Effect of rTMS at SMA on task-based connectivity in PD.

BACKGROUND: Transcranial magnetic stimulation (TMS) can aid in alleviating clinical symptoms in Parkinson's disease (PD). To better understand the neural mechanism of the intervention, neuroimaging modalities have been used to assess the effects of rTMS. OBJECTIVE: To study the changes in cortical connectivity and motor performance with rTMS at supplementary motor area (SMA) in PD using clinical assessment tools and task-based functional MRI. METHODOLOGY: 3000 pulses at 5 Hz TMS were delivered at the left SMA once a week for a total of 8 consecutive weeks in 4 sham sessions (week 1-4) and 4 real sessions (week 5 to week 8) in 16 subjects with PD. The outcomes were assessed with UPDRS, PDQ 39 and task-based fMRI at baseline, after sham sessions at week 4, and after real sessions at week 8. Visuo-spatial functional MRI task along with T1 weighted scans (at 3 Tesla) were used to evaluate the effects of rTMS intervention. Multivariate pattern analysis (MVPA) was used to analyse task-based fMRI using Conn toolbox. RESULTS: Improvements (p < 0.05) were observed in UPDRS II, III, Mobility and ADL of PDQ39 after real sessions of rTMS. MVPA of task-based connectivity revealed clusters of activation in right hemispheric precentral area, superior frontal gyrus, middle frontal gyrus, thalamus and cerebellum (cluster threshold pFDR=0.001). CONCLUSIONS: Weekly rTMS sessions at SMA incurred clinical motor benefits as revealed by an improvement in clinical scales and dexterity performance. These benefits could be attributed to changes in connectivity remote brain regions in the motor network.

Mechanisms of 1 Hz Inhibitory and 5 Hz Excitatory Repetitive Transcranial Magnetic Stimulations in Parkinson's Disease: A Functional Magnetic Resonance Imaging Study.

Background: Parkinson's disease (PD) is a progressive disorder with alterations in cortical functional activity. Transcranial magnetic stimulation is known to incur motor benefits in PD by inducing motor activity through cortical connectivity, although the mechanisms are unclear. Objective: The effects of repetitive transcranial magnetic stimulation (rTMS) (at three cortical sites) on functional and structural plasticity were studied in PD to understand inhibitory or excitatory rTMS-induced motor improvement. Methodology: The study was a single blind, randomized, sham-controlled type involving three groups. Three thousand rTMS pulses of frequency 1 Hz were given at primary motor area (in 13 patients of Group A) or premotor area (in Group B, n = 18) and a frequency 5 Hz at supplementary motor area in Group C (n = 19). Clinical rating scores (Unified Parkinson's Disease Rating Scale [UPDRS], Parkinson's Disease Questionaire-39 [PDQ-39]) and motor dexterity were assessed at baseline, after sham and real rTMS sessions. Visuospatial functional magnetic resonance imaging task along with T1-weighted scans (at three Tesla) were used to evaluate the motor execution and planning post rTMS intervention. Results: Improvements (p < 0.05) in UPDRS II, III, Mobility, and activities of daily living of PDQ-39, Purdue Pegboard were observed. Increased blood oxygen level-dependent (BOLD) activations (family-wise error [FWE]-corrected P-value [pFWE] <0.01) were observed in motor cortices, parietal association areas, and cerebellum in groups C and decrease in group A and B after real TMS as compared with sham. Conclusions: Repetitive TMS at motor (1 Hz) and supplementary motor (5 Hz) areas resulted in significant clinical benefits by inducing cortical plasticity. Impact statement TMS daily protocols have been commonly employed to modulate cortical connectivity in Parkinson's disease (PD). This study uses functional magnetic resonance imaging to assess rTMS-related effects in PD. Repetitive TMS protocol at higher pulses (3000/session) in primary and supplementary motor cortices administered weekly was clinically effective and safe. The results revealed functional restoration along with cortical plasticity mechanisms of externally generated movement in PD in response to noninvasive brain stimulation.

Annual Cost of Care of Parkinson's Disease and Its Determinants in North India - A Cost of Illness Study with Patient Perspective.

Background: Parkinson's disease (PD) is a slowly progressive and disabling disorder, so the cost of illness may change with time. We aimed this study to know the annual cost of care of PD in India. Methods: After ethics approval, a prospective cohort study was conducted at the movement disorder clinic of tertiary care hospital for 2 years (2014-2016). The outcomes were a description of the total annual direct cost of Parkinson's disease including health care as well as non-health care cost. We also did correlation analysis to know the determinants of the total cost. Results: A total of 200 consecutive patients of PD with 141 (70.50%) males and 59 (29.50%) females with a mean age of 56.84 ± 10.51 years were enrolled. The annual Median Direct cost of care was INR 27,315.0 (IQR 13636.6-44908.4), whereas the Indirect cost was INR 21,400 (IQR 9800 - 96800). Cost on drugs (Direct health care) formed 68.50% (Median) of the total Direct cost. Total direct cost formed 11.38% of the Median total yearly income of our patients. Of the direct cost, the Median expenditure on drugs was INR 18,712.8 (8064.0 -30696.0). Only 5% of patients had health care insurance. The total direct cost was determined by the stage of Parkinson's disease and duration of disease (P = < 0.01) but not predicted by age, gender, age at onset, and the yearly income of patients. Conclusion: Annual cost of care of Parkinson's disease is high and increases with the duration of the disease as well as the progression of the disease.

Alteration of Mitochondrial Function in Oxidative Stress in Parkinsonian Neurodegeneration: A Cross-Sectional Study.

CONTEXT: Appropriate mitochondrial function and oxidative balance are critical to neuronal survival. Accumulation of reactive oxygen species leads to oxidative stress that can cause free radical damage to biomolecules of the cell components and the molecules in the cellular milieu that eventually lead to a variety of chronic diseases including neurodegenerative disorders. Mitochondrial dysfunction initiates neuronal apoptosis thereby leading to neurodegenerative diseases including Parkinson's disease (PD). AIM: To evaluate oxidative stress vis-a-vis mitochondrial function (Cytochrome C oxidase activity) in PD patients, Parkinson plus syndrome (PPS) patients in comparison with healthy controls (HCs). SETTINGS AND DESIGN: Cross-sectional Study. METHODS: We assessed oxidative stress by chemiluminescence using luminol, and cytochrome c oxidase activity (CCO) by CCO kit using spectrophotometry in PD patients (n = 80), PPS patients (n = 40), and HCs (n = 40). STATISTICAL ANALYSIS: Data were presented as number (%) or mean ± SD/median as approximate. Quantitative baseline variables were compared among the groups using one-way ANOVA and qualitative variables were compared using Chi-square test. The difference in median was compared using Kruskal-Wallis test followed by Post-hoc Bonferronni correction. RESULTS: Compared to HCs (Median 7.53 ± 15.58 RLU/sec/cell), ROS level in PD (14.13 ± 29.5), and PPS (17.43 ± 15.91) patients was significantly higher (P = 0.0029: HC vs, PD & P = 0.0500: HC vs. PPS). Also, ROS in PD patients (14.13 ± 29.5) was higher that PPS patients (17. 43 ± 15.91) but the difference was not statistically significant (P = 0.84). The CCO activity was found to be diminished in PD (Median: 0.025 ± 0.013 units/ml) and PPS patients (0.027 ± 0.008) in comparison to HCs (0.117 ± 0.049). CONCLUSION: Mitochondrial dysfunction and oxidative stress is associated with PD and PPS and may play an important role in etiopathogenesis. Though the cause-effect conundrum has not been comprehensively probed but addressing oxidative stress and mitochondrial damage may serve as an adjunctive therapy for PD and PPS. Iron metabolism as reflected in the red cell indices may aid in differentiating PD from PPS.

Cross-sectional analysis of the Parkinson's disease Non-motor International Longitudinal Study baseline non-motor characteristics, geographical distribution and impact on quality of life.

Growing evidence suggests that non-motor symptoms (NMS) in Parkinson's disease (PD) have differential progression patterns that have a different natural history from motor progression and may be geographically influenced. We conducted a cross-sectional analysis of 1607 PD patients of whom 1327 were from Europe, 208 from the Americas, and 72 from Asia. The primary objective was to assess baseline non-motor burden, defined by Non-Motor Symptoms Scale (NMSS) total scores. Other aims included identifying the factors predicting quality of life, differences in non-motor burden between drug-naïve and non-drug-naïve treated patients, and non-motor phenotypes across different geographical locations. Mean age was 65.9 ± 10.8 years, mean disease duration 6.3 ± 5.6 years, median Hoehn and Yahr stage was 2 (2-3), and 64.2% were male. In this cohort, mean NMSS scores were 46.7 ± 37.2. Differences in non-motor burden and patterns differed significantly between drug-naïve participants, those with a disease duration of less than five years, and those with a duration of five years or over (p ≤ 0.018). Significant differences were observed in geographical distribution (NMSS Europe: 46.4 ± 36.3; Americas: 55.3 ± 42.8; Asia: 26.6 ± 25.1; p < 0.001), with differences in sleep/fatigue, urinary, sexual, and miscellaneous domains (p ≤ 0.020). The best predictor of quality of life was the mood/apathy domain (ß = 0.308, p < 0.001). This global study reveals that while non-motor symptoms are globally present with severe NMS burden impacting quality of life in PD, there appear to be differences depending on disease duration and geographical distribution.

Study of EEG microstates in Parkinson's disease: a potential biomarker?

The spontaneous activity of the brain is dynamic even at rest and the deviation from this normal pattern of dynamics can lead to different pathological states. EEG microstate analysis of resting-state neuronal activity in Parkinson's disease (PD) could provide insight into altered brain dynamics of patients exhibiting dementia. Resting-state EEG microstate maps were derived from 128 channel EEG data in 20 PD without dementia (PDND), 18 PD with dementia (PDD) and 20 Healthy controls (CON) using Cartool and sLORETA softwares. Microstate map parameters including global explained variance, mean duration, frequency of occurrence (TF) and time coverage were compared statistically among the groups. Eight maps that explained 72% of the topographic variance were identified and only three maps differed significantly across the groups. TF of Map1 was lower in both PDND and PDD (p < 0.001) and that of Map3 (p = 0.02) in PDND compared to control. Cortical sources showed higher activation in precuneus, cuneus and superior parietal lobe (Threshold: Log-F = 1.74, p < 0.05) with maximum activity in the precuneus region (MNI co-ordinates: - 25, - 75, - 40; Log-F = 1.9) in PDND compared to control only for Map1. Lower TF of Map1 (prototypical microstate D) may potentially serve as a biomarker for PD with or without dementia whereas higher activation of precuneus, cuneus and superior parietal lobe at resting-state could favour signal processing, lack of which could be associated with dementia in Parkinson's disorder.

Compound heterozygous variants in Wiskott-Aldrich syndrome like (WASL) gene segregating in a family with early onset Parkinson's disease.

BACKGROUND: Knowledge of genetic determinants in Parkinson's disease is still limited. Familial forms of the disease continue to provide a rich resource to capture the genetic spectrum in disease pathogenesis, and this approach is exploited in this study. METHODS: Informative members from a three-generation family of Indian ethnicity manifesting a likely autosomal recessive mode of inheritance of Parkinson's disease were used for whole exome sequencing. Variant data analysis and in vitro functional characterisation of variant(s) segregating with the phenotype were carried out in HEK-293 and SH-SY5Y cells using gene constructs of interest. RESULTS: Two compound heterozygous variants, a rare missense (c.1139C > T:p.P380L) and a novel splice variant (c.1456 + 2 delTAGA, intron10) in Wiskott-Aldrich syndrome like gene (WASL, 7q31), both predicted to be deleterious were shared among the proband and two affected siblings. WASL, a gene not previously linked to a human Mendelian disorder is known to regulate actin polymerisation via Arp2/3 complex. Based on exon trapping assay using pSPL3 vector in HEK-293 cells, the splice variant showed skipping of exon10. Characterisation of the missense variant in SH-SY5Y cells demonstrated: i) significant alterations in neurite length and number; ii) decreased reactive oxygen species tolerance in mutation carrying cells on Tetrabutylphosphonium hydroxide induction and iii) increase in alpha-synuclein protein. Screening for WASL variants in two independent PD cohorts identified four individuals with heterozygous but none with biallelic variants. CONCLUSION: WASL, with demonstrated functional relevance in neurons may be yet another strong candidate gene for autosomal recessive PD encouraging assessment of its contribution across populations.

Novel and reported variants in Parkinson's disease genes confer high disease burden among Indians.

BACKGROUND: Genetic heterogeneity in Parkinson's disease (PD) has been unambiguously reported across different populations. Assuming a higher genetic load, we tested variant burden in PD genes to an early onset PD cohort from India. METHODS: Whole exome sequencing was performed in 250 PD patients recruited following MDS-UPDRS criteria. The number of rare variants in the 20 known PD genes per exome were used to calculate average rare variant burden with the 616 non-PD exomes available in-house as a comparison group. SKAT-O test was used for gene level analysis. RESULTS: 80 patients harboured rare variants in 20 PD genes, of which six had known pathogenic variants accounting for 2.4% of the cohort. Of 80 patients, 12 had homozygous and nine had likely compound heterozygous variants in recessive PD genes and 59 had heterozygous variants in only dominant PD genes. Of the 16 novel variants of as yet unknown significance identified, four homozygous across ATP13A2, PRKN, SYNJ1 and PARK7; and 12 heterozygous among LRRK2, VPS35, EIF4G1 and CHCHD2 were observed. SKAT-O test suggested a higher burden in GBA (punadjusted = 0.002). Aggregate rare variant analysis including 75 more individuals with only heterozygous variants in recessive PD genes (excluding GBA), with an average of 0.85 protein-altering rare variants per PD patient exome versus 0.51 in the non-PD group, revealed a significant enrichment (p < 0.0001). CONCLUSION: This first study in an early onset PD cohort among Indians identified 16 novel variants in known genes and also provides evidence for a high genetic burden in this ethnically distinct population.

Development and Validation of Quality of Life in Parkinson's Disease Instrument.

CONTEXT: Parkinson's disease (PD) has devastating effects on quality of life (QoL), but there is no instrument that has been developed for Hindi-speaking persons with Parkinson's disease (PWP). OBJECTIVE: The objective of this study was to develop and validate an instrument in Hindi language to measure health-related QoL (HRQoL) in PWP. SUBJECTS AND METHODS: Literature review and interviews of stakeholders were done to create a pool of 68 items to develop a questionnaire. Self-rated global QoL item was also included in the questionnaire. Questionnaire was tested on 300 Hindi-speaking PWP. Item reduction was achieved through factor analysis and clinimetrics to finalize the QoL in PD (QLPD) instrument. Validity and reliability of the QLPD were tested. RESULTS: "QLPD" is a 45-item instrument with nine subscales, namely, activities of daily living, mobility, psychological, fear, social, family, treatment, finance, and nonmotor symptom subscales. Internal consistency of QLPD's summary score and all subscales except treatment subscale was high (α = 0.74-0.94). Intraclass correlation coefficient between summary score and global QoL was 0.79. Summary score and subscale scores were significantly different (P < 0.0001) for predefined five categories on global QoL (very good to very bad). QLPD subscales exhibited good convergent and divergent validity with subscales of 39-item PD questionnaire and short form-36 scale. Higher Hoehn and Yahr stage, lower monthly per capita income, and higher levodopa equivalent daily dosage were found to be independently associated with poor HRQoL. CONCLUSION: QLPD is a valid and reliable instrument to measure HRQoL in Hindi-speaking PWP.

Pain Assessment in Indian Parkinson's Disease Patients Using King's Parkinson's Disease Pain Scale.

BACKGROUND: Pain is a common symptom in Parkinson's disease (PD) patients. Scales to rate pain in PD are marred by several flaws, either not being available in other languages or not specific for PD. OBJECTIVES: To assess the frequency of pain among bilingual Indian PD patients using "King's Parkinson's disease pain scale" (KPPS) and to validate it. METHODS: We randomly administered KPPS in Hindi/English to all consecutive bilingual persons with PD. The results were appropriately analyzed. RESULTS: A total of 119 PD patients were enrolled with a mean age of 64.34 (± 9.57) years. Median Hoehn and Yahr stage was 2 (42.85%). Pain was present in 62 (52.1%) PD patients. The most common type was musculoskeletal (74.19%). The mean total KPPS score was 16.02 ± 10.57. KPPS score was significantly higher in women and correlated positively with unified Parkinson's disease rating scale (UPDRS) part 2 and 4 scores (r = 0.27 and r = 0.25). Risk factors for pain were female gender, higher H and Y stage, total UPDRS score, and individual UPDRS part 3 and 4 scores. Difficulty falling asleep (P = 0.01), frequent awakenings (P = 0.01), diminished smell sensation (P = 0.003), diminished speech volume (P = 0.02), gait freezing (P = 0.03), and falls (P = 0.001) correlated with the presence of pain. The interclass correlation coefficient between the Hindi and English versions of KPPS was 0.835, while Bland-Altman analysis showed 96.7% agreement suggesting excellent correlation and validation. CONCLUSIONS: KPPS is an easy tool for characterization, scoring, and follow-up of pain in PD patients. The Hindi version has good agreement with the original English version.

Is Dementia in Parkinson' Disease Related to Chronic Stress, Anxiety, and Depression?

OBJECTIVES: Stress, anxiety, and depression are known to be associated with the development of neurodegenerative disorders through interactions with the underlying pathophysiology. We hypothesized that the presence of these symptoms contributes to cognitive disturbances and dementia in Parkinson's disease (PD). The present study aimed to investigate the levels of stress, anxiety, and depression in PD patients relative to healthy individuals. MATERIALS AND METHODS: Anxiety, stress, and depression levels were assessed using standardized questionnaires in PD without dementia (PDND, n = 30), PD with dementia (PDD, n = 28), and healthy controls (HC, n = 26). Arithmetic subtraction task was used as a stressor. Galvanic skin response, heart rate and salivary cortisol, and alpha-amylase were measured during baseline and after induced stress (arithmetic task). RESULTS: Acute anxiety, acute stress, and depression levels were significantly higher in PDND compared to HC, whereas both acute and chronic anxiety, stress, and depression levels were significantly higher in PDD compared to PDND and HC. Cortisol and alpha-amylase levels were significantly higher in PDND compared to HC during both baseline and postarithmetic task. Posttask levels of cortisol were lower in PDD compared to PDND. CONCLUSION: This study concludes that higher levels of salivary cortisol and alpha-amylase at baseline and poststress task with normal levels of chronic stress and anxiety were associated with no dementia in PD. Presence of higher levels of acute, chronic anxiety, and stress along with depression with lower cortisol reactivity to stressor suggests onset of dementia in Parkinson's patients.

Elevated Serum SIRT 2 May Differentiate Parkinson's Disease From Atypical Parkinsonian Syndromes.

Atypical Parkinson syndromes (APSs) often have symptoms that overlap with those of Parkinson's disease (PD), especially early in the disease, making these disorders difficult to diagnose. Previous studies have demonstrated an association of oligomeric α-synuclein (α-Syn), a key element in the pathogenesis of PD, with Sirtuin (SIRT)2 proteins for modulating PD. We aimed to evaluate SIRT protein expression in serum of PD patients and compare it with APSs and normal elderly control (GC) and to correlate this with α-Syn. SIRT protein expression was evaluated in sera of 68 PD; 34 APS and 68 GC without any neuro-psychiatric illness as controls by surface plasmon resonance (SPR). SIRT2 expression was correlated with α-Syn in PD and GC. Significant (p < 0.0001) differences were observed between serum SIRT2 concentration in PD and APS and GC as well as between APS and GC. Receiver operating characteristic (ROC) analysis revealed the strong cut-off value to differentiate PD from APS and GC and also APS from GC. Significant correlation was observed among SIRT2 levels in early PD patients with Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr (H & Y) and increased duration of disease. In addition, a strong positive correlation of SIRT2 with α-Syn (p < 0.0001) was observed. However, no such difference was detected for serum SIRT1 in cases of PD and APS or for GC. The present study is the first to report elevated serum SIRT2 in PD. The study also provided a simple test to distinguish PD from APS and may have translational utility for diagnosis.

Influence of Interleukin-6 (IL-6) Promoter Gene Polymorphisms (-174G>C, -572G>C, and -597G>A) on IL-6 Plasma Levels and Their Impact in the Development of Acute Ischemic Stroke in Young Indians.

This study aimed to determine whether there is an influence of interleukin 6 (IL-6) gene promoter polymorphisms on IL-6 plasma levels and its role in the development of ischemic stroke in young Indians. One hundred young patients with ischemic stroke (age ≥ 45 years) and equal number of age- and sex-matched controls were genotyped for 174G>C, -572G>C, and -597G>A promoter polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Plasma IL-6 levels were measured by enzyme-linked immunosorbent assay. Plasma IL-6 levels were significantly higher in patients as compared to controls (patients: 28.61 ± 8.61 pg/mL, controls: 7.60 ± 4.10 pg/mL, P = .001). Both -174G>C (allelic χ2/P value: 4.79/.028, genotypic χ2/P value: 5.3/.021) and -572G>C (allelic χ2/P value: 9.63/.00113 Genotypic χ2/P value: 74/.0002) polymorphisms exhibited genotypic as well as allelic significant association with the disease phenotype. Comparison was made between patients and controls for all 3 polymorphisms using a recessive model with respect to plasma IL-6 levels; no polymorphism showed any significant correlative association with the increased IL-6 levels (P = .31, .51, .32). Interleukin 6 is an inflammatory marker that is considerably influenced by nongenetic factors and is not a good candidate gene for studying genetic components associated with ischemic stroke. It seems that the variability in IL-6 levels is an integrated effect of nongenetic influences and the inflammatory events that follow ischemic stroke instead of being its cause. It is suggested that there is no direct association between -174G>C, -572G>C, and -597G>A polymorphisms and elevated IL-6 levels in the development of ischemic stroke.

Practice Trends in Treating Central Nervous System Tuberculosis and Outcomes at a Tertiary Care Hospital: A Cohort Study of 244 Cases.

INTRODUCTION: Tubercular meningitis (TBM) is a common cause of chronic meningitis in India; however, there is a paucity of literature on optimum duration and choice of drug therapy. MATERIALS AND METHODS: This was an ambispective cohort study. RESULTS: Two hundred and forty-four patients of central nervous system tuberculosis (CNS TB) who were seronegative for HIV were studied of whom 198 had TBM and 46 patients had tuberculoma without meningitis. Before completion of treatment, 84% of TBM patients underwent imaging. There was no difference in disability or mortality in patients, who were treated with various drug regimens in terms of duration of therapy or number of drugs at initiation of treatment. However when patients developed new complications, adding more drugs improved survival. Prolonging corticosteroid administration in patients with nonsatisfactory improvement at 8 weeks was not associated with prevention of disability. CONCLUSIONS: CNS TB is treated by neurologists and physicians in India, as per their experience due to different recommendations in various guidelines. There is a tendency to decide when to stop treatment based on neuroimaging given the fear of poor outcomes associated with recurrence of the disease. The duration of treatment or choice of drugs at the start of treatment did not affect disability.

Effect of sleep quality on memory, executive function, and language performance in patients with refractory focal epilepsy and controlled epilepsy versus healthy controls - A prospective study.

We aimed to evaluate the effect of sleep quality on memory, executive function, and language performance in patients with refractory focal epilepsy and controlled epilepsy and compare these with healthy individuals. We prospectively enrolled 37 adolescent and adult patients with refractory focal epilepsy (Group 1) and controlled epilepsy (Group 2) in each group. History pertaining to epilepsy and sleep were recorded, and all patients underwent overnight polysomnography. Language, memory, and executive function assessments were done using Western Aphasia Battery, Post Graduate Institute (PGI) memory scale, and battery of four executive function tests (Trail Making Test A & B, Digit symbol test, Stroop Task, and Verbal Fluency Test), respectively. Forty age- and sex-matched controls were also included in the study. Significant differences were noted in both objective and subjective sleep parameters among all the groups. On polysomnography, parameters like total sleep time, sleep efficiency, sleep latency, and rapid eye movement (REM) latency were found to be significantly worse in Group 1 as compared with Group 2. Cognitive and executive parameters were significantly impaired in Group 1. Shorter total sleep time, poorer sleep efficiency, and prolonged sleep latencies were observed to be associated with poor memory and executive function in patients with refractory epilepsy. Our study strongly suggests that sleep disturbances, mainly shorter total sleep time, poor sleep efficiency, and prolonged sleep latencies, are associated with impaired memory and executive function in patients with refractory focal epilepsy and to a lesser extent, among those with medically controlled epilepsy.

Alterations in mitochondrial membrane potential in peripheral blood mononuclear cells in Parkinson's Disease: Potential for a novel biomarker.

BACKGROUND: Progressive apoptosis in the dopaminergic neurons of substantia nigra lead to Parkinson's disease. Since neurons require substantially higher supply of energy, their mitochondria have a pivotal status in neuronal survival. These organelles have a key role to play in apoptosis and any impairment thereof may lead to apoptosis mediated cell death. OBJECTIVES: To evaluate and compare the mitochondrial membrane potential (Δψ) in Parkinson's disease patients and healthy controls. METHODS: We evaluated the mitochondrial membrane potential (Δψ) in the peripheral blood mononuclear cells by Flow cytometry using a lipophillic cationic dye JC-1 in Parkinson's disease patients (N = 61) and healthy controls (N = 37). RESULTS: JC-1 fluorescence was measured and represented as percentage positivity i.e., Mean±SEM in FL-2 (representing non-apoptotic aggregates) and FL-1 (indicating apoptotic cell population having depolarized or damaged mitochondria) channels. The ratio of % FL-2 and % FL-1, which is an indicator of cellular mitochondrial membrane potential, was found to be significantly higher in healthy controls (Mean±SEM = 60.48±18.42) as compared to patients (Mean±SEM = 24.30±4.671) in both stimulated and unstimulated conditions. CONCLUSIONS: Mitochondrial membrane potential is altered and hence its evaluation in peripheral blood mononuclear cells may serve as an early marker of apoptosis in PD and, therefore, may pave way for early interventions. Since Δψ has a role in the maintenance of electrochemical gradient, the disruption of which may lead to neuronal apoptosis, Δψ is intricately nested within etiopathogenesis of PD and may prove to be useful in design of diagnostics, prognostics and therapeutics for PD.

Deficit in specific cognitive domains associated with dementia in Parkinson's disease.

Impairment in different cognitive domains such as executive functions, language, memory and visuospatial skills occur frequently in Parkinson disease (PD) leading to significant disability and deterioration in quality of life. Heterogeneity of cognitive impairment enhances risk of developing dementia as disease progress. The objective is to explore the pattern of cognitive impairment with reference to the affected domains in PD with or without dementia relative to healthy controls. In this study, 110 PD patients and 26 healthy control were categorized into groups using Mini Mental State Examination and Clinical Dementia Rating scores as PD without dementia (PDND, n = 65; MMSE score >24; CDR = 0-1), PD with dementia (PDD, n = 45; MMSE score ≤24; CDR = 0.5-3) and healthy control (HC, n = 26; MMSE score >26; CDR = 0). Both Patients and controls underwent individual assessments of working memory, semantic memory, attention, language, executive functions, psychomotor and visuospatial skills and dementia using different cognitive function tests. Findings revealed lower scores of word memory, attention, psychomotor speed, visuospatial skills and executive functions in PDD compared to PDND. Interestingly, in PDD scores of picture memory, semantic memory and language functions were comparable with PDND. Compared to HC, PDND had no impairment in working memory, attention and executive functions, whereas PDD had lower scores in all the cognitive domains tested. Results indicate that the deficits in word memory, attention, psychomotor speed, visuospatial skills and executive functions distinguishes PDD from PDND. Impairment in specific cognitive domains may be a biomarker for predicting onset of dementia in Parkinson's disease.

Evaluation of the diagnostic yield of ARQIP: A new restless legs syndrome diagnostic questionnaire and validation of its Hindi translation.

BACKGROUND: Restless legs syndrome (RLS) is misdiagnosed due to a variety of clinical presentations and lack of a diagnostic biomarker. Sociocultural differences in patients' reporting of symptoms further contribute to this under diagnosis. We developed an expanded diagnostic tool for RLS, incorporating all International RLS Study Group (IRLSSG) diagnostic criteria with a number of additional questions mainly focusing on specific sociocultural influences in RLS symptom reporting among Indians. The purpose of this study was to examine the change in the diagnostic yield of RLS, if any, through administration of this expanded questionnaire. MATERIALS AND METHODS: The AIIMS RLS questionnaire for Indian patients (ARQIP) was developed in English language, and then translated into Hindi. All consecutive patients attending Neurology and sleep disorders clinic with complaints of leg discomfort were recruited in the study. Two examiners evaluated all patients with complaints of leg discomfort seen by a senior Sleep Medicine expert, one using only IRLSSG diagnostic criteria and the other using the ARQIP. Patients were categorized as RLS or "no-RLS" by the expert, and this was considered as the "standard" for analysis. RESULTS: A total of 155 participants (78 males, 50.3%) with a mean age of 44.1 ± 14.5 years were enrolled. A total of 105 patients were diagnosed as having RLS (group 1) and the rest as having "non-RLS" (group 2). The ARQIP was found to have a much higher sensitivity (100% vs 73%), specificity (44% vs 32.7%), negative predictive value (100% vs 36.4%), and positive predictive value (79% vs 70%) compared to the standard questionnaire. The diagnostic yield of this tool was 26.7% (Confidence interval = 100-73.3). CONCLUSIONS: The ARQIP for RLS diagnosis, validated in this study, has been observed to have a high sensitivity and a negative predictive value with a high diagnostic accuracy.