Neuroanatomical and prognostic associations of depression in Parkinson's disease.

BACKGROUND: Depression is reported as a risk factor, prodromal feature and late consequence of Parkinson's disease (PD). We aimed to evaluate the timing, neuroanatomy and prognostic implications of depression in PD. METHODS: We used data from 434 023 participants from UK Biobank with 14.1 years of follow-up. Multivariable regression models established associations of depression with incident PD and regional brain volumes. Cox proportional hazards models assessed prognostic associations of depression in PD with incident dementia and all-cause mortality. RESULTS: Of 2632 individuals with incident PD, 539 (20.5%) were diagnosed with depression at some point. Depression was associated with an increased risk of subsequent PD (risk ratio 1.53, 95% CI 1.37 to 1.72). Among incident PD cases, depression prevalence rose progressively from 10 years pre-PD diagnosis (OR 2.10, 95% CI 1.57 to 2.83) to 10 years postdiagnosis (OR 3.51, 95% CI 1.33 to 9.22). Depression severity in PD was associated with reduced grey matter volume in structures including the thalamus and amygdala. Depression prior to PD diagnosis increased risk of dementia (HR 1.47, 95% CI 1.05 to 2.07) and mortality (HR 1.30, 95% CI 1.07 to 1.58). CONCLUSIONS: This large-scale prospective study demonstrated that depression prevalence increases from 10 years before PD diagnosis and is a marker of cortical and subcortical volume loss. Depression before PD diagnosis signals a worse prognosis in terms of dementia and mortality. This has clinical implications in stratifying people with poorer cognitive and prognostic trajectory in PD.

Plasma proteomic profiles of UK Biobank participants with multiple sclerosis.

OBJECTIVE: We aimed to describe plasma protein biomarkers of multiple sclerosis risk and to explore protein biomarkers of disease severity using radiological outcome measures. METHODS: Multiple sclerosis cases and controls were identified in UK Biobank, a longitudinal cohort study of ~500,000 British adults. Plasma proteins were assayed in ~50,000 UK Biobank participants using the Olink proximity extension assay. We performed case-control association testing to examine the association between 2911 proteins and multiple sclerosis, using linear models adjusted for confounding covariates. Associations with radiological lesion burden and brain volume were determined in a subset of the cohort with available magnetic resonance imaging, using normalized T2-hyperintensity volume or whole brain volume as the outcome measure. RESULTS: In total, 407 prevalent multiple sclerosis cases and 39,979 healthy controls were included. We discovered 72 proteins associated with multiple sclerosis at a Bonferroni-adjusted p value of 0.05, including established markers such as neurofilament light chain and glial fibrillary acidic protein. We observed a decrease in plasma Granzyme A, a marker of T cell and NK cell degranulation, which was specific to multiple sclerosis. Higher levels of plasma proteins involved in coagulation were associated with lower T2 lesion burden and preserved brain volume. INTERPRETATION: We report the largest plasma proteomic screen of multiple sclerosis, replicating important known associations and suggesting novel markers, such as the reduction in granzyme A. While these findings require external validation, they demonstrate the power of biobank-scale datasets for discovering new biomarkers for multiple sclerosis.

Association Between Antiepileptic Drugs and Incident Parkinson Disease.

Importance: Recent studies have highlighted an association between epilepsy and Parkinson disease (PD). The role of antiepileptic drugs (AEDs) has not been explored. Objective: To investigate the association between AEDs and incident PD. Design, Setting, and Participants: This nested case-control study started collecting data from the UK Biobank (UKB) in 2006, and data were extracted on June 30, 2021. Individuals with linked primary care prescription data were included. Cases were defined as individuals with a Hospital Episode Statistics (HES)-coded diagnosis of PD. Controls were matched 6:1 for age, sex, race and ethnicity, and socioeconomic status. Prescription records were searched for AEDs prescribed prior to diagnosis of PD. The UKB is a longitudinal cohort study with more than 500 000 participants; 45% of individuals in the UKB have linked primary care prescription data. Participants living in the UK aged between 40 and 69 years were recruited to the UKB between 2006 and 2010. All participants with UKB-linked primary care prescription data (n = 222 106) were eligible for enrollment in the study. Individuals with only a self-reported PD diagnosis or missing data for the matching variables were excluded. In total, 1477 individuals were excluded; 49 were excluded due to having only self-reported PD, and 1428 were excluded due to missing data. Exposures: Exposure to AEDs (carbamazepine, lamotrigine, levetiracetam, and sodium valproate) was defined using routinely collected prescription data derived from primary care. Main Outcomes and Measures: Odds ratios and 95% CIs were calculated using adjusted logistic regression models for individuals prescribed AEDs before the first date of HES-coded diagnosis of PD. Results: In this case-control study, there were 1433 individuals with an HES-coded PD diagnosis (cases) and 8598 controls in the analysis. Of the 1433 individuals, 873 (60.9%) were male, 1397 (97.5%) had their race and ethnicity recorded as White, and their median age was 71 years (IQR, 65-75 years). An association was found between AED prescriptions and incident PD (odds ratio, 1.80; 95% CI, 1.35-2.40). There was a trend for a greater number of prescription issues and multiple AEDs being associated with a greater risk of PD. Conclusions and Relevance: This study, the first to systematically look at PD risk in individuals prescribed the most common AEDs, to our knowledge, found evidence of an association between AEDs and incident PD. With the recent literature demonstrating an association between epilepsy and PD, this study provides further insights.

The shared genetic architecture of modifiable risk for Alzheimer's disease: a genomic structural equation modelling study.

Targeting modifiable risk factors may help to prevent Alzheimer's disease (AD), but the pathways by which these risk factors influence AD risk remain incompletely understood. We identified genome-wide association studies for AD and its major modifiable risk factors. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling. We identified complex networks of genetic overlap among AD risk factors, but AD itself was largely genetically distinct. The data were best explained by a bi-factor model, incorporating a Common Factor for AD risk, and 3 orthogonal sub-clusters of risk factors. Taken together, our findings suggest that there is extensive shared genetic architecture between AD modifiable risk factors, but this is largely independent of AD genetic pathways. Extensive genetic pleiotropy between risk factors may influence AD indirectly by decreasing cognitive reserve or increasing risk of multimorbidity, leading to poorer brain health. Further work to understand the biology reflected by this communality may provide novel mechanistic insights that could help to prioritise targets for dementia prevention.

Dementia risk in a diverse population: A single-region nested case-control study in the East End of London.

Background: Most evidence about dementia risk comes from relatively affluent people of White European ancestry. We aimed to determine the association between ethnicity, area level socioeconomic deprivation and dementia risk, and the extent to which variation in risk might be attributable to known modifiable clinical risk factors and health behaviours. Methods: In this nested case-control study, we analysed data from primary care medical records of a population of 1,016,277 from four inner East London boroughs, United Kingdom, collected between 2009 and 2018. The outcome measures were odds ratios for dementia according to ethnicity and deprivation, before and after the addition of major modifiable risk factors for dementia; and weighted population attributable risk for comparison between individual risk factors. Findings: We identified 4137 dementia cases and 15,754 matched controls (mean age for cases and controls were 80·7 years, (SD 8·7); 81·3 years, (SD 8·9) respectively, range 27-103). Black and South Asian ethnicity were both associated with increased risk of dementia relative to White (odds ratios [95% CI]: Black 1·43 [1·31-1·56]; South Asian 1.17 [1·06-1·29]). Area-level deprivation was independently associated with an increased risk of dementia in a dose-dependent manner. Black and South Asian ethnicity were both associated with a younger age at dementia diagnosis (odds ratios [95%CI]: 0·70 [0·61-0·80] and 0·55 [0·47-0·65], respectively). Population attributable risk was higher for ethnicity (9·7%) and deprivation (11·7%) than for any established modifiable risk factor in this population. Interpretation: Ethnicity and area-level deprivation are independently associated with dementia risk in East London. This effect may not be attributable to the effect of known risk factors. Funding: Barts Charity (MGU0366).

Assessment of Risk Factors and Early Presentations of Parkinson Disease in Primary Care in a Diverse UK Population.

IMPORTANCE: Early features of Parkinson disease (PD) have been described through population-based studies that overrepresent White, affluent groups and may not be generalizable. OBJECTIVE: To investigate the association between risk factors and prediagnostic presentations of PD in an ethnically diverse UK population with high socioeconomic deprivation but universal access to health care. DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study was conducted using electronic health care records on 1 016 277 individuals from primary care practices in East London to extract clinical information recorded between 1990 and February 6, 2018. The data were analyzed between September 3, 2020, and September 3, 2021. Individuals with a diagnosis of PD were compared with controls without PD or other major neurological conditions. MAIN OUTCOMES AND MEASURES: A matched analysis (10 controls matched for each patient with PD according to age and sex) and an unmatched analysis (adjusted for age and sex) were undertaken using multivariable logistic regression to determine associations between risk factors and prediagnostic presentations to primary care with subsequent diagnosis of PD. Three time periods (<2, 2-<5, and 5-10 years before diagnosis) were analyzed separately and together. RESULTS: Of 1 016 277 individuals included in the data set, 5699 were excluded and 1055 patients with PD and 1 009 523 controls were included in the analysis. Patients with PD were older than controls (mean [SD], 72.9 [11.3] vs 40.3 [15.2] years), and more were male (632 [59.9%] vs 516 862 [51.2%]). In the matched analysis (1055 individuals with PD and 10 550 controls), associations were found for tremor (odds ratio [OR], 145.96; 95% CI, 90.55-235.28) and memory symptoms (OR, 8.60; 95% CI, 5.91-12.49) less than 2 years before the PD diagnosis. The associations were also found up to 10 years before PD diagnosis for tremor and 5 years for memory symptoms. Among midlife risk factors, hypertension (OR, 1.36; 95% CI, 1.19-1.55) and type 2 diabetes (OR, 1.39; 95% CI, 1.19-1.62) were associated with subsequent diagnosis of PD. Associations with early nonmotor features, including hypotension (OR, 6.84; 95% CI, 3.38-13.85), constipation (OR, 3.29; 95% CI, 2.32-4.66), and depression (OR, 4.69; 95% CI, 2.88-7.63), were also noted. Associations were found for epilepsy (OR, 2.5; 95% CI, 1.63-3.83) and hearing loss (OR, 1.66; 95% CI, 1.06-2.58), which have not previously been well reported. These findings were replicated using data from the UK Biobank. No association with future PD diagnosis was found for ethnicity or deprivation index level. CONCLUSIONS AND RELEVANCE: This study provides data suggesting that a range of comorbidities and symptoms are encountered in primary care settings before PD diagnosis in an ethnically diverse and deprived population. Novel temporal associations were observed for epilepsy and hearing loss with subsequent development of PD. The prominence of memory symptoms suggests an excess of cognitive dysfunction in early PD in this population or difficulty in correctly ascertaining symptoms in traditionally underrepresented groups.

Individual differences in vocal size exaggeration.

The human voice carries socially relevant information such as how authoritative, dominant, and attractive the speaker sounds. However, some speakers may be able to manipulate listeners by modulating the shape and size of their vocal tract to exaggerate certain characteristics of their voice. We analysed the veridical size of speakers' vocal tracts using real-time magnetic resonance imaging as they volitionally modulated their voice to sound larger or smaller, corresponding changes to the size implied by the acoustics of their voice, and their influence over the perceptions of listeners. Individual differences in this ability were marked, spanning from nearly incapable to nearly perfect vocal modulation, and was consistent across modalities of measurement. Further research is needed to determine whether speakers who are effective at vocal size exaggeration are better able to manipulate their social environment, and whether this variation is an inherited quality of the individual, or the result of life experiences such as vocal training.

Singers show enhanced performance and neural representation of vocal imitation.

Humans have a remarkable capacity to finely control the muscles of the larynx, via distinct patterns of cortical topography and innervation that may underpin our sophisticated vocal capabilities compared with non-human primates. Here, we investigated the behavioural and neural correlates of laryngeal control, and their relationship to vocal expertise, using an imitation task that required adjustments of larynx musculature during speech. Highly trained human singers and non-singer control participants modulated voice pitch and vocal tract length (VTL) to mimic auditory speech targets, while undergoing real-time anatomical scans of the vocal tract and functional scans of brain activity. Multivariate analyses of speech acoustics, larynx movements and brain activation data were used to quantify vocal modulation behaviour and to search for neural representations of the two modulated vocal parameters during the preparation and execution of speech. We found that singers showed more accurate task-relevant modulations of speech pitch and VTL (i.e. larynx height, as measured with vocal tract MRI) during speech imitation; this was accompanied by stronger representation of VTL within a region of the right somatosensory cortex. Our findings suggest a common neural basis for enhanced vocal control in speech and song. This article is part of the theme issue 'Voice modulation: from origin and mechanism to social impact (Part I)'.

Processing of Degraded Speech in Brain Disorders.

The speech we hear every day is typically "degraded" by competing sounds and the idiosyncratic vocal characteristics of individual speakers. While the comprehension of "degraded" speech is normally automatic, it depends on dynamic and adaptive processing across distributed neural networks. This presents the brain with an immense computational challenge, making degraded speech processing vulnerable to a range of brain disorders. Therefore, it is likely to be a sensitive marker of neural circuit dysfunction and an index of retained neural plasticity. Considering experimental methods for studying degraded speech and factors that affect its processing in healthy individuals, we review the evidence for altered degraded speech processing in major neurodegenerative diseases, traumatic brain injury and stroke. We develop a predictive coding framework for understanding deficits of degraded speech processing in these disorders, focussing on the "language-led dementias"-the primary progressive aphasias. We conclude by considering prospects for using degraded speech as a probe of language network pathophysiology, a diagnostic tool and a target for therapeutic intervention.

Cooperation Not Competition: Bihemispheric tDCS and fMRI Show Role for Ipsilateral Hemisphere in Motor Learning.

What is the role of ipsilateral motor and premotor areas in motor learning? One view is that ipsilateral activity suppresses contralateral motor cortex and, accordingly, that inhibiting ipsilateral regions can improve motor learning. Alternatively, the ipsilateral motor cortex may play an active role in the control and/or learning of unilateral hand movements. We approached this question by applying double-blind bihemispheric transcranial direct current stimulation (tDCS) over both contralateral and ipsilateral motor cortex in a between-group design during 4 d of unimanual explicit sequence training in human participants. Independently of whether the anode was placed over contralateral or ipsilateral motor cortex, bihemispheric stimulation yielded substantial performance gains relative to unihemispheric or sham stimulation. This performance advantage appeared to be supported by plastic changes in both hemispheres. First, we found that behavioral advantages generalized strongly to the untrained hand, suggesting that tDCS strengthened effector-independent representations. Second, functional imaging during speed-matched execution of trained sequences conducted 48 h after training revealed sustained, polarity-independent increases in activity in both motor cortices relative to the sham group. These results suggest a cooperative rather than competitive interaction of the two motor cortices during skill learning and suggest that bihemispheric brain stimulation during unimanual skill learning may be beneficial because it harnesses plasticity in the ipsilateral hemisphere.SIGNIFICANCE STATEMENT Many neurorehabilitation approaches are based on the idea that is beneficial to boost excitability in the contralateral hemisphere while attenuating that of the ipsilateral cortex to reduce interhemispheric inhibition. We observed that bihemispheric transcranial direct current stimulation (tDCS) with the excitatory anode either over contralateral or ipsilateral motor cortex facilitated motor learning nearly twice as strongly as unihemispheric tDCS. These increases in motor learning were accompanied by increases in fMRI activation in both motor cortices that outlasted the stimulation period, as well as increased generalization to the untrained hand. Collectively, our findings suggest a cooperative rather than a competitive role of the hemispheres and imply that it is most beneficial to harness plasticity in both hemispheres in neurorehabilitation of motor deficits.

Flexible head-casts for high spatial precision MEG.

BACKGROUND: In combination with magnetoencephalographic (MEG) data, accurate knowledge of the brain's structure and location provide a principled way of reconstructing neural activity with high temporal resolution. However, measuring the brain's location is compromised by head movement during scanning, and by fiducial-based co-registration with magnetic resonance imaging (MRI) data. The uncertainty from these two factors introduces errors into the forward model and limit the spatial resolution of the data. NEW METHOD: We present a method for stabilizing and reliably repositioning the head during scanning, and for co-registering MRI and MEG data with low error. RESULTS: Using this new flexible and comfortable subject-specific head-cast prototype, we find within-session movements of <0.25mm and between-session repositioning errors around 1mm. COMPARISON WITH EXISTING METHOD(S): This method is an improvement over existing methods for stabilizing the head or correcting for location shifts on- or off-line, which still introduce approximately 5mm of uncertainty at best (Adjamian et al., 2004; Stolk et al., 2013; Whalen et al., 2008). Further, the head-cast design presented here is more comfortable, safer, and easier to use than the earlier 3D printed prototype, and give slightly lower co-registration errors (Troebinger et al., 2014b). CONCLUSIONS: We provide an empirical example of how these head-casts impact on source level reproducibility. Employment of the individual flexible head-casts for MEG recordings provide a reliable method of safely stabilizing the head during MEG recordings, and for co-registering MRI anatomical images to MEG functional data.

Admission for osteoporotic pelvic fractures and predictors of length of hospital stay, mortality and loss of independence.

OBJECTIVE: To study the implications of osteoporotic pelvic fractures in older patients in terms of mortality, length of hospital stay and independent living. METHODS: The study included 110 consecutive patients, aged over 60 years, with osteoporotic pelvic fractures admitted to the Queen Elizabeth Hospital, Gateshead, between July 2009 and March 2011. Demographic and routine clinical data were collected prospectively until date of discharge, and vital status data were collected up to 3 months post-fracture. These data were analysed to assess associations with outcomes such as length of hospital stay, mortality and loss of independence (according to changes in residential housing status). RESULTS: Fourteen patients died either in hospital, or within 3 months of fracture. Length of hospital stay was associated with age (b=0.77 days per year, 95% CI 0.001, 1.54, P=0.05) and was significantly longer in those with acute medical problems on admission (b=21.2 days, 95% CI 8.72, 33.73, P=0.001). The odds of changing from independent to institutionalised accommodation were significantly associated with age (OR 1.08 per year, 95% CI 1.01, 1.04, P=0.007) and length of hospital stay (OR 1.12 per day, 95% CI 1.01, 1.04, P=0.007). CONCLUSION: In-hospital mortality rates in this patient group are similar to those seen for hip fractures, yet pelvic fractures in older people receive relatively little in the way of attention or funding. Guidelines to improve the management of such fractures in older people are important to improve care while in hospital, reduce time spent in hospital and reduce the impact on independent living.