Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.

BACKGROUND: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. METHODS: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. FINDINGS: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset ß=-2·00 [SE=0·57], p=0·0005, for African ancestry; and ß=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. INTERPRETATION: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. FUNDING: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.

Poststroke emotionalism with dacrystic (Crying) episodes - making a case for risperidone.

Emotionalism is the abnormal expression of emotions like crying and laughing and could follow stroke, traumatic brain injury, multiple sclerosis and amyotrophic lateral sclerosis. Emotionalism has been known to respond therapeutically to different classes of drugs including tricyclic antidepressants like imipramine, Selective Serotonin Reuptake Inhibitors (SSRI) like sertraline and citalopram, anticonvulsants like lamotrigine, dopamine precursors like levodopa and NMDA receptor antagonists like dextromethorphan. Classical antipsychotics are hardly prescribed for emotionalism alone without psychotic features. In this case report, an eighty year old woman with a dominant fronto-temporal infarctive stroke with right faciohemiparesis presented with frequent crying (dacrystic) episodes after a month of onset of stroke and who did not satisfy DSM IV criteria for depression nor had other psychotic features. Serial trial of SSRIs and dextromethorphan/quinidine could not help until risperidone, an antipsychotic was introduced with resolution of crying episodes. The response to risperidone after trial of SSRIs and dextromethorphan/quinidine which are considered the gold standard for post-stroke emotionalism (PSE), could be another therapeutic dimension in the management of emotionalism in general and PSE in particular.

Résumé L'émotivité est l'expression anormale d'émotions comme les pleurs et les rires et pourrait suivre un accident vasculaire cérébral, une lésion cérébrale traumatique, la sclérose en plaques et la sclérose latérale amyotrophique. L'émotionnisme a été connu pour répondre thérapeutiquement à différentes classes de médicaments incluant les antidépresseurs tricycliques comme l'imipramine, les inhibiteurs sélectifs du recaptage de la sérotonine (ISRS) comme la sertraline et le citalopram, les anticonvulsivants comme la lamotrigine, les précurseurs de la dopamine comme la lévodopa et les antagonistes des récepteurs NMDA comme le dextrométhorphane. Les antipsychotiques classiques ne sont guère prescrits pour l'émotivité seule sans caractéristiques psychotiques. Dans ce cas, une femme de quatre-vingts ans avec un infarctus fronto-temporal dominant avec faciohemiparesis droite a présenté des épisodes pleurs fréquents (dacrystiques) après un mois d'apparition de l'accident vasculaire cérébral et qui ne répondaient pas aux critères du DSM IV. fonctionnalités. Essai en série des ISRS et dextrométhorphane / quinidine n'a pas pu aider jusqu'à risperidone, un antipsychotique a été introduit avec la résolution des épisodes de pleurs. La réponse à la rispéridone après essai des ISRS et de la dextrométhorphane / quinidine, considérés comme l'étalon-or de l'émotivité post-AVC, pourrait constituer une autre dimension thérapeutique dans la gestion de l'émotivité en général et des EPS en particulier.

Burden of informal caregivers of stroke survivors: Validation of the Zarit burden interview in an African population.

BACKGROUND: Informal care giving can be burdensome particularly where the option of institutionalized informal care scarcely exist. OBJECTIVE: To look at the burden of informal caregivers of stroke survivors using the Zarit burden interview (ZBI). METHOD: 64 stroke survivors were assessed for demographics of age, gender, duration of follow-up since discharged from in-patient care, modified Rankin score at the time of discharge and at the time of evaluation for this study and the most important informal care giver at home was also assessed for whether care giving was telling on their health or life in any negative way. All the caregivers were subsequently assessed with the ZBI. RESULTS: Mean age of most important informal care givers was 40.67 ± 14.27 years and the sex distribution was 33(51.6%) female and 29(45.4%) males. 21(32.8%) reported that caregiving was a health burden. Mean ZBI scores were significantly higher (30.19 ± 14.81 vs 20.30 ± 12.96, P < 0.01) in those that reported that caregiving was telling on their health. ZBI overall rating of burden of caregiving was also significantly associated with whether caregiving was telling on the health of caregiver (P = 0.01) and also symmetrically agreed with whether the burden of caregiving was telling on health (k = 0.33, P< 0.01). The sensitivity and specificity of ZBI were 70% and 68.4% respectively on ROC statistics (AUC = 0.67, P = 0.017). CONCLUSION: Reported burden of informal caregiving of about 33% is in our opinion huge. The moderate sensitivity and specificity of the ZBI means it could be safely used in the population studied.

Should non acute and recurrent headaches have neuroimaging before review by a Neurologist?--a review in a Southern Nigerian Tertiary Hospital.

BACKGROUND: Headache is a common complaint in general practice and it is known that most headaches are primary and that the yield of neuroimaging like cranial computed tomography (CT) in headache is generally low. In this study, we were able to demonstrate that the yield of neuroimaging in non-acute and recurrent headache could be higher if cases are reviewed first by a specialist Neurologist before cranial CT. METHOD: Seventy-four cases that were referred to the specialist neurology clinic with complaints of chronic and recurrent headaches without focal neurological deficit that had CT scan were reviewed consecutively using the short form of the International Classification of Headache Disorders second edition (ICHD 2) criteria after their demographics of age, sex were captured, to find out the proportion and characteristics of study cases that had identifiable cranial lesions on cranial CT scan. All cases were reviewed by a specialist Neurologist before CT scan and all CT films were reviewed by a specialist Radiologist. Age, sex and the distribution of CT findings were described from a frequency table and mean age of study cases with and without identifiable lesions on CT were compared with t-test for any significant difference and the effect of gender on the presence of identifiable lesions was tested with chi square and the agreement between clinical and CT diagnoses were tested on kappa statistics. RESULTS: (1) Mean age of cases was 37.55 (22.06) years. (2) No significant effect of gender was found on intracranial lesions (P = 0.345). (3) Intracranial lesions were found in 47.3% of cases and the mean age was higher compared to cases with normal findings on cranial CT (P = 0.019). (4) Clinical and CT diagnoses agreed in 56.2% of the cases (P = 0.000). CONCLUSION: The high yield of intracranial lesions may be accounted for by the method of selection of cases for cranial CT.