Parkinson's disease is a progressive neurodegenerative movement disorder with a long latent phase and currently no disease-modifying treatments. Reliable predictive biomarkers that could transform ...efforts to develop neuroprotective treatments remain to be identified. Using UK Biobank, we investigated the predictive value of accelerometry in identifying prodromal Parkinson's disease in the general population and compared this digital biomarker with models based on genetics, lifestyle, blood biochemistry or prodromal symptoms data. Machine learning models trained using accelerometry data achieved better test performance in distinguishing both clinically diagnosed Parkinson's disease (n = 153) (area under precision recall curve (AUPRC) 0.14 ± 0.04) and prodromal Parkinson's disease (n = 113) up to 7 years pre-diagnosis (AUPRC 0.07 ± 0.03) from the general population (n = 33,009) compared with all other modalities tested (genetics: AUPRC = 0.01 ± 0.00, P = 2.2 × 10
; lifestyle: AUPRC = 0.03 ± 0.04, P = 2.5 × 10
; blood biochemistry: AUPRC = 0.01 ± 0.00, P = 4.1 × 10
; prodromal signs: AUPRC = 0.01 ± 0.00, P = 3.6 × 10
). Accelerometry is a potentially important, low-cost screening tool for determining people at risk of developing Parkinson's disease and identifying participants for clinical trials of neuroprotective treatments.
Understanding rare genetic brain disorders with overlapping neurological and psychiatric phenotypes is of increasing importance given the potential for developing disease models that could help to ...understand more common, polygenic disorders. However, the traditional clinical boundaries between neurology and psychiatry result in frequent segregation of these disorders into distinct silos, limiting cross-specialty understanding that could facilitate clinical and biological advances. In this Review, we highlight multiple genetic brain disorders in which neurological and psychiatric phenotypes are observed, but for which in-depth, cross-spectrum clinical phenotyping is rarely undertaken. We describe the combined phenotypes observed in association with genetic variants linked to epilepsy, dystonia, autism spectrum disorder and schizophrenia. We also consider common underlying mechanisms that centre on synaptic plasticity, including changes to synaptic and neuronal structure, calcium handling and the balance of excitatory and inhibitory neuronal activity. Further investigation is needed to better define and replicate these phenotypes in larger cohorts, which would help to gain greater understanding of the pathophysiological mechanisms and identify common therapeutic targets.
Background and purpose
Accurate epidemiological information is essential for the improved understanding of dystonia syndromes, as well as better provisioning of clinical services and providing ...context for diagnostic decision‐making. Here, we determine epidemiological, social deprivation, and mortality characteristics of adult‐onset idiopathic dystonia in the Welsh population.
Methods
A retrospective population‐based cohort study using anonymized electronic health care data in Wales was conducted to identify individuals with dystonia between 1 January 1994 and 31 December 2017. We developed a case‐ascertainment algorithm to determine dystonia incidence and prevalence, as well as characterization of the dystonia cohort, based on social deprivation and mortality.
Results
The case‐ascertainment algorithm (79% sensitivity) identified 54,966 cases; of these cases, 41,660 had adult‐onset idiopathic dystonia (≥20 years). Amongst the adult‐onset form, the median age at diagnosis was 41 years, with males significantly older at time of diagnosis compared to females. Prevalence rates ranged from 0.02% in 1994 to 1.2% in 2017. The average annual incidence was 87.7/100,000/year, increasing from 49.9/100,000/year (1994) to 96.21/100,000/year (2017). In 2017, people with dystonia had a similar life expectancy to the Welsh population.
Conclusions
We have developed a case‐ascertainment algorithm, supported by the introduction of a neurologist‐reviewed validation cohort, providing a platform for future population‐based dystonia studies. We have established robust population‐level prevalence and incidence values for adult‐onset idiopathic forms of dystonia, with this reflecting increasing clinical recognition and identification of causal genes. Underlying causes of death mirrored those of the general population, including circulatory disorders, respiratory disorders, cancers, and dementia.
We have developed and validated a case‐ascertainment algorithm, providing a platform for future population‐based dystonia studies. We demonstrate that prevalence and incidence rates of dystonia are higher than previously estimated, 1220/100,000/year (1.2%) and 96/100,000/year, respectively. We have shown that a diagnosis of dystonia does not appear to have a detrimental impact on socioeconomic status, and there was no evidence of decreased life expectancy.
A 35-year-old woman with a progressive, bilateral upper limb tremor, personality change, behavioral disturbance, and primary ovarian insufficiency was found to have
-related leukodystrophy. She had ...congenital nystagmus which evolved to head titubation by age 8 years and then developed an upper limb tremor in her mid-teens. These symptoms stabilized during her 20s, but soon after this presentation at age 35 years, neurologic and behavioral disturbances progressed rapidly over a 12-month period requiring transition to an assisted living facility with care support (4 visits/day) and assistance for all activities of daily living. MRI of the brain demonstrated confluent white matter changes predominantly involving the frontal lobes consistent with a leukodystrophy. All other investigations were unremarkable. Nongenetic causes of a leukodystrophy including sexually transmitted diseases and recreational drug use were excluded. Family history was negative for similar symptoms. Gene panel testing identified compound heterozygous pathogenic
mutations. This case highlights the importance of MRI brain imaging in progressive tremor syndromes, the utility of gene panels in simultaneous testing of multiple disorders with overlapping phenotypes, and the need for awareness of comorbid endocrinological disorders in many of the genetic leukodystrophies, whose identification may aid in clinical diagnosis.
Purpose of Review
To review recent literature evaluating psychiatric and cognitive symptoms in dystonia, the two non-motor symptom groups most frequently evaluated in dystonia research and recognised ...in clinical practice.
Recent Findings
Recent work has embedded clinical recognition of psychiatric symptoms in dystonia, with depressive and anxiety-related symptoms routinely observed to be the most common. Less explored symptoms, such as self-harm, suicidal ideation, and substance abuse, represent newer areas of investigation, with initial work suggesting higher rates than the background population. Investigation of cognitive function has provided less consistent results, both within individual dystonia subtypes and across the spectrum of dystonias, partly reflecting the heterogeneity in approaches to assessment. However, recent work indicates impairments of higher cognitive function, e.g. social cognition, and disrupted visual and auditory sensory processing.
Summary
Dystonia demonstrates psychiatric and cognitive symptom heterogeneity, with further work needed to recognise endophenotypes and improve diagnostic accuracy, symptom recognition, and management.
Myoclonus-dystonia is an early onset genetic disorder characterised by subcortical myoclonus and less prominent dystonia. Its primary causative gene is the epsilon-sarcoglycan gene but the syndrome ...of “myoclonic dystonia” has been shown to be a heterogeneous group of genetic disorders. The underlying pathophysiology of myoclonus-dystonia is incompletely understood, although it may relate to dysfunction of striatal monoamine neurotransmission or disruption of cerebellothalamic networks (possibly via a GABAergic deficit of Purkinje cells). A broad range of oral medical therapies have been used in the treatment of myoclonus-dystonia with a varying response, and limited data relating to efficacy and tolerability, yet this condition responds dramatically to alcohol. Few well conducted randomized controlled trials have been undertaken leading to an empirical ad hoc approach for many patients. We review the current evidence for pharmacological therapies in myoclonus-dystonia, discuss implications for underlying pathogenesis of the condition and propose a treatment algorithm for these patients.
•Myoclonus-dystonia is a complex disorder with many different facets, for which there remains a paucity of data on specific medical therapies.•Oral medications typically have a variable response in M-D, with poor tolerability limiting their use in many patients.•We review the current evidence for pharmacological therapies in M-D and discuss implications for underlying pathogenesis of the condition.•Large controlled studies are required in genetically well-defined cohorts to further validate the therapeutic options in this condition.
Sleep disturbance is an increasingly recognized non-motor trait in dystonia, with varying findings reported to date. Here, we examine sleep in a UK Biobank derived dystonia cohort using subjective ...self-reported sleep symptoms and objective accelerometer-derived sleep measures, with comparison to a control population.
A total of 241 dystonia cases were compared to 964 matched controls in analysis of self-reported sleep symptoms and changes in sleep architecture using wrist-worn triaxial accelerometers.
Dystonia participants had poorer self-reported sleep patterns compared to controls. Accelerometery measurements demonstrated later sleep times, reduced time in bed, and shifts in circadian rhythm. No association was observed with pain, and only limited relationships with psychiatric symptoms.
This study demonstrates the utility of accelerometers in longer term evaluation of sleep in dystonia, for measurement of disturbance and response to treatment. Compared to controls, altered sleep and circadian rhythm were more common in dystonia patients which may contribute to the clinical phenotype.
While motor and psychiatric phenotypes in idiopathic dystonia are increasingly well understood, a few studies have examined the rate, type, and temporal pattern of other clinical co-morbidities in ...dystonia. Here, we determine the rates of clinical diagnoses across 13 broad systems-based diagnostic groups, comparing an overall idiopathic dystonia cohort, and sub-cohorts of cervical dystonia, blepharospasm, and dystonic tremor, to a matched-control cohort. Using the SAIL databank, we undertook a longitudinal population-based cohort study (January 1st 1994–December 31st 2017) using anonymised electronic healthcare records for individuals living in Wales (UK), identifying those diagnosed with dystonia through use of a previously validated algorithm. Clinical co-morbid diagnoses were identified from primary health care records, with a 10% prevalence threshold required for onward analysis. Using this approach, 54,166 dystonia cases were identified together with 216,574 matched controls. Within this cohort, ten of the main ICD-10 diagnostic codes exceeded the 10% prevalence threshold over the 20-year period (infection, neurological, respiratory, gastrointestinal, genitourinary, dermatological, musculoskeletal, circulatory, neoplastic, and endocrinological). In the overall dystonia cohort, musculoskeletal (aOR: 1.89, aHR: 1.74), respiratory (aOR: 1.84; aHR: 1.65), and gastrointestinal (aOR: 1.72; aHR: 1.6) disorders had the strongest associations both pre- and post-dystonia diagnosis. However, variation in the rate of association of individual clinical co-morbidities was observed across the cervical, blepharospasm, and tremor dystonia groups. This study suggests an increased rate of specific co-morbid clinical disorders both pre- and post-dystonia diagnosis which should be considered during clinical assessment of those with dystonia to enable optimum symptomatic management.
Background and purpose
Although psychiatric diagnoses are recognized in idiopathic dystonia, no previous studies have examined the temporal relationship between idiopathic dystonia and psychiatric ...diagnoses at scale. Here, we determine rates of psychiatric diagnoses and psychiatric medication prescription in those diagnosed with idiopathic dystsuponia compared to matched controls.
Methods
A longitudinal population‐based cohort study using anonymized electronic health care data in Wales (UK) was conducted to identify individuals with idiopathic dystonia and comorbid psychiatric diagnoses/prescriptions between 1 January 1994 and 31 December 2017. Psychiatric diagnoses/prescriptions were identified from primary and secondary health care records.
Results
Individuals with idiopathic dystonia (n = 52,589) had higher rates of psychiatric diagnosis and psychiatric medication prescription when compared to controls (n = 216,754, 43% vs. 31%, p < 0.001; 45% vs. 37.9%, p < 0.001, respectively), with depression and anxiety being most common (cases: 31% and 28%). Psychiatric diagnoses predominantly predated dystonia diagnosis, particularly in the 12 months prior to diagnosis (incidence rate ratio IRR = 1.98, 95% confidence interval CI = 1.9–2.1), with an IRR of 12.4 (95% CI = 11.8–13.1) for anxiety disorders. There was, however, an elevated rate of most psychiatric diagnoses throughout the study period, including the 12 months after dystonia diagnosis (IRR = 1.96, 95% CI = 1.85–2.07).
Conclusions
This study suggests a bidirectional relationship between psychiatric disorders and dystonia, particularly with mood disorders. Psychiatric and motor symptoms in dystonia may have common aetiological mechanisms, with psychiatric disorders potentially forming prodromal symptoms of idiopathic dystonia.
Individuals with idiopathic dystonia had higher rates of psychiatric diagnosis and psychiatric medication prescription when compared to controls, with depression and anxiety being most common. Psychiatric diagnoses predominantly predated dystonia diagnosis, particularly in the 12 months prior to diagnosis. There was, however, an elevated rate of most psychiatric diagnoses throughout the study period, including the 12 months after dystonia diagnosis, suggesting a bidirectional relationship between psychiatric disorders and dystonia.
Sleep and circadian rhythm disturbances are central features of many movement disorders, exacerbating motor and non-motor symptoms and impairing quality of life. Understanding these disturbances to ...sleep is clinically important and may further our understanding of the underlying movement disorder. This review evaluates the current anatomical and neurochemical understanding of normal sleep and the recognised primary sleep disorders. In addition, we undertook a systematic review of the evidence for disruption to sleep across multiple movement disorders. Rapid eye movement sleep behaviour disorder has emerged as the most reliable prodromal biomarker for the alpha synucleinopathies, including Parkinson's disease and multiple system atrophy, often preceding motor symptom onset by several years. Abnormal sleep has also been described for many other movement disorders, but further evidence is needed to determine whether this is a primary or secondary phenotypic component of the underlying condition. Medication used in the treatment of motor symptoms also affects sleep and can aggravate or cause certain sleep disorders. Within the context of movement disorders, there is also some suggestion of a shared underlying mechanism for motor and sleep pathophysiology, with evidence implicating thalamic and brainstem structures and monoaminergic neurotransmission. This review highlights the need for an understanding of normal and abnormal sleep within the movement disorder clinic, an ability to screen for specific causes of poor sleep and to treat sleep disturbance to improve quality of life. Key sleep disorders also act as important biomarkers and have implications in diagnosis, prognosis and the development of future therapies.
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