A retrospective analysis of hand tapping as a longitudinal marker of disease progression in Huntington's disease.

BACKGROUND: Current clinical assessments of motor function in Huntington's Disease (HD) rely on subjective ratings such as the Unified Huntington's Disease Rating scale (UHDRS). The ability to track disease progression using simple, objective, inexpensive, and robust measures would be beneficial. METHODS: One objective measure of motor performance is hand-tapping. Over the last 14 years we have routinely collected, using a simple device, the number of taps made by the right and left hand over 30 seconds in HD patients attending our NHS clinics. RESULTS: Here we report on a longitudinal cohort of 237 patients, which includes patients at all stages of the disease on a wide range of drug therapies. Hand tapping in these patients declines linearly at a rate of 5.1 taps per year (p < 0.0001; 95% CI = 3.8 to 6.3 taps), and for each additional year of age patients could perform 0.9 fewer taps (main effect of age: p = 0.0007; 95% CI = 0.4 to 1.4). Individual trajectories can vary widely around this average rate of decline, and much of this variation could be attributed to CAG repeat length. Genotype information was available for a subset of 151 patients, and for each additional repeat, patients could perform 5.6 fewer taps (p < 0.0001; 95% CI = 3.3 to 8.0 taps), and progressed at a faster rate of 0.45 fewer taps per year (CAG by time interaction: p = 0.008; 95% CI = 0.12 to 0.78 taps). In addition, for each unit decrease in Total Functional Capacity (TFC) within individuals, the number of taps decreased by 6.3 (95% CI = 5.4 to 7.1, p < 0.0001). CONCLUSIONS: Hand tapping is a simple, robust, and reliable marker of disease progression. As such, this simple motor task could be a useful tool by which to assess disease progression as well therapies designed to slow it down.

Impacts of gait freeze on quality of life in Parkinson's disease, from the perspectives of patients and their carers.

BACKGROUND: The World Health Organisation (WHO) reports that morbidity and mortality due to Parkinson's disease (PD) are increasing faster than for other neurodegenerative conditions. People with Parkinson's (PwP) present with a variety of motor symptoms, such as tremor, bradykinesia, and rigidity. Freezing of gait (FoG) is a significant motor symptom that manifests as temporary episodes of inability to move one's feet, despite the intention to walk. AIMS: This study examined the impact of FoG on quality of life (QoL) within an Irish cohort of PwP, from the perspectives of both PwP and their carers, using validated questionnaires that had been adapted for online use. METHODS: PwP and their carers were recruited by outreach to the Irish Parkinson's Community. Anonymous online questionnaires were distributed, which combined a demographic survey with several clinically validated surveys, including Freezing of Gait Questionnaire (FoG-Q), Parkinson's Disease Questionnaire 8 (PDQ-8), and Parkinson's Disease Carer Questionnaire (PDQ-C). RESULTS: There was a strong correlation (p < 0.001) between severity of FoG and lower QoL among PwP. Significant correlation was also found between FoG severity and several motor symptoms, such as postural instability and difficulty with balance, and non-motor symptoms, such as cognitive changes and pain/discomfort. FoG severity correlated with disease progression. Significant correlation was also found between FoG and symptoms, as assessed from the perspective of the patients' carers. CONCLUSIONS: This study shows that FoG is a significant detriment to the QoL of PwP, from the perspectives of patients and carers. This method of assessing FoG and QoL using online questionnaires has potential to enhance the reach and flexibility of this type of research. These findings will inform future studies on larger cohorts and highlight unmet clinical needs in PwP.

Intensive training programme improves handwriting in a community cohort of people with Parkinson's disease.

BACKGROUND: People with Parkinson's disease (PwP) often report problems with their handwriting before they receive a formal diagnosis. Many PwP suffer from deteriorating handwriting throughout their illness, which has detrimental effects on many aspects of their quality of life. AIMS: To assess a 6-week online training programme aimed at improving handwriting of PwP. METHODS: Handwriting samples from a community-based cohort of PwP (n = 48) were analysed using systematic detection of writing problems (SOS-PD) by two independent raters, before and after a 6-week remotely monitored physiotherapy-led training programme. Inter-rater variability on multiple measures of handwriting quality was analysed. The handwriting data was analysed using pre-/post-design in the same individuals. Multiple aspects of the handwriting samples were assessed, including writing fluency, transitions between letters, regularity in letter size, word spacing, and straightness of lines. RESULTS: Analysis of inter-rater reliability showed high agreement for total handwriting scores and letter size, as well as speed and legibility scores, whereas there were mixed levels of inter-rater reliability for other handwriting measures. Overall handwriting quality (p = 0.001) and legibility (p = 0.009) significantly improved, while letter size (p = 0.012), fluency (p = 0.001), regularity of letter size (p = 0.009), and straightness of lines (p = 0.036) were also enhanced. CONCLUSIONS: The results of this study show that this 6-week intensive remotely-monitored physiotherapy-led handwriting programme improved handwriting in PwP. This is the first study of its kind to use this tool remotely, and it demonstrated that the SOS-PD is reliable for measuring handwriting in PwP.

The motor and cognitive features of Parkinson's disease in patients with concurrent Gaucher disease over 2 years: a case series.

We report the cognitive features and progression of Parkinson's disease (PD) in five patients with concurrent Gaucher disease. The patients presented at an earlier age than patients with sporadic PD, as previously noted by others; but in contrast to many previous reports, our patients followed a variable clinical course. While two patients developed early cognitive deficits and dementia, three others remained cognitively intact over the follow-up period. Thus, in this small case series, PD in the context of GD more closely resembles idiopathic PD in terms of its clinical heterogeneity in contrast to PD associated with GBA heterozygote mutations.

Dermal fibroblasts from patients with Parkinson's disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations.

Background: Recently, the development of Parkinson's disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Methods: We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.

REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways.

Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease-specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient-derived material for large-scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts. Via functional experiments where we overexpress and knockdown the REST-controlled neuron-specific microRNAs miR-9 and miR-124, we show that the effect of REST inhibition is only partially mediated via microRNA up-regulation. Transcriptional analysis confirmed that REST knockdown activates an overlapping subset of neuronal genes as microRNA overexpression and also a distinct set of neuronal genes that are not activated via microRNA overexpression. Based on this, we developed an optimized one-step method to efficiently reprogram dermal fibroblasts from elderly individuals using a single-vector system and demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's, as well as Alzheimer's disease.

The Genetic Basis of Cognitive Impairment and Dementia in Parkinson's Disease.

Cognitive dysfunction is a common feature of Parkinson's disease (PD) with mild cognitive impairment affecting around a quarter of patients in the early stages of their disease, and approximately half developing dementia by 10 years from diagnosis. However, the pattern of cognitive impairments and their speed of evolution vary markedly between individuals. While some of this variability may relate to extrinsic factors and comorbidities, inherited genetic heterogeneity is also known to play an important role. A number of common genetic variants have been identified, which contribute to cognitive function in PD, including variants in catechol-O-methyltransferase, microtubule-associated protein tau, and apolipoprotein E. Furthermore, rarer mutations in glucocerebrosidase and α-synuclein and are strongly associated with dementia risk in PD. This review explores the functional impact of these variants on cognition in PD and discusses how such genotype-phenotype associations provide a window into the mechanistic basis of cognitive heterogeneity in this disorder. This has consequent implications for the development of much more targeted therapeutic strategies for cognitive symptoms in PD.

Novel Nut and Bolt Task Quantifies Motor Deficits in Premanifest and Manifest Huntington's Disease.

BACKGROUND: We investigated the use of a simple novel nut and bolt task in premanifest and manifest Huntington's disease (HD) patients to detect and quantify motor impairments at all stages of the disease. METHODS: Premanifest HD (n=24), manifest HD (n=27) and control (n=32) participants were asked to screw a nut onto a bolt in one direction, using three different sized bolts with their left and right hand in turn. RESULTS: We identified some impairments at all stages of HD and in the premanifest individuals, deficits in the non-dominant hand correlated with disease burden scores. CONCLUSION: This simple, cheap motor task was able to detect motor impairments in both premanifest and manifest HD and as such might be a useful quantifiable measure of motor function for use in clinical studies.

The Addenbrooke's Cognitive Examination-Revised accurately detects cognitive decline in Huntington's disease.

Cognitive features, which begin before manifestation of the motor features, are an integral part of Huntington's disease and profoundly affect quality of life. A number of neuropsychological batteries have been used to assess this aspect of the condition, many of which are difficult to administer and time consuming, especially in advanced disease. We, therefore, investigated a simple and practical way to monitor cognition using the Addenbrooke's Cognitive Examination-Revised (ACE-R) in 126 manifest Huntington's disease patients, 28 premanifest gene carriers and 21 controls. Using this test, we demonstrated a selective decrease in phonemic, but not semantic, fluency in premanifest participants Cognitive decline in manifest Huntington's disease varied according to disease severity with extensive cognitive decline observed in early-stage Huntington's disease patients, indicating that this would be an optimal stage for interventions designed to halt cognitive decline, and lesser changes in the advanced cases. We next examined cognitive performance in patients prescribed antidopaminergic drugs as these drugs are known to decrease cognition when administered to healthy volunteers. We paradoxically found that these drugs may be beneficial, as early-stage Huntington's disease participants in receipt of them had improved attention and Mini-Mental State Examination scores. In conclusion, this is the first study to test the usefulness of the ACE-R in a Huntington's disease population and demonstrates that this is a brief, inexpensive and practical way to measure global cognitive performance in clinical practice with potential use in clinical trials.