiplos sistemas (AMS). Alguns estudos têm sugerido a presença de disfunção cognitiva mais leve nos pacientes com AMS do tipo cerebelar (AMS-C) do que na variante parkinsoniana (AMS-P). Objetivo Avaliar os perfis cognitivos de uma série de pacientes argentinos com “Provável AMS”. Método Foram selecionados 6 AMS-P e 3 AMS–C aos quais foi aplicada uma extensa bateria de testes cognitivos. Resultados Depressão foi detectada em 43% dos pacientes. Sete pacientes apresentaram comprometimento de pelo menos um domínio cognitivo. As funções de orientação temporo-espacial, habilidades visuo-espaciais, função executiva e de atenção, memória episódica e linguagem foram comprometidas em pacientes com AMS-P. Nos pacientes com AMS-C as dificuldades cognitivas ficaram restritas às funções executivas e de atenção. Conclusão Apesar do pequeno tamanho da amostra, nossos achados sugerem que pacientes com AMS-P apresentam um comprometimento cognitivo mais amplo do que pacientes com AMS-C. .

Clinical and genetic characteristics in patients with Huntington's Disease from Argentina.

UNLABELLED: Huntington's Disease (HD) is a neurodegenerative disease, caused by the expansion of an unstable (CAG)(n) in the HTT gene. There is scarce data about the disease in Argentina. OBJECTIVE: To describe the demographic, clinical and molecular data in patients with HD from Argentina. PATIENTS AND METHODS: 59 HD patients were recruited at our department. Comprehensive interviews, neurological examination and genetic analysis were performed in probands. Statistical analysis was conducted using G-Stat 2.0 and non-parametric tests (Wilcoxon). RESULTS: 32 women and 27 men were diagnosed with a mean age of 45.7 ± 16.2 years and a mean age at onset of 35.8 ± 14.8 years. We found no gender prevalence and an inverse correlation between size of mutant CAG repeat sequence and age at onset, r = -0.58, r(2) = 33.6, Pearson's correlation coefficient p = 0.0008. Juvenile HD in this series of patients was higher than previously reported (16.6% vs. <10%). The mean CAG repeat in the expanded allele was 45.1. The number of CAG repeats in Argentinean controls was 17.8, which is similar to the literature of the European population. CONCLUSIONS: This is the first series of Argentinean HD patients with demographic, clinical and molecular data. Our findings appear similar to the ones described in Western European populations.

[Apathy in Parkinson's disease. Impairment in quality of life]. / Apatía en enfermedad de Parkinson. Impacto sobre la calidad de vida.

Apathy is one of the most prominent non-motor symptoms in Parkinson Disease (PD). Its range of prevalence in PD has been estimated in 20 to 45%. The objective of this work is to assess the prevalence of apathy in PD patients, and its relation with depression and executive function impairment. Fifty seven PD patients (54% women), mean age of 68.7 years, and a disease duration of 7.5 years from diagnosis were included. We used the following scales: UPDRS, Hoehn & Yahr, Mini Mental State Examination, the 14-item Apathy Scale (AS), the Beck Depression Inventory, and Trail Making Test versions A and B (TMT), and Parkinson's Disease Quality of Life Questionnaire (PDQL). Apathy was identified in 31.6%; apathy without depression was present in 33.3% of patients. The TMT A and B were abnormal in 66.7% and 83.3% respectively of the apathetic patients vs. 46.2% and 61.5% in non-apathetic patients. Quality of life was impaired in apathetic patients. In our PD sample apathy is highly prevalent, has a great impact on quality of life and it may occur in the absence of depression. The alterations of TMT in apathetic patients contributes to suggest a positive relationship between apathy and the impairment of executive function secondary to the involvement of frontal-subcortical circuits.

Apatía en enfermedad de Parkinson: Impacto sobre la calidad de vida / Apathy in Parkinson's disease: Impairment in quality of life

La apatía es uno de los síntomas "no motores" más importantes de la Enfermedad de Parkinson (EP). Su prevalencia en EP oscila entre 20 y 45%. El objetivo de nuestro trabajo fue establecer la prevalencia de apatía en pacientes con EP y su relación con depresión y trastornos en las funciones ejecutivas. Se evaluaron 57 pacientes con EP (54% mujeres), con una edad promedio de 68.7 años y una duración promedio de enfermedad de 7.5 años. Se utilizaron las siguientes escalas: UPDRS, Hoehn & Yahr, Mini Mental State Examination, Escala de Apatía de 14 ítem (EA), Inventario de Depresión de Beck, Trail Making Test (TMT) A y B y Parkinson's Disease Quality of Life Questionnaire (PDQL). El 31.6% de los pacientes presentaban apatía; en el 33.3% de los apáticos este síntoma se presentó en ausencia de depresión. Alteraciones en el TMT A y B se observaron en 66.7% y 83.3% respectivamente de los pacientes apáticos contra el 46.2% y 61.5% de los no apáticos. La calidad de vida fue afectada en los pacientes apáticos. La apatía en EP es frecuente en esta población, ejerce un impacto negativo sobre la calidad de vida de los pacientes y puede ocurrir en ausencia de depresión. Las alteraciones del TMT en los pacientes apáticos sugerirían una posible relación entre apatía y las alteraciones de las funciones ejecutivas, probablemente por compromiso de circuitos fronto-subcorticales.

Apathy is one of the most prominent non-motor symptoms in Parkinson Disease (PD). Its range of prevalence in PD has been estimated in 20 to 45%. The objective of this work is to assess the prevalence of apathy in PD patients, and its relation with depression and executive function impairment. Fifty seven PD patients (54% women), mean age of 68.7 years, and a disease duration of 7.5 years from diagnosis were included. We used the following scales: UPDRS, Hoehn & Yahr, Mini Mental State Examination, the 14-item Apathy Scale (AS), the Beck Depression Inventory, and Trail Making Test versions A and B (TMT), and Parkinson's Disease Quality of Life Questionnaire (PDQL). Apathy was identified in 31.6%; apathy without depression was present in 33.3% of patients. The TMT A and B were abnormal in 66.7% and 83.3% respectively of the apathetic patients vs. 46.2% and 61.5% in nonapathetic patients. Quality of life was impaired in apathetic patients. In our PD sample apathy is highly prevalent, has a great impact on quality of life and it may occur in the absence of depression. The alterations of TMT in apathetic patients contributes to suggest a positive relationship between apathy and the impairment of executive function secondary to the involvement of frontal-subcortical circuits.

Prevalence of restless legs syndrome: a community-based study from Argentina.

BACKGROUND AND PURPOSE: The number of restless legs syndrome (RLS) prevalence studies performed outside Europe and North America remains small. We conducted a community-based study to estimate the relative prevalence of RLS in Argentina. PATIENTS AND METHODS: A total sample of 471 participants from high (Buenos Aires) and low population density areas (three cities with <35,000 inhabitants), completed a self-assessment questionnaire, including the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria, to determine RLS symptoms. RESULTS: In the present study, the four RLS criteria were reported in 20.2%. In accordance with other studies, we found a female/male ratio of 3:1, with women being younger than men. However, RLS prevalence in "clinically significant" participants, that is symptoms present at least two or more times a week, were 10.8% (12.4% in participants from high population density versus 2.60% in participants from low population density areas). CONCLUSIONS: In the present study, RLS appears as a common disorder in this population. The RLS prevalence found is in agreement with some epidemiological reports from the American and European populations but it is significantly higher than the prevalence reported for Native South Americans (i.e., 0.8-3.2%). These differences could be explained by the composition of the Argentinean population with predominantly European roots. Taking into account the significant impact of RLS on health and quality of life, our study represents a preliminary approach to characterize this chronic disease in this community.