Resequencing the complete SNCA locus in Indian patients with Parkinson's disease.

The genetic loci implicated in familial Parkinson's disease (PD) have limited generalizability to the Indian PD population. We tested mutations and the frequency of known mutations in the SNCA gene in a PD cohort from India. We selected 298 PD cases and 301 age-matched controls for targeted resequencing (before QC), along with 363 PD genomes of Indian ancestry and 1029 publicly available whole genomes from India as healthy controls (IndiGenomes), to determine the frequency of monogenic SNCA mutations. The raw sequence reads were analyzed using an in-house analysis pipeline, allowing the detection of small variants and structural variants using Manta. The in-depth analysis of the SNCA locus did not identify missense or structural variants, including previously identified SNCA mutations, in the Indian population. The familial forms of SNCA gene variants do not play a major role in the Indian PD population and this warrants further research in the under-represented population.

Microbiological acceptance criteria, specifications of herbal drugs and herbal drug preparations in various pharmacopoeias: a global scenario.

PURPOSE: A pharmacopoeia is a compendium of guidelines and criteria for drug quality. It was established by a national or regional entity and has legal significance. This applies to administration of drugs in a particular nation or region. METHOD: In this study, the differences and similarities of microbiological acceptance criteria, specifications for microbial enumeration of herbal drugs and herbal drug preparations in 14 national and international pharmacopeias were investigated. RESULTS: It was found that 12 pharmacopeias have given separate microbial limits for total aerobic microbial count (TAMC) and total yeast and mold count (TYMC), and a list of specified microorganisms for which acceptance criteria are defined. However, similarities were noticed in Ph.Eur, Ph. Helv and, BP. Salmonella, and Escherichia coli are the most common pathogens specified for herbal preparations in which boiling water is added prior to use and for internal use in all Pharmacopoeias because they serve as indicators of potential contamination. CONCLUSION: From this study, it can be concluded that the differences in microbial limit tests and their acceptance criteria as specified in the various pharmacopoeias need to be harmonized. It will become a more convenient option for global drug manufacturers to import/export herbal drugs, and this would also eliminate the burden of performing various analytical methods and comply with different microbial acceptance criteria set by various pharmacopoeias. The comparative data obtained from this study will be used to develop strategies for revisions of pharmacopoeias in a harmonized manner with respect to microbiological acceptance criteria, specifications for microbial enumeration of herbal drugs and herbal drug preparations.

Association of Insulin-like Growth Factor-1 and Neurofilament Light Chain in Patients with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is the most common primary tauopathy. The definite diagnosis of PSP is established by histopathologic changes in the brain. There are no reliable blood-based biomarkers to aid the diagnosis of this fatal disease at an early stage. Also, the precise etiopathology of PSP and its variants is inadequately understood. Objective: Blood-based molecules such as neurofilament light chain (NfL) and insulin-like growth factor-1 (IGF-1) are shown as important markers of neurodegenerative and aging processes, respectively. These two biomarkers have not been analyzed simultaneously in PSP patients. Methods: To address this knowledge gap, 40 PSP patients and equal number of healthy individuals were recruited and serum levels of NfL and IGF-1 were assayed in all the study participants by enzyme-linked immunosorbent assay (ELISA). Motor and nonmotor symptoms were evaluated in PSP patients using various scales/questionnaires. Cardiac autonomic function tests were performed in a subset of patients (n = 27). Results: A significantly high serum level of NfL (P < 0.01) and a reduced level of IGF-1 (P = 0.02) were observed in PSP patients compared to healthy controls. Besides, a negative correlation (r = -0.54, P < 0.01) between NfL and IGF-1 levels was observed in PSP patients. Conclusion: The finding of this study reinforces the important role of blood NfL level as a potential biomarker of PSP. Further, the current study provides novel insights into the reciprocal correlation between NfL and IGF-1 in PSP patients. Combined analysis of blood levels of these two functionally relevant markers might be useful in the prediction and diagnosis of PSP.

Yoga as an Add-on Therapy in Parkinson's Disease: A Single Group Open-label Trial.

OBJECTIVE: We aimed to evaluate the effect of yoga on motor and non-motor symptoms and cortical excitability in patients with Parkinson's disease (PD). METHODS: We prospectively evaluated 17 patients with PD at baseline, after one month of conventional care, and after one month of supervised yoga sessions. The motor and non-motor symptoms were evaluated using the Unified Parkinson's disease Rating Scale (motor part III), Hoehn and Yahr stage, Montreal Cognitive Assessment, Hamilton depression rating scale, Hamilton anxiety rating scale, non-motor symptoms questionnaire and World Health Organization quality of life questionnaire. Transcranial magnetic stimulation was used to record resting motor threshold, central motor conduction time, ipsilateral silent period (iSP), contralateral silent period (cSP), short interval intracortical inhibition (SICI), and intracortical facilitation. RESULTS: The mean age of the patients was 55.5 ± 10.8 years, with a mean duration of illness of 4.0 ± 2.5 years. The postural stability of the patients significantly improved following yoga (0.59 ± 0.5 to 0.18 ± 0.4, p = 0.039). There was a significant reduction in the cSP from baseline (138.07 ± 27.5 ms) to 4 weeks of yoga therapy (116.94 ± 18.2 ms, p = 0.004). In addition, a significant reduction in SICI was observed after four weeks of yoga therapy (0.22 ± 0.10) to (0.46 ± 0.23), p = 0.004). CONCLUSION: Yoga intervention can significantly improve postural stability in patients with PD. A significant reduction of cSP and SICI suggests a reduction in GABAergic neurotransmission following yoga therapy that may underlie the improvement observed in postural stability. CLINICALTRIALSGOV IDENTIFIER: CTRI/2019/02/017564.

Clinical and Imaging Profile of Patients with Cerebrotendinous Xanthomatosis - a Video Case Series from India.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by bi-allelic pathogenic variants in CYP27A1 gene that results in the deposition of cholestanol in the eyes, tendons, soft tissues and nervous system leading to cataracts, xanthomas, and various neuropsychiatric manifestations. The aim of our study is to describe the clinical, radiological and genetic profile of patients with CTX. Methods: This is a retrospective chart review of patients with CTX diagnosed based on classical clinical and radiological findings. The available clinical details, and investigations, including imaging, electrophysiological, pathological and genetic data, were documented. Results: Five patients (4 males) were recruited in the study. The median age at presentation was 32 years (range: 21-66 years). Walking difficulty was the most common symptom at presentation. All patients had cataracts, tendon xanthomas, eye movement abnormalities, dysarthria, pyramidal signs, ataxia and gait abnormality. Dystonia was noted in three patients. Palatal tremor and parkinsonism were noted in one patient each. In MRI brain, dentate, and corticospinal tract involvement were the most frequent imaging findings. Bilateral hypertrophic olivary degeneration was noted in one patient and hot cross bun sign in two. Three patients underwent genetic testing and all had pathogenic variants confirming the diagnosis. Discussion: CTX is a rare treatable disorder. Apart from the usual neurological presentation with spastic-ataxia, it can present at a later age with parkinsonism. Typical patterns of imaging findings are helpful in early diagnosis which aids in the treatment to prevent the neurological sequelae of the disease.

P66Shc Mediates SUMO2-induced Endothelial Dysfunction.

Sumoylation is a post-translational modification that can regulate different physiological functions. Increased sumoylation, specifically conjugation of SUMO2/3 (small ubiquitin like modifier 2/3), is detrimental to vascular health. However, the molecular mechanism mediating this effect is poorly understood. Here, we demonstrate that SUMO2 modifies p66Shc, which impairs endothelial function. Using multiple approaches, we show that p66Shc is a direct target of SUMO2. Mass spectrometry identified that SUMO2 modified lysine-81 in the unique collagen homology-2 domain of p66Shc. SUMO2ylation of p66Shc increased phosphorylation at serine-36, causing it to translocate to the mitochondria. Notably, sumoylation-deficient p66Shc (p66ShcK81R) was resistant to SUMO2-induced p66ShcS36 phosphorylation and mitochondrial translocation. Ingenuity pathway analysis showed that majority of effects of p66Shc SUMO2ylation were mediated via p66ShcK81. Finally, p66ShcK81R knockin mice were resistant to SUMO2-induced endothelial dysfunction. Collectively, our work uncovers a posttranslational modification of redox protein p66Shc and identifies SUMO2-p66Shc signaling as a regulator of vascular endothelial function.

Morphometric alterations of the mesocorticolimbic network in Parkinson's disease with impulse control disorders.

Impulse control disorders (ICDs) are a group of non-motor symptoms of Parkinson disease (PD) leading to significant psychosocial detrimental outcome. The mesocorticolimbic network plays a distinctive role in reward learning and executive decision making and has been suggested to be involved in ICDs in PD. To study morphometric changes of the mesocorticolimbic network in PD with ICD. A total of 18 patients of PD with ICD (PD + ICD), 19 patients of PD without ICD (PD - ICD) and 19 healthy controls (HC) were included in the study. ICDs were diagnosed using Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS). MRI was done using a 3T scanner and assessment of cortical thickness and subcortical volumes were done using FreeSurfer. Brain regions known to be part of the mesocorticolimbic network were extracted and included for statistical analysis. There was no difference between PD + ICD and PD - ICD with regard to duration of illness or total dopaminergic medication. In comparison to HC, patients with PD + ICD demonstrated atrophy of the left frontal pole, and this atrophy neared significance in comparison to PD - ICD. The QUIP-RS had a negative correlation with left caudate volume in PD + ICD. The PD + ICD group showed distinct morphometric changes in regions involved in the mesocorticolimbic system which may contribute to the presence of ICD.

Sexual dysfunction in men with young onset Parkinson's disease.

Sexual dysfunction (SD) is a common, yet under-reported non-motor symptom of PD. Common sexual symptoms among male PD patients include erectile dysfunction, premature ejaculation, and decreased sexual desire. Few research papers have examined sexual dysfunction in PD, especially in YOPD male patients, and there is no Indian research study on sexual dysfunction in YOPD. In this study, we determined the frequency of sexual dysfunction in men with YOPD, and its correlation with other motor and NMS. This prospective cross-sectional study was conducted on YOPD males who presented to the Department of Neurology, NIMHANS, Bangalore, India, from May 2021 to April 2023. The diagnosis of YOPD was made based on MDS criteria for IPD 2015. Sexual functions were evaluated by ASEX, PEDT, QUIP-RS, and sex hormone assay. The patients also underwent other motor and non-motor assessments. Statistical analysis was done using SPSS version 22.0. The study was funded by the PDMD fund. This study included 62 male YOPD patients. The mean age of cases was 44.74 ± 8.54 years. The mean duration of symptoms was 8.45 ± 6.23 years. 43.5% of the cases of PD were Akinetic rigid type. By ASEX Score grading, 46.8% of the cases had erectile dysfunction and 71% of the cases of YOPD had premature ejaculation by PEDT Score grading. 9.7% of the cases had hypersexuality by QUIP-RS. Duration of YOPD was a better predictor of Erectile Dysfunction and premature ejaculation when compared with other variables. SD was related to anxiety and depression and it had a negative impact on the patient's health-related quality of life (HR-QoL). SD should be investigated and treated as an integral part of the neurological assessment in YOPD.

Intracranial lipoma: an incidental finding and a rare cause of secondary headache.

AIM OF THE STUDY: Expand the differential diagnosis of secondary headache to include rare intracranial tumours, detected incidentally on brain imaging. Intracranial lipomas are rare congenital malformations, and are usually pericallosal asymptomatic midline lesions. However, some cases present with headache and seizures. Symptomatic intracranial lipomas are very rare and often detected incidentally on brain imaging. METHODS: We present a 52-year-old woman referred to our tertiary centre with a history of hypothyroidism presented with headache for 2 years. She had generalised body pains for six months. Her headache was persistent despite being on medications. Physical and neurological examination was unremarkable. Her visual acuity and fundus examination were normal. RESULTS: Her brain imaging revealed a lesion over the corpus callosum and in the interhemispheric fissure with signal attenuation on the fat suppression sequence, features suggestive of curvilinear pericallosal lipoma. Symptomatic treatment with analgesics and anti-inflammatory agents were slightly effective. It is debatable whether tumour removal is required, as the risks of surgical intervention far outweigh the potential benefits. CONCLUSION: Corpus callosal lipoma is a rare and unrecognised cause of secondary headache. It should be suspected in patients with an atypical headache without papilledema and who are unresponsive to analgesics. This may be the only presenting feature of intracranial lipomas rendering it even more difficult to suspect and diagnose, thus emphasising the importance of evaluating secondary headaches. Diagnosis is important because long-term follow-up may be required if patients develop new focal deficits, which may necessitate surgical intervention.

Clinical and genetic profile of patients with dystonia: An experience from a tertiary neurology center from India.

BACKGROUND: The genetics of dystonia have varied across different ethnicities worldwide. Its significance has become more apparent with the advent of deep brain stimulation. OBJECTIVE: To study the clinico-genetic profile of patients with probable genetic dystonia using whole exome sequencing (WES). METHODS: A prospective, cross-sectional study was conducted from May 2021 to September 2022, enrolling patients with dystonia of presumed genetic etiology for WES. The study compared genetically-determined cases harboring pathogenic/likely-pathogenic variants (P/LP subgroup) with the presumed idiopathic or unsolved cases. RESULTS: We recruited 65 patients (males, 69.2%) whose mean age of onset (AAO) and assessment were 25.0 ± 16.6 and 31.7 ± 15.2 years, respectively. Fifteen had pathogenic/likely-pathogenic variants (yield = 23.1%), 16 (24.6%) had variants of uncertain significance (VUS), 2 were heterozygous carriers while the remaining 32 cases tested negative (presumed idiopathic group). The P/LP subgroup had a significantly younger AAO (16.8 ± 12.3 vs 31.3 ± 17.0 years, p = 0.009), longer duration of illness (10.9 ± 10.3 vs 4.8 ± 4.3 years, p = 0.006), higher prevalence of generalized dystonia (n = 12, 80.0% vs n = 10, 31.3%, p = 0.004), lower-limb onset (n = 5, 33.3% vs n = 1, 3.1%, p = 0.009), higher motor (p = 0.035) and disability scores (p = 0.042). The classical DYT genes with pathogenic/likely pathogenic variants included 3 cases each of TOR1A, and KMT2B, and single cases each of SGCE, EIF2AK2, and VPS16. Non-DYT pathogenic/likely-pathogenic cases included PINK1, PANK2, CTSF, POLG, MICU1, and TSPOAP1. CONCLUSIONS: The yield of WES was 23.1% among cases of probable genetic dystonia. Pathogenic or likely pathogenic variants in TOR1A, KMT2B, and SGCE genes were commoner. The absence of family history emphasizes the importance of accurate assessment of clinical predictors before genetic testing.

Abnormal cortical excitability in patients with spinocerebellar ataxia type 12.

BACKGROUND: Spinocerebellar ataxia type 12 (SCA-12) is an uncommon autosomal dominant cerebellar ataxia characterized by action tremors in the upper limbs, dysarthria, head tremor, and gait ataxia. We aimed to evaluate the motor cortical excitability in patients with SCA-12 using transcranial magnetic stimulation (TMS). METHODS: The study was done in the department of Neurology at the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore. Nine patients with SCA-12 (2 females) and 10 healthy controls (2 females) were included in the study. TMS was performed in all the subjects and various parameters such as resting motor threshold (RMT), central motor conduction time (CMCT) and contralateral silent period (cSP) were recorded. The left motor cortex was stimulated and the recording was done from right first dorsal interossei muscle. The severity of ataxia was assessed using the scale for assessment and rating in ataxia (SARA). RESULTS: The mean age of the patients was 58.11 ± 7.56 years mean age at onset: 51.67 ± 4.18 years. The mean duration of illness was 9.44 ± 4.88 years. The mean SARA score was 13.83 ± 3.60. Patients with SCA-12 had significantly increased RMT (88.80 ± 12.78 %) compared to HC (44.90 ± 9.40 %, p < 0.05). A significantly prolonged CMCT was observed in patients (13.70 ± 2.52 msec) compared to HC (7.31 ± 1.21 msec, p < 0.05). In addition, cSP was significantly increased in SCA-12 patients (144.43 ± 25.79 msec) compared to HC (82.14 ± 28.90 msec, p < 0.05). CONCLUSIONS: Patients with SCA-12 demonstrate a reduced cortical excitability and increased cortical inhibition suggesting an increase in the GABAergic neurotransmission.

Impact of Non-Motor Symptoms on Quality of Life in Patients with Early-Onset Parkinson's Disease.

BACKGROUND: Early-onset Parkinson's disease (EOPD) refers to patients with Parkinson's disease (PD) whose age at disease onset is less than 50 years. Literature on the non-motor symptoms (NMS) in these patients is very limited in the Indian context. We aimed to study the NMS in patients with EOPD and its impact on the quality of life (QoL). METHODS: We included 124 patients with EOPD with a mean age at disease onset between 21 and 45 years and 60 healthy controls (HC). NMS were assessed using validated scales, and the QoL domains were evaluated using the PD QoL-39 scale (PDQ-39). RESULTS: The mean age at disease onset in EOPD patients was 37.33 ± 6.36 years. Majority of the patients were male (66.12%). The average disease duration was 6.62 ± 5.3 years. EOPD patients exhibited a significantly higher number of NMS per patient (7.97 ± 4.69) compared to HC (1.3 ± 1.39; p < 0.001). The most common NMS reported were urinary dysfunction, body pain, poor sleep quality, constipation, anxiety, depression, cognitive impairment, and REM sleep behavior disorder. The total NMS burden correlated with the QoL measures. Distinctive patterns of QoL subdomain involvement were identified, with sleep/fatigue, mood/cognition, and urinary dysfunction independently influencing QoL metrics. CONCLUSIONS: Our study provides valuable insights into the NMS profile and its impact on QoL in patients with EOPD, addressing an important knowledge gap in the Indian context. By understanding the specific NMS and their influence on QoL, healthcare professionals can develop targeted interventions to address these symptoms and improve the overall QoL.

Reactivity of [Cp*Fe(η5 -As5 )] towards Carbenes, Silylenes and Germylenes.

The reaction behavior of [Cp*Fe(η5 -As5 )] (I) (Cp*=C5 Me5 ) towards carbenes and their heavier analogs was investigated. The reaction of I with NHCs (NHCs=N-heterocyclic carbenes) results in the first substitution products of polyarsenic ligand complexes by NHCs [Cp*Fe(η4 -As5 NHC)] (1 a: NHC=IMe=1,3,4,5-tetramethylimidazolin-2-ylidene, 1 b: NHC=IMes=1,3-bis(2,4,6-trimethylphenyl)-imidazolin-2-ylidene). In contrast, the reaction of I with Et CAAC (Et CAAC=2,6-diisopropylphenyl)-4,4-diethyl-2,2-dimethyl-pyrrolidin-5-ylidene) leads to a fragmentation and the formation of an unprecedented As6 -sawhorse-type compound [As2 (AsEt CAAC)4 ] (2). The reaction of (LE)2 (L=PhC(Nt Bu)2 ; E=Si, Ge) with I resulted in a rearrangement and an insertion of LE fragments, forming unique silicon- (4: [Cp*Fe(η4 -As4 SiL)], 5 a: [Cp*Fe(η4 -As6 SiL)) and germanium-containing (5 b: [Cp*Fe(η4 -As6 GeL)) cyclic polyarsenic ligand complexes.