Kannan Nithi

The influence of age and gender on motor and non-motor features of early Parkinson's disease: initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort.

BACKGROUND Identifying factors influencing phenotypic heterogeneity in Parkinsons Disease is crucial for understanding variability in disease severity and progression. Age and gender are two most basic epidemiological characteristics, yet their effect on expression of PD symptoms is not fully defined. We aimed to delineate effects of age and gender on the phenotype in an incident cohort of PD patients and healthy controls from the Oxford Parkinson Disease Centre (OPDC). METHODS Clinical features, including demographic and medical characteristics and non-motor and motor symptoms, were analyzed in a group of PD patients within 3 years of diagnosis and a group of healthy controls from the OPDC cohort. Disease features were stratified according to age and compared between genders, controlling for effects of common covariates. RESULTS 490 PD patients and 176 healthy controls were analyzed. Stratification by age showed increased disease severity with age on motor scales. Some non-motor features showed similar trend, including cognition and autonomic features. Comparison across genders highlighted a pattern of increased severity and greater symptom symmetricality in the face, neck and arms in men with women having more postural problems. Amongst the non-motor symptoms, men had more cognitive impairment, greater rate of REM behavior disorder (RBD), more orthostatic hypotension and sexual dysfunction. CONCLUSIONS Age in PD is a strong factor contributing to disease severity even after controlling for the effect of disease duration. Gender-related motor phenotype can be defined by a vertical split into more symmetrical upper-body disease in men and disease dominated by postural symptoms in women.

REM sleep behaviour disorder is associated with worse quality of life and other non-motor features in early Parkinson's disease

Background Concomitant REM sleep behaviour disorder (RBD) is commonly observed in patients with Parkinsons disease (PD). Although the brainstem structures responsible for the symptoms of RBD correspond to the premotor stages of PD, the association of RBD with motor and non-motor features in early PD remains unclear. Methods The study evaluated 475 patients with PD within 3.5 years of diagnosis for the presence of probable RBD (pRBD) using the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A neurologist and a trained research nurse carried out evaluation of each participant blinded to the results of the RBDSQ. Standardised rating scales for motor and non-motor features of PD, as well as health-related quality of life measures, were assessed. Multiple linear and logistic regression analyses were used to determine the relationship between pRBD and a variety of outcomes, controlling for confounding factors. Results The overall frequency of pRBD was 47.2% (95% CI 42.7% to 51.9%). None of the patients had a previous diagnosis of RBD. Patients with PD and concomitant pRBD did not differ on motor phenotype and scored comparably on the objective motor scales, but reported problems with motor aspects of daily living more frequently. Adjusted for age, sex, disease duration and smoking history, pRBD was associated with greater sleepiness (p=0.001), depression (p=0.001) and cognitive impairment (p=0.006). Conclusions pRBD is common and under-recognised in early PD. It is associated with increased severity and frequency of non-motor features, poorer subjective motor performance and a greater impact on health-related quality of life.

Peripheral and central motor conduction in amyotrophic lateral sclerosis.

Conventional peripheral motor conduction studies and transcranial magnetic stimulation (TMS) studies, to measure central motor conduction time (CMCT), to the first dorsal interosseous muscle (FDI) were performed on 65 patients with amyotrophic lateral sclerosis (ALS). The hands of each patient were classified into one of four groups depending on the presence of physical signs of lower motor neurone (LMN) and/or upper motor neurone (UMN) involvement. Statistical analysis was made of the results from patients compared with previously established normal values and with those from a control group of 53 normal subjects. Results between the four groups of patients were compared in order to assess any correlation between neurophysiological findings and physical signs. A reduction in the amplitude of compound muscle action potentials (CMAP), prolongation of distal motor latency (DML) and F wave latency were found in 36%, 34% and 19% of hands respectively. These abnormalities were more common in hands with LMN signs. In nine hands, prolongation of DML occurred in the absence of muscle wasting or weakness. CMCT abnormalities were present in 17% of patients with ALS but did not appear to correlate with physical signs.

Predictors of cognitive impairment in an early stage Parkinson's disease cohort.

The impact of Parkinsons disease (PD) dementia is substantial and has major functional and socioeconomic consequences. Early prediction of future cognitive impairment would help target future interventions. The Montreal Cognitive Assessment (MoCA), the Mini‐Mental State Examination (MMSE), and fluency tests were administered to 486 patients with PD within 3.5 years of diagnosis, and the results were compared with those from 141 controls correcting for age, sex, and educational years. Eighteen‐month longitudinal assessments were performed in 155 patients with PD. The proportion of patients classified with normal cognition, mild cognitive impairment (MCI), and dementia varied considerably, depending on the MoCA and MMSE thresholds used. With the MoCA total score at screening threshold, 47.7%, 40.5%, and 11.7% of patients with PD were classified with normal cognition, MCI, and dementia, respectively; by comparison, 78.7% and 21.3% of controls had normal cognition and MCI, respectively. Cognitive impairment was predicted by lower education, increased age, male sex, and quantitative motor and non‐motor (smell, depression, and anxiety) measures. Longitudinal data from 155 patients with PD over 18 months showed significant reductions in MoCA scores, but not in MMSE scores, with 21.3% of patients moving from normal cognition to MCI and 4.5% moving from MCI to dementia, although 13.5% moved from MCI to normal; however, none of the patients with dementia changed their classification. The MoCA may be more sensitive than the MMSE in detecting early baseline and longitudinal cognitive impairment in PD, because it identified 25.8% of those who experienced significant cognitive decline over 18 months. Cognitive decline was associated with worse motor and non‐motor features, suggesting that this reflects a faster progressive phenotype.

Parkinson's Disease Subtypes in the Oxford Parkinson Disease Centre (OPDC) Discovery Cohort.

Abstract Background: Within Parkinson’s there is a spectrum of clinical features at presentation which may represent sub-types of the disease. However there is no widely accepted consensus of how best to group patients. Objective: Use a data-driven approach to unravel any heterogeneity in the Parkinson’s phenotype in a well-characterised, population-based incidence cohort. Methods: 769 consecutive patients, with mean disease duration of 1.3 years, were assessed using a broad range of motor, cognitive and non-motor metrics. Multiple imputation was carried out using the chained equations approach to deal with missing data. We used an exploratory and then a confirmatory factor analysis to determine suitable domains to include within our cluster analysis. K-means cluster analysis of the factor scores and all the variables not loading into a factor was used to determine phenotypic subgroups. Results: Our factor analysis found three important factors that were characterised by: psychological well-being features; non-tremor motor features, such as posture and rigidity; and cognitive features. Our subsequent five cluster model identified groups characterised by (1) mild motor and non-motor disease (25.4%), (2) poor posture and cognition (23.3%), (3) severe tremor (20.8%), (4) poor psychological well-being, RBD and sleep (18.9%), and (5) severe motor and non-motor disease with poor psychological well-being (11.7%). Conclusion: Our approach identified several Parkinson’s phenotypic sub-groups driven by largely dopaminergic-resistant features (RBD, impaired cognition and posture, poor psychological well-being) that, in addition to dopaminergic-responsive motor features may be important for studying the aetiology, progression, and medication response of early Parkinson’s.

Changes in motor evoked potentials to short-interval paired transcranial magnetic stimuli in multiple sclerosis

OBJECTIVE Paired transcranial magnetic stimuli (TMS) were applied in 8 multiple sclerosis (MS) patients with asymmetrical clinical signs and in 8 healthy controls to test the hypothesis that the circuits responsible for the generation and transmission of I-waves are abnormal in the former group METHODS A figure-of-8 coil discharging through a Magstim 200/Bistim configuration delivered identical stimuli at an intensity 10% above the motor threshold of the relaxed first dorsal interosseous muscle. The interstimulus intervals (ISIs) used were varied in a pseudo-randomized fashion in steps of 0.2 ms between 1.0 and 5 ms. RESULTS In 9 of 12 unilateral studies in the control group, a pattern of 3 peaks of increased motor evoked potential size was found at ISIs of 1.2-1.6 ms, 2.4-3.2 ms and 4.4-5.0 ms. A similar pattern was present in only 5 of 12 studies in the patients (Fishers exact test, P = 0.1), while it was absent in all the 4 studies of the side with greater clinical involvement in patients (P = 0.01) CONCLUSION Our results suggest that I-wave generation is more likely to be defective in MS than in normal subjects, that this defect resides in the cortex, and that it correlates with severity of physical signs.

Delineating Nonmotor Symptoms in Early Parkinson's Disease and First-Degree Relatives

Nonmotor symptoms (NMS) are an important prodromal feature of Parkinsons disease (PD). However, their frequency, treatment rates, and impact on health‐related quality of life (HRQoL) in the early motor phase is unclear. Rates of NMS in enriched at‐risk populations, such as first‐degree PD relatives, have not been delineated. We assessed NMS in an early cohort of PD, first‐degree PD relatives and control subjects to address these questions. In total, 769 population‐ascertained PD subjects within 3.5 years of diagnosis, 98 first‐degree PD relatives, and 287 control subjects were assessed at baseline across the following NMS domains: (1) neuropsychiatric; (2) gastrointestinal; (3) sleep; (4) sensory; (5) autonomic; and (6) sexual. NMS were much more common in PD, compared to control subjects. More than half of the PD cases had hyposmia, pain, fatigue, sleep disturbance, or urinary dysfunction. NMS were more frequent in those with the postural instability gait difficulty phenotype, compared to the tremor dominant (mean total number of NMS 7.8 vs. 6.2; P < 0.001). PD cases had worse HRQoL scores than controls (odds ratio: 4.1; P < 0.001), with depression, anxiety, and pain being stronger drivers than motor scores. NMS were rarely treated in routine clinical practice. First‐degree PD relatives did not significantly differ in NMS, compared to controls, in this baseline study. NMS are common in early PD and more common in those with postural instability gait difficulty phenotype or on treatment. Despite their major impact on quality of life, NMS are usually under‐recognized and untreated.

Mapping motor cortex projections to single motor units in humans with transcranial magnetic stimulation

We devised a method to investigate the cortical organization of corticomotoneurons (CMs) to upper limb muscles. A spike‐triggering technique was used, in which a tonically discharging single motor unit (SMU) triggered transcranial magnetic stimulation (TMS) of motor cortex, and the probability of producing short‐latency discharges (primary excitatory responses [PERs]) was measured. PER probabilities were mapped in 34 SMUs, using a 16 cm2 scalp grid with the central reference point having a probability of 0.5. Maps showed a single optimum point of scalp stimulation and significant decreases in PER probability with shifts of 2 cm from this point, for all subjects. These findings suggest that the colony of CMs projecting to an individual SMN is contained within a small volume of motor cortex. Changes in PER probability with shifts in stimulation site may reflect the organization of other intracortical neurons mediating TMS activation of these CMs.

Personality and addictive behaviours in early Parkinson's disease and REM sleep behaviour disorder.

Introduction Changes in personality have been described in Parkinsons disease (PD), with suggestion that those with established disease tend to be risk averse with a disinclination for addictive behaviour. However, little is known about the earliest and prodromal stages. Personality and its relationship with addictive behaviours can help answer important questions about the mechanisms underlying PD and addiction. Methods 941 population-ascertained PD subjects within 3.5 years of diagnosis, 128 patients with rapid eye movement sleep behaviour disorder (RBD) and 292 control subjects were fully characterised for motor symptoms, non-motor symptoms and across the following 5 personality domains: 1) neuroticism 2) extraversion 3) conscientiousness 4) agreeableness 5) openness using the Big Five Inventory. Results Patients with early PD were more neurotic (p < 0.001), less extraverted (p < 0.001) and less open than controls (p < 0.001). RBD subjects showed the same pattern of being more neurotic (p < 0.001), less extraverted (p = 0.03) and less open (p < 0.001). PD patients had smoked less (p = 0.02) and drunk less alcohol (p = 0.03) than controls, but caffeine beverage consumption was similar. Being more extraverted (p < 0.001), more open (p < 0.001), and less neurotic (p < 0.001) predicted higher alcohol use, while being more extravert (p = 0.007) and less agreeable (p < 0.001) was associated with smoking more. Conclusions A similar pattern of personality changes is seen in PD and RBD compared to a control population. Personality characteristics were associated with addictive behaviours, suggestive of a common link, but the lower rates of addictive behaviours before and after the onset of motor symptoms in PD persisted after accounting for personality.

The tremor associated with non-paraproteinaemic acquired demyelinating polyneuropathy: A case study

Sirs: The association between tremor and neuropathy is most frequent in the chronic demyelinating neuropathies, particularly hereditary motor sensory neuropathy (HMSN) [5, 6] and IgM paraproteinaemic neuropathy with anti myelin associated glycoprotein (MAG) activity [7, 8]. We report a patient with disabling tremor associated with an acquired non-paraproteinaemic demyelinating polyneuropathy in whom resolution of the tremor correlated with resolution of the polyneuropathy following immunosuppressive therapy. A 48-year-old man presented with a two-year history of dysaesthesia in the feet and 3 months of disabling arm tremor and gait ataxia. He was unable to walk, feed or dress without assistance. There was no relevant past medical or drug history, no history of toxin exposure and no family history. Examination revealed a severe kinetic and postural tremor of the arms and gait ataxia. Muscle power and tone were normal and tendon reflexes absent. Pinprick sensation was blunted in the fingertips and below the knees, with vibration and proprioceptive loss confined to the feet. Cranial nerve and general examination were normal. Serum analysis, including immunoglobulins, was unremarkable. Neither Anti-MAG nor antiSulphoglucuronyl Paragloboside antibodies were detected. Cranial MRI was normal and the CSF was acellular with a protein of 0.41 g/l without oligoclonal bands. Subsequent to nerve conduction studies (NCS) suggesting a demyelinating neuropathy treatment was initiated with prednisolone 60 mg daily and a 5-day course of plasma exchange. After 2 weeks, and no change in disability, he was given 5 days of human IVIg (0.4 g/Kg/day). Improvement began 1 week later; one month from first starting treatment the tremor was only bothersome when performing fine tasks and he was able to walk unaided, at 6 months he considered himself unimpeded and by 9 months there was only minimal postural hand tremor and no other abnormal signs. Prednisolone dosage was slowly reduced. Pre-treatment NCS demonstrated absent sensory nerve action potentials and gross slowing and dispersion in motor nerves e. g. right median velocity – 6m/s. Magnetic stimulation assessed central motor conduction time as approximately 4.8 ms (normal). Visual evoked responses were well defined and of normal latency and cortical somatosensory evoked potentials from upper and lower limbs were indistinct and had a latency compatible with the peripheral delay. Rhythmic activity was shown in the right triceps, biceps, first dorsal interosseous and abductor pollicis brevis using surface EMG recordings. (Fig. 1c). Tremor frequency was higher in proximal muscles compared with distal (Fig. 1a). In parallel with the remarkable clinical improvement there was an increase in right median nerve conduction velocity to 31 m/s and an increase in tremor frequency. (Fig. 1b). An initial doubling of conduction velocity produced a doubling in tremor frequency, but a further threefold increase in velocity was associated with no further frequency change. LETTER TO THE EDITORS