Neurocognitive correlates of semantic memory navigation in Parkinson's disease.

Cognitive studies on Parkinson's disease (PD) reveal abnormal semantic processing. Most research, however, fails to indicate which conceptual properties are most affected and capture patients' neurocognitive profiles. Here, we asked persons with PD, healthy controls, and individuals with behavioral variant frontotemporal dementia (bvFTD, as a disease control group) to read concepts (e.g., 'sun') and list their features (e.g., hot). Responses were analyzed in terms of ten word properties (including concreteness, imageability, and semantic variability), used for group-level comparisons, subject-level classification, and brain-behavior correlations. PD (but not bvFTD) patients produced more concrete and imageable words than controls, both patterns being associated with overall cognitive status. PD and bvFTD patients showed reduced semantic variability, an anomaly which predicted semantic inhibition outcomes. Word-property patterns robustly classified PD (but not bvFTD) patients and correlated with disease-specific hypoconnectivity along the sensorimotor and salience networks. Fine-grained semantic assessments, then, can reveal distinct neurocognitive signatures of PD.

Frequency of Hereditary and GBA1-Related Parkinsonism in Latin America: A Systematic Review and Meta-Analysis.

BACKGROUND: Identifying hereditary parkinsonism is valuable for diagnosis, genetic counseling, patient prioritization in trials, and studying the disease for personalized therapies. However, most studies were conducted in Europeans, and limited data exist on admixed populations like those from Latin America. OBJECTIVES: This study aims to assess the frequency and distribution of genetic parkinsonism in Latin America. METHODS: We conducted a systematic review and meta-analysis of the frequency of parkinsonian syndromes associated with genetic pathogenic variants in Latin America. We defined hereditary parkinsonism as those caused by the genes outlined by the MDS Nomenclature of Genetic Movement Disorders and heterozygous carriers of GBA1 pathogenic variants. A systematic search was conducted in PubMed, Web of Science, Embase, and LILACS in August 2022. Researchers reviewed titles and abstracts, and disagreements were resolved by a third researcher. After this screening, five researchers reanalyzed the selection criteria and extracted information based on the full paper. The frequency for each parkinsonism-related gene was determined by the presence of pathogenic/likely pathogenic variants among screened patients. Cochran's Q and I2 tests were used to quantify heterogeneity. Meta-regression, publication bias tests, and sensitivity analysis regarding study quality were also used for LRRK2-, PRKN-, and GBA1-related papers. RESULTS: We included 73 studies involving 3014 screened studies from 16 countries. Among 7668 Latin American patients, pathogenic variants were found in 19 different genes. The frequency of the pathogenic variants in LRRK2 was 1.38% (95% confidence interval [CI]: 0.52-2.57), PRKN was 1.16% (95% CI: 0.08-3.05), and GBA1 was 4.17% (95% CI: 2.57-6.08). For all meta-analysis, heterogeneity was high and publication bias tests were negative, except for PRKN, which was contradictory. Information on the number of pathogenic variants in the other genes is further presented in the text. CONCLUSIONS: This study provides insights into hereditary and GBA1-related parkinsonism in Latin America. Lower GBA1 frequencies compared to European/North American cohorts may result from limited access to gene sequencing. Further research is vital for regional prevalence understanding, enabling personalized care and therapies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Huntington's Disease in Chile: Epidemiological and Genetic Aspects.

INTRODUCTION: Huntington's disease (HD) is a neurodegenerative, autosomal dominant disabling condition due to an expansion of the CAG trinucleotide in the HTT gene. Motor, psychiatric, and cognitive disorders characterize it. Chilean reports on HD in the era of molecular diagnosis were wanted. METHODS: This is a retrospective analysis of a prospective cohort of patients with HD seen at the Center for Movement Disorders (CETRAM) in Chile between 2013 and 2019. Sociodemographic, genotype, and neuropsychiatric features were investigated. RESULTS: One hundred three probands with HD were identified. The majority (63.1%) were born in the metropolitan region, followed by the VIII and V regions with 8.73% and 7.76%, respectively. When pedigrees were analyzed, ninety unrelated families encompassing 1,007 individuals were identified; among relatives, other 35 manifested HD, and 106 died of HD. Besides, five hundred seventy-nine individuals were at genetic risk. The minimum estimated prevalence of HD in Chile in 2019 was 0.72 × 100,000 inhabitants. The mean CAG repeats (CAGR) of 47.2 ± 10.74 for the expanded allele and 17.93 ± 2.05 for the normal allele. The mean age of onset was 41.39 ± 13.47 years. Juvenile cases represented 7.8% of this cohort, and 4.9% had a late onset. There was a negative correlation between the age of onset and the CAGR of the expanded allele (r =-0.84 p < 0.0001). Besides, 79.6% had a family history of HD. CONCLUSIONS: This is the first report characterizing genetics, motor, and neuropsychiatric features in patients with HD in Chile. The mean length of CAGR expansion of the abnormal allele was similar to previous reports in North America (i.e., Mexico and Canada) and higher than that reported in the neighboring country of Argentina. According to previous estimations, the minimal prevalence of HD in Chile may be lower than expected.

Hospitalización de pacientes con enfermedad de Parkinson en la población chilena entre 2001 y 2018 / Hospital admissions in Chile among patients with Parkinson's disease from 2001 to 2018

BACKGROUND: The progression of Parkinson's disease is associated with complications, most of them preventable. AIM: To analyze hospitalizations with a diagnosis of Parkinson's disease in Chile, comparing the different health subsystems. MATERIAL AND METHODS: Analysis of hospital discharge database available at the website of the Chilean Ministry of Health. Discharges that incorporated the diagnosis of Parkinson's disease (ICD 10 code G20), between the years 2001 and 2018 were analyzed. RESULTS: The rate of discharges with the diagnosis of Parkinson's disease was 34.5 per 100,000 hospitalizations. The figures were 55.2 and 29.8 discharges per 100,000 in 2001 and 2018, respectively. Sixty seven percent of hospital admissions for Parkinson's occurred in the public sector and corresponded to beneficiaries of the public health insurance system (FONASA). Beneficiaries of private insurance systems accounted for 12% of hospital admissions. The mean hospital stay was 13.4 days. CONCLUSIONS: There is a decrease over time in the rate of hospitalizations with Parkinson's disease. This trend may be related with the incorporation of this disease in a special governmental program that guarantees a timely access to diagnosis and treatment.

Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas.

In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the -13910∗T allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the -13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries' dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of -13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the -13910∗T allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the -13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the -13910∗T allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent.

Epidemiology of Parkinson's Disease in Chile.

INTRODUCTION: Parkinson's disease (PD) is one of the most common neurodegenerative disorders. There is no epidemiological description of PD in Chile and not many descriptions in Latin America. This study aims to describe the incidence and prevalence of PD in Chile. METHODS: The study group was the population on the public health system in Chile between 2010 and 2018 that were registered in the GES system as having PD. Crude and standardized prevalence and incidence were calculated with a 95% confidence interval. RESULTS: 33,345 patients were found in the register as confirmed cases with PD. The crude incidence in 2018 was 23.7/100,000; the crude prevalence in 2018 was 160.7/100,000. The male-to-female ratio was 1.03. CONCLUSION: The prevalence and incidence observed in the Chilean population are consistent with studies from other countries.

Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.

OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.

Potent neutralization of clinical isolates of SARS-CoV-2 D614 and G614 variants by a monomeric, sub-nanomolar affinity nanobody.

Despite unprecedented global efforts to rapidly develop SARS-CoV-2 treatments, in order to reduce the burden placed on health systems, the situation remains critical. Effective diagnosis, treatment, and prophylactic measures are urgently required to meet global demand: recombinant antibodies fulfill these requirements and have marked clinical potential. Here, we describe the fast-tracked development of an alpaca Nanobody specific for the receptor-binding-domain (RBD) of the SARS-CoV-2 Spike protein with potential therapeutic applicability. We present a rapid method for nanobody isolation that includes an optimized immunization regimen coupled with VHH library E. coli surface display, which allows single-step selection of Nanobodies using a simple density gradient centrifugation of the bacterial library. The selected single and monomeric Nanobody, W25, binds to the SARS-CoV-2 S RBD with sub-nanomolar affinity and efficiently competes with ACE-2 receptor binding. Furthermore, W25 potently neutralizes SARS-CoV-2 wild type and the D614G variant with IC50 values in the nanomolar range, demonstrating its potential as antiviral agent.

[Hospital admissions in Chile among patients with Parkinson's disease from 2001 to 2018]. / Hospitalización de pacientes con enfermedad de Parkinson en la población chilena entre 2001 y 2018.

BACKGROUND: The progression of Parkinson's disease is associated with complications, most of them preventable. AIM: To analyze hospitalizations with a diagnosis of Parkinson's disease in Chile, comparing the different health subsystems. MATERIAL AND METHODS: Analysis of hospital discharge database available at the website of the Chilean Ministry of Health. Discharges that incorporated the diagnosis of Parkinson's disease (ICD 10 code G20), between the years 2001 and 2018 were analyzed. RESULTS: The rate of discharges with the diagnosis of Parkinson's disease was 34.5 per 100,000 hospitalizations. The figures were 55.2 and 29.8 discharges per 100,000 in 2001 and 2018, respectively. Sixty seven percent of hospital admissions for Parkinson's occurred in the public sector and corresponded to beneficiaries of the public health insurance system (FONASA). Beneficiaries of private insurance systems accounted for 12% of hospital admissions. The mean hospital stay was 13.4 days. CONCLUSIONS: There is a decrease over time in the rate of hospitalizations with Parkinson's disease. This trend may be related with the incorporation of this disease in a special governmental program that guarantees a timely access to diagnosis and treatment.

The Potential Role of SARS-COV-2 in the Pathogenesis of Parkinson's Disease.

Considering their current burden and epidemiological projections, nowadays Parkinson's disease and the COVID-19 pandemic are two key health problems. There is evidence of the pathogenic role of neurotropic viruses in neurodegenerative diseases and coronaviruses are neurotropic, with some of them selectively targeting the basal ganglia. Moreover, some authors demonstrated the longevity of these viruses in the affected cells of the nervous system for long periods. Coronavirus was detected in brain autopsies and SARS-CoV-2 has been isolated from the CSF of affected patients. The marked inflammatory response in some particular patients with COVID-19 with a consequent increase of pro-inflammatory cytokines is considered a prognostic factor. Immunologic changes are observed in patients with Parkinson's disease, possibly having a role in its pathogenesis. A dynamic pro-inflammatory state accompanies α-synuclein accumulation and the development and progression of neurodegeneration. Also, some viral infectious diseases might have a role as triggers, generating a cross autoimmune reaction against α-synuclein. In the past Coronaviruses have been related to Parkinson's disease, however, until now the causal role of these viruses is unknown. In this paper, our focus is to assess the potential relationship between SARS-CoV-2 infection and Parkinson's disease.

Evaluación de síntomas no motores y descontrol de impulsos en usuarios con enfermedad de Parkinson por el médico en atención primaria / Nonmotor symptoms in 32 patients with Parkinson disease

BACKGROUND: Nonmotor symptoms of Parkinson disease significantly hamper the quality of life of patients and have prognostic significance. AIM: To evaluate the presence of nonmotor symptoms in patients with Parkinson disease. MATERIAL AND METHODS: A structured interview was carried out in 32 patients aged 74 ± 9 years (53% men) with Parkinson disease asking specifically for impulse control disorders and dopaminergic dysregulation. The following scales were also applied: Hoehn & Yahr scale, Montreal Cognitive Assessment, Geriatric depression scale, Nonmotor symptom scale and REM sleep scale. RESULTS: A high frequency of nonmotor symptoms was recorded, specially mood, sleep, urinary and gastrointestinal problems and impulse control disorders. CONCLUSIONS: Nonmotor symptoms must be actively sought and managed in patients with Parkinson disease.

Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates.

Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here, we studied the impact of IGF2 signaling on protein aggregation in models of Huntington's disease (HD) as proof of concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients and spinocerebellar ataxia cases. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 was independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human postmortem brain tissue and blood samples from HD patients showed a reduction in IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein species.

Pharmacokinetic evaluation of [18F]PR04.MZ for PET/CT imaging and quantification of dopamine transporters in the human brain.

PURPOSE: Dopamine transporters (DAT) modulate pre-synaptic dopamine and physiological functions such as movement and reward. DAT also mirrors disease state in neurological disorders, rendering it an essential diagnostic target. [18F]PR04.MZ is a new PET imaging agent for DAT with an improved affinity and selectivity profile, for which we here describe the complete pharmacokinetic evaluation in healthy controls. METHODS: Thirty-two healthy subjects underwent T1-weighted MRI and dynamic PET scans for 180 min with arterial blood sampling (n = 5) or 90 min without blood sampling (n = 25) after injection of 197.6 ± 12.2 MBq [18F]PR04.MZ. Blood and plasma metabolite analysis were performed. MRI-based normalization of brain images, delineation of VOIs, and kinetic modeling was conducted to determine distribution volumes (Vt) and binding potentials (BPnd). The impact of scan duration was evaluated and repeated PET scans were performed to assess test-retest variability (n = 5). A static imaging protocol has been validated for clinical applications. RESULTS: [18F]PR04.MZ showed rapid metabolization in circulation, very high uptake in striatum and midbrain, and very low non-specific binding. The two-tissue compartment model 2TCM provided best fits for measured time-activity-curves and calculated Vts in putamen, caudate, substantia nigra pars compacta (SNpc), and cerebellar cortex were 11.83, 9.73, 2.12, and 0.57, respectively. All non-invasive models correlated well with BPnd values derived from 2TCM but underestimated DAT availability by about 28-33%. Of those, simplified reference tissue model (SRTM) provided the best fits, lowest Akaike Information Criteria values, and BPnd values of 14.82, 11.95, and 2.63 in putamen, caudate, and SNpc, respectively. BPnd estimates for striatal regions and SNpc were stable between 90 and 130 min post-injection. Test-retest results were excellent, showing low variability in all and excellent reliability in most relevant regions. Static imaging from 60 to 90-min post-injection is a viable alternative for quantification. CONCLUSIONS: [18F]PR04.MZ is a PET tracer with very high affinity, selectivity, and specific uptake in striatum and midbrain. 2TCM and SRTM provide good fits, high and stable Vts or BPnds, and good test-retest reliability for precise quantification of DAT in human subjects.

[Nonmotor symptoms in 32 patients with Parkinson disease]. / Evaluación de síntomas no motores y descontrol de impulsos en usuarios con enfermedad de Parkinson por el médico en atención primaria.

BACKGROUND: Nonmotor symptoms of Parkinson disease significantly hamper the quality of life of patients and have prognostic significance. AIM: To evaluate the presence of nonmotor symptoms in patients with Parkinson disease. MATERIAL AND METHODS: A structured interview was carried out in 32 patients aged 74 ± 9 years (53% men) with Parkinson disease asking specifically for impulse control disorders and dopaminergic dysregulation. The following scales were also applied: Hoehn & Yahr scale, Montreal Cognitive Assessment, Geriatric depression scale, Nonmotor symptom scale and REM sleep scale. RESULTS: A high frequency of nonmotor symptoms was recorded, specially mood, sleep, urinary and gastrointestinal problems and impulse control disorders. CONCLUSIONS: Nonmotor symptoms must be actively sought and managed in patients with Parkinson disease.