A Novel PINK1 p.F385S Loss-of-Function Mutation in an Indian Family with Parkinson's Disease.

BACKGROUND: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. OBJECTIVE: The aim of this study was to characterize a novel phosphatase tensin homolog-induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family. METHODS: Exome sequencing of a well-characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. RESULTS: We identified a homozygous chr1:20648535-20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved Deutsche Forschungsgemeinschaft (DFG) motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. CONCLUSIONS: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Understanding the role of genetic variability in LRRK2 in Indian population.

BACKGROUND: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. OBJECTIVES: To resolve the role of LRRK2 in the Indian population. METHODS: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. RESULTS: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. CONCLUSIONS: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society.

Spermine protects alpha-synuclein expressing dopaminergic neurons from manganese-induced degeneration.

Manganese exposure is among the many environmental risk factors linked to the progression of neurodegenerative diseases, such as manganese-induced parkinsonism. In animal models, chronic exposure to manganese causes loss of cell viability, neurodegeneration, and functional deficits. Polyamines, such as spermine, have been shown to rescue animals from age-induced neurodegeneration in an autophagy-dependent manner; nonetheless, it is not understood whether polyamines can prevent manganese-induced toxicity. In this study, we used two model systems, the Caenorhabditis elegans UA44 strain and SK-MEL-28 cells, both expressing the protein alpha-synuclein (α-syn) to determine whether spermine could ameliorate manganese-induced toxicity. Manganese caused a substantial reduction in the viability of SK-MEL-28 cells and hastened neurodegeneration in the UA44 strain. Spermine protected both the SK-MEL-28 cells and the UA44 strain from manganese-induced toxicity. Spermine also reduced the age-associated neurodegeneration observed in the UA44 strain compared with a control strain without α-syn expression and led to improved avoidance behavior in a functional assay. Treatment with berenil, an inhibitor of polyamine catabolism, which leads to increased intracellular polyamine levels, also showed similar cellular protection against manganese toxicity. While both translation blocker cycloheximide and autophagy blocker chloroquine caused a reduction in the cytoprotective effect of spermine, transcription blocker actinomycin D had no effect. This study provides new insights on the effect of spermine in preventing manganese-induced toxicity, which is most likely via translational regulation of several candidate genes, including those of autophagy. Thus, our results indicate that polyamines positively influence neuronal health, even when exposed to high levels of manganese and α-syn, and supplementing polyamines through diet might delay the onset of diseases involving degeneration of dopaminergic neurons.

Severity of Writer's Cramp is Related to Faulty Motor Preparation.

We characterized, in 37 writer's cramp (WC) patients and 14 healthy volunteers (HV), the buildup of motor representations contralateral ("intended") and ispsilateral ("unintended") to the movement to be produced and the excitability changes in left primary motor cortex during the early reaction time (RT) of a pre-cued reaching movement to pick up a pen with either hand to write. We also tested the excitability of interhemispheric pathways from right dorsal premotor and motor cortices to left motor cortex. During early RT (1) the motor cortex excitability of unintended muscle representations did not decrease in patients as in HV and (2) the connection from the contralateral dorsal premotor cortex to the "intended" motor representation did not function in patients. In HV, the efficiency of intracortical GABA-ergic circuits at rest predicted the degree of excitability changes in the intended motor representation in the early RT. This was not true in patients who had lower efficiency of GABA-ergic circuits. Interestingly, the more severe was the writing impairment, the higher was the level of excitability in the intended and unintended motor representations. It demonstrates, for the first time, that abnormal motor preparation influences the severity of the writing impairment in WC patients.

Deep brain stimulation for movement disorders.

Deep Brain Stimulation (DBS) was introduced into clinical practice nearly four decades ago and is currently the standard of care for patients with Parkinson's disease experiencing motor complications. Apart from this, it has several other established and emerging applications in movement disorders. The exact mechanisms by which DBS provides relief in movement disorders are still unclear; disruption of pathological neuronal synchrony and abnormal information flow through the neuronal circuits involved, are the most likely underlying mechanisms. DBS has been established to be a relatively safe procedure if patients are carefully selected and followed up by experienced multidisciplinary teams. Alternatives to the traditional stereotactic frame based techniques of lead implantation are emerging, and these, along with the other recent technological advances, are likely to extend the availability of this therapy to an increasing number of patients in the future.

Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex.

Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field.

The decade after subthalamic stimulation in advanced Parkinson's disease: A balancing act.

AIM: The duration of improvement in quality of life after subthalamic nucleus deep brain stimulation (STN DBS) for Parkinson's disease (PD) and the presurgical identification of factors predicting sustained clinical benefits have implications in patient selection and timing of surgery. These aspects were assessed in patients who underwent yearly assessment for at least 7 years after surgery. MATERIALS AND METHODS: The quality of life, motor and cognitive outcomes of 25 patients who completed the 7-year assessment, and 12 patients who completed the 10-year assessment, were analyzed. RESULTS: The improvement in quality of life was sustained only for 5 years, while the severity of motor signs and motor fluctuations remained reduced at 7 and 10 years. Tremor and rigidity showed more enduring reduction than bradykinesia and axial signs. The dose reduction in medications could be maintained until 7 years, by which time, the axial scores were worse than that seen at the pre-DBS levels. At 10 years, a higher levodopa requirement and recurrence of dyskinesias were noted. Patients with greater pre-DBS levodopa-responsive motor signs had greater long-term motor improvement. CONCLUSIONS: STN DBS performed in patients with advanced motor fluctuations and severe dyskinesias provide only an average of 5 years of quality of life improvement. STN DBS in patients with motor signs that are less responsive to levodopa results in shorter duration of clinical benefits. The improvements in the severity of motor fluctuations, rigidity, and tremor are the most enduring benefits of STN DBS that last a decade . However, these are offset by worsening axial and cognitive functions, bradykinesia, a higher levodopa requirement, and recurrence of dyskinesias by the end of the decade.

Cerebellar sensory processing alterations impact motor cortical plasticity in Parkinson's disease: clues from dyskinetic patients.

The plasticity of primary motor cortex (M1) in patients with Parkinson's disease (PD) and levodopa-induced dyskinesias (LIDs) is severely impaired. We recently reported in young healthy subjects that inhibitory cerebellar stimulation enhanced the sensorimotor plasticity of M1 that was induced by paired associative stimulation (PAS). This study demonstrates that the deficient sensorimotor M1 plasticity in 16 patients with LIDs could be reinstated by a single session of real inhibitory cerebellar stimulation but not sham stimulation. This was evident only when a sensory component was involved in the induction of plasticity, indicating that cerebellar sensory processing function is involved in the resurgence of M1 plasticity. The benefit of inhibitory cerebellar stimulation on LIDs is known. To explore whether this benefit is linked to the restoration of sensorimotor plasticity of M1, we conducted an additional study looking at changes in LIDs and PAS-induced plasticity after 10 sessions of either bilateral, real inhibitory cerebellar stimulation or sham stimulation. Only real and not sham stimulation had an antidyskinetic effect and it was paralleled by a resurgence in the sensorimotor plasticity of M1. These results suggest that alterations in cerebellar sensory processing function, occurring secondary to abnormal basal ganglia signals reaching it, may be an important element contributing to the maladaptive sensorimotor plasticity of M1 and the emergence of abnormal involuntary movements.

Validity of Montreal Cognitive Assessment in non-english speaking patients with Parkinson's disease.

BACKGROUND: The Montreal Cognitive Assessment is a brief and easy screening tool for accurately testing cognitive dysfunction in Parkinson's disease. We tested its validity for use in non-English (Malayalam) speaking patients with Parkinson's disease. MATERIALS AND METHODS: We developed a Malayalam (a south-Indian language) version of Montreal Cognitive Assessment and applied to 70 patients with Parkinson's disease and 60 age- and education-matched healthy controls. Metric properties were assessed, and the scores were compared with the performance in validated Malayalam versions of Mini Mental Status Examination and Addenbrooke's Cognitive Examination. RESULTS: The Montreal Cognitive Assessment-Malayalam showed good internal consistency and test-retest reliability and its scores correlated with Mini Mental Status Examination (patients: R = 0.70; P < 0.001; healthy controls: R = 0.26; P = 0.04) and Addenbrooke's Cognitive Examination (patients: R = 0.8; P < 0.001; healthy controls: R = 0.52; P < 0.001) scores. CONCLUSION: This study establishes the reliability of cross-cultural adaptation of Montreal Cognitive Assessment for assessing cognition in Malayalam-speaking Parkinson's disease patients for early screening and potential future interventions for cognitive dysfunction.

A case of misplaced permacath dialysis catheter.

Central venous placement using ultrasound has significantly reduced the complications associated with blind puncture. The central venous catheter can still get misplaced if it follows an anomalous route after appropriate puncture of desired vessel. We report a case of misplaced dialysis catheter into the accessory hemiazygos vein which resulted in a large hemothorax, and we recommend the routine use of a fluoroscope for placement of dialysis catheters so as to avoid serious complications.

Defective cerebellar control of cortical plasticity in writer's cramp.

A large body of evidence points to a role of basal ganglia dysfunction in the pathophysiology of dystonia, but recent studies indicate that cerebellar dysfunction may also be involved. The cerebellum influences sensorimotor adaptation by modulating sensorimotor plasticity of the primary motor cortex. Motor cortex sensorimotor plasticity is maladaptive in patients with writer's cramp. Here we examined whether putative cerebellar dysfunction in dystonia is linked to these patients' maladaptive plasticity. To that end we compared the performances of patients and healthy control subjects in a reaching task involving a visuomotor conflict generated by imposing a random deviation (-40° to 40°) on the direction of movement of the mouse/cursor. Such a task is known to involve the cerebellum. We also compared, between patients and healthy control subjects, how the cerebellum modulates the extent and duration of an ongoing sensorimotor plasticity in the motor cortex. The cerebellar cortex was excited or inhibited by means of repeated transcranial magnetic stimulation before artificial sensorimotor plasticity was induced in the motor cortex by paired associative stimulation. Patients with writer's cramp were slower than the healthy control subjects to reach the target and, after having repeatedly adapted their trajectories to the deviations, they were less efficient than the healthy control subjects to perform reaching movement without imposed deviation. It was interpreted as impaired washing-out abilities. In healthy subjects, cerebellar cortex excitation prevented the paired associative stimulation to induce a sensorimotor plasticity in the primary motor cortex, whereas cerebellar cortex inhibition led the paired associative stimulation to be more efficient in inducing the plasticity. In patients with writer's cramp, cerebellar cortex excitation and inhibition were both ineffective in modulating sensorimotor plasticity. In patients with writer's cramp, but not in healthy subjects, behavioural parameters reflecting their capacity for adapting to the rotation and for washing-out of an earlier adaptation predicted the efficacy of inhibitory cerebellar conditioning to influence sensorimotor plasticity: the better the online adaptation, the smaller the influence of cerebellar inhibitory stimulation on motor cortex plasticity. Altered cerebellar encoding of incoming afferent volleys may result in decoupling the motor component from the afferent information flow, and also in maladjusted sensorimotor calibration. The loss of cerebellar control over sensorimotor plasticity might also lead to building up an incorrect motor program to specific adaptation tasks such as writing.

A Review on Implantable Neuroelectrodes.

The efficacy of every neuromodulation modality depends upon the characteristics of the electrodes used to stimulate the chosen target. The geometrical, chemical, mechanical and physical configuration of electrodes used in neurostimulation affects several performance attributes like stimulation efficiency, selectivity, tissue response, etc. The efficiency of stimulation in relation to electrode impedance is influenced by the electrode material and/or its geometry. The nature of the electrode material determines the charge transfer across the electrode-tissue interface, which also relates to neuronal tissue damage. Electrode morphology or configuration pattern can facilitate the modulation of extracellular electric field (field shaping). This enables selective activation of neurons and minimizes side effects. Biocompatibility and biostability of the electrode materials or electrode coating have a role in glial formation and tissue damage. Mechanical and electrochemical stability (corrosion resistance) determines the long-term efficacy of any neuromodulation technique. Here, a review of electrodes typically used for implantable neuromodulation is discussed. Factors affecting the performance of electrodes like stimulation efficiency, selectivity and tissue responses to the electrode-tissue interface are discussed. Technological advancements to improve electrode characteristics are also included.

Quantifying abnormal writing kinematics in writer's cramp using a novel software platform.

BACKGROUND: Writer's cramp is a task-specific focal hand dystonia, which is diagnosed clinically. Quantification of defect in WC is done using clinical scales, while digitized platforms are lacking. OBJECTIVE: To design and test a platform that can differentiate and quantify the abnormal kinematics of writing using a software interface and to validate it in adult-onset isolated writer's cramp (WC). METHODS: A native platform was designed using Java and Wacom Intuos pro tablet and the data analyzed using a MATLAB-based platform called Large Data-Based Evaluation of Kinematics in Handwriting (LEKH). We standardized this new platform by comparing the handwriting between patients with WC and age, and gender and education-matched healthy controls, using standard tasks to assess the kinematics. RESULTS: Comparison of the writing of right-handed WC patients (N = 21) and 39 healthy controls (N = 39) showed that patients differed from controls in the frequency of strokes (P < 0.001), number of inversions of velocity (P < 0.001), number of breaks (P = 0.02), air time and paper time (P < 0.001). CONCLUSIONS: Using the LEKH platform, the kinematic profile of patients with WC could be differentiated from healthy controls. Studies in larger samples will be needed to derive statistical models that can differentiate the flexion and extension types of WC which can help in muscle selection and to quantify the effects of treatment.

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.

Acute dopamine boost has a negative effect on plasticity of the primary motor cortex in advanced Parkinson's disease.

Plasticity of primary motor cortex is severely impaired in Parkinson's disease and chronic dopaminergic treatment is reported not to rescue it. The effect of an acute dose of levodopa on cortical plasticity reported so far is variable. In this study, it was hypothesized that cortical plasticity would be restored in Parkinson's disease as a long duration response to treatment in stable responders while those with motor complications would have a reduction or loss of plasticity similar to the decay of long duration response of motor signs. Patients were carefully stratified based on their motor response to levodopa into stable responders (n=17), fluctuating non-dyskinetics (n=18) and fluctuating dyskinetics (n=20). Theta burst stimulation was applied to the motor cortex to induce long-term potentiation and long-term depression-like plasticity in both OFF and ON conditions. In OFF, stable responders could express both types of plasticity, fluctuating non-dyskinetics had long-term potentiation, but no long-term depression and both types of plasticity were lost in fluctuating dyskinetics. This suggests the presence of a long duration response in early stages of levodopa treatment and a gradual loss of chronic treatment benefit on plasticity, particularly for long-term depression, when motor complications develop. An acute dose of levodopa led to a worsening of long-term potentiation in fluctuating non-dyskinetic patients, and it did not have any effect on the plasticity that was absent in OFF in the fluctuating dyskinetic patients. Acute dosing led to a worsening of long-term depression in all the groups. In the fluctuating dyskinetic patients, there was a paradoxical potentiation instead of depression. Our results suggest that an acute non-physiological dopamine boost has a negative effect on cortical plasticity as disease advances. We propose that the loss of long duration response and the negative effect of acute doses on cortical plasticity with progression of disease may contribute to the pathophysiology of motor complications. Repeated non-physiological surges in synaptic dopamine during acute levodopa dosing could potentially lead to persistent dysfunction of key enzymes of the intracellular signalling cascade that are involved in the induction and maintenance of both forms of plasticity.

Cerebellar and basal ganglia structural connections in humans: Effect of aging and relation with memory and learning.

Introduction: The cerebellum and basal ganglia were initially considered anatomically distinct regions, each connected via thalamic relays which project to the same cerebral cortical targets, such as the motor cortex. In the last two decades, transneuronal viral transport studies in non-human primates showed bidirectional connections between the cerebellum and basal ganglia at the subcortical level, without involving the cerebral cortical motor areas. These findings have significant implications for our understanding of neurodevelopmental and neurodegenerative diseases. While these subcortical connections were established in smaller studies on humans, their evolution with natural aging is less understood. Methods: In this study, we validated and expanded the previous findings of the structural connectivity within the cerebellum-basal ganglia subcortical network, in a larger dataset of 64 subjects, across different age ranges. Tractography and fixel-based analysis were performed on the 3 T diffusion-weighted dataset using Mrtrix3 software, considering fiber density and cross-section as indicators of axonal integrity. Tractography of the well-established cerebello-thalamo-cortical tract was conducted as a control. We tested the relationship between the structural white matter integrity of these connections with aging and with the performance in different domains of Addenbrooke's Cognitive Examination. Results: Tractography analysis isolated connections from the dentate nucleus to the contralateral putamen via the thalamus, and reciprocal tracts from the subthalamic nucleus to the contralateral cerebellar cortex via the pontine nuclei. Control tracts of cerebello-thalamo-cortical tracts were also isolated, including associative cerebello-prefrontal tracts. A negative linear relationship was found between the fiber density of both the ascending and descending cerebellum-basal ganglia tracts and age. Considering the cognitive assessments, the fiber density values of cerebello-thalamo-putaminal tracts correlated with the registration/learning domain scores. In addition, the fiber density values of cerebello-frontal and subthalamo-cerebellar (Crus II) tracts correlated with the cognitive assessment scores from the memory domain. Conclusion: We validated the structural connectivity within the cerebellum-basal ganglia reciprocal network, in a larger dataset of human subjects, across wider age range. The structural features of the subcortical cerebello-basal ganglia tracts in human subjects display age-related neurodegeneration. Individual morphological variability of cerebellar tracts to the striatum and prefrontal cortex was associated with different cognitive functions, suggesting a functional contribution of cerebellar tracts to cognitive decline with aging. This study offers new perspectives to consider the functional role of these pathways in motor learning and the pathophysiology of movement disorders involving the cerebellum and striatum.

Depotentiation of associative plasticity is intact in Parkinson's disease with mild dyskinesia.

OBJECTIVE: Depotentiation of homosynaptic plasticity of the primary motor cortex (M1) is impaired in patients with Parkinson's disease (PD) who have developed dyskinesias. In this exploratory study, we tested whether this holds true for heterosynaptic plasticity induced by paired associative stimulation (PAS). METHODS: Dyskinetic (n=11) and Non-dyskinetic (n=11), levodopa-treated PD patients were tested in M1 with PAS25ms alone, PAS25ms preceded by continuous theta-burst stimulation of the cerebellum (cTBSCB-PAS) as a method to evoke a larger plastic response in M1, and each of these two interventions followed by a depotentiation protocol (cTBS150pulses) to M1. RESULTS: PAS25ms and cTBSCB-PAS25ms induced long-term potentiation (LTP)-like responses in both groups of PD patients, with cTBSCB significantly boosting the plastic response. Both these LTP-like responses could be depotentiated by cTBS150, in both groups of patients. CONCLUSIONS: Cerebellar stimulation enhances heterosynaptic plasticity in PD irrespective of dyskinesias. Depotentiation mechanisms of heterosynaptic plasticity are preserved in PD patients, including those with dyskinesias. The lack of depotentiation of LTP-like plasticity as a hallmark of dyskinesia in PD patients is not absolute. The ability to depotentiate LTP-like plasticity may potentially depend on the type of plasticity induced (homosynaptic or heterosynaptic), the circuits involved in these responses and the adequacy of dopaminergic stimulation.

Cognitive outcome following bilateral subthalamic nucleus deep brain stimulation for Parkinson's disease-a comparative observational study in Indian patients.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms and motor complications of Parkinson's disease (PD). The intervention is expected to result in some cognitive changes, the nature of which is not uniform across the studies which have reported them. PD itself is associated with progressive cognitive decline and hence longitudinal follow-up studies with medically managed control group of patients are needed to explore the cognitive deficits attributable to DBS. METHODS: We conducted a prospective comparative observational study to assess the effects of bilateral STN DBS on cognition. Cognitive functions were assessed at baseline and after a minimum of two years after surgery, and compared with baseline and follow-up assessments in patients on medical management alone. RESULTS: Thirty-four patients with PD who underwent bilateral STN DBS and thirty-four medically managed patients participated in the study. At a mean follow-up of around 33 months, we found a significant decline in verbal fluency scores in the DBS group compared to those on medical management alone (1.15 ± 1.23 vs 0.59 ± 0.93, p = 0.034) and a trend for decline was noted in digit span test. There was no difference in the performance in tests addressing other cognitive domains, or tests of global cognitive function. No patient developed dementia. Motor functions and activities of daily living (ADL) were significantly better in the surgical group. CONCLUSION: STN DBS results in minor deficits in executive functions, particularly verbal fluency. These may be inconsequential, considering the marked improvement in motor functions and ADL.

Gender differences in progressive supranuclear palsy.

The gender differences in progressive supranuclear palsy (PSP) are not extensively studied. The objective of this study was to determine the gender differences in the phenotypic expression and progression in PSP. We did a retrospective review of medical records of patients diagnosed with PSP over a 21-year period. The interval between disease onset and attainment of the five clinical disability milestones namely wheel chair dependency, unintelligible speech, severe dysphagia, severe cognitive impairment and urinary catheterization was used to determine the progression. Data was analysed from the case records of 334 patients with PSP. 209 patients (62.2%) were male and 125 (37.4%) among the patients were women (male:female ratio = 1.6:1). Males had older age at onset with longer duration of illness at time of presentation. Tremors were more common, PSP-P phenotype was more frequent and time to attain wheelchair dependency was earlier in males. Falls within 1 year of disease onset, apathy and executive dysfunction were more frequent and time to attain unintelligible speech, severe dysphagia and cognitive impairment were earlier in females. This study in a large cohort of clinically diagnosed cases of PSP has showed that gender differences exist in PSP in terms of clinical characteristics, progression of the disease.