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.

Binary reversals: a diagnostic sign in primary progressive aphasia.

BACKGROUND: Binary reversals (exemplified by 'yes'/'no' confusions) have been described in patients with primary progressive aphasia (PPA) but their diagnostic value and phenotypic correlates have not been defined. METHODS: We conducted a retrospective cohort study analysing demographic, clinical, neuropsychological, linguistic and behavioural data from patients representing all major PPA syndromes (non-fluent/agrammatic variant, nfvPPA; logopenic variant, lvPPA; semantic variant, svPPA) and behavioural variant frontotemporal dementia (bvFTD). The prevalence of binary reversals and behavioural abnormalities, illness duration, parkinsonian features and neuropsychological test scores were compared between neurodegenerative syndromes, and the diagnostic predictive value of binary reversals was assessed using logistic regression. RESULTS: Data were obtained for 83 patients (21 nfvPPA, 13 lvPPA, 22 svPPA, 27 bvFTD). Binary reversals occurred in all patients with nfvPPA, but significantly less frequently and later in lvPPA (54%), svPPA (9%) and bvFTD (44%). Patients with bvFTD with binary reversals had significantly more severe language (but not general executive or behavioural) deficits than those without reversals. Controlling for potentially confounding variables, binary reversals strongly predicted a diagnosis of nfvPPA over other syndromes. CONCLUSIONS: Binary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.

No association between oral contraceptive exposure and subsequent MS: A population-based nested case-control study in primary care.

BACKGROUND: Conflicting data exist around oral contraceptive exposure and subsequent multiple sclerosis (MS). OBJECTIVE: To use routinely collected primary healthcare data to explore the potential association between oral contraceptive exposure and subsequent MS in females at population level. METHODS: We performed a nested case-control study using electronic primary care data, with complete electronic ascertainment from 1990. Logistic regression was used to evaluate associations between contraceptive exposure and MS, without and with adjusting for age, ethnicity and deprivation. RESULTS: A total of 4455 females were included: 891 cases and 3564 controls. No association was seen between oral contraceptive exposure and subsequent MS, or between any contraceptive, combined oral contraceptive pill (COCP) or progesterone-only pill (POP) use 0-2, 2-5 or >5 years prior to MS. Conclusions: In the largest population-based study to date, we find no evidence of an association between oral contraceptive exposure and subsequent MS diagnosis.

Symptom-based staging for logopenic variant primary progressive aphasia.

BACKGROUND AND PURPOSE: Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum. METHODS: An international lvPPA caregiver cohort was surveyed on symptom development under an 'exploratory' survey (34 UK caregivers). Feedback from this survey informed the development of a 'consolidation' survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed-methods approach. RESULTS: Six clinical stages were endorsed. Early symptoms included word-finding difficulty, with loss of message comprehension and speech intelligibility signalling later-stage progression. Additionally, problems with hearing in noise, memory and route-finding were prominent early non-verbal symptoms. 'Milestone' symptoms were identified that anticipate daily-life functional transitions and care needs. CONCLUSIONS: This work introduces a new symptom-based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia.

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (non-fluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

INTRODUCTION: Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. METHODS: An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design. RESULTS: Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid ("PPA-Squared"). DISCUSSION: This work introduces a symptom-led staging scheme and functional scale for semantic and non-fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA. HIGHLIGHTS: We introduce new symptom-led perspectives on primary progressive aphasia (PPA). The focus is on non-fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non-verbal features of PPA and clinical trajectories is featured. We introduce a symptom-led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.

The true tempo of evolutionary radiation and decline revealed on the Hawaiian archipelago.

Establishing the relationship between rates of change in species richness and biotic and abiotic environmental change is a major goal of evolutionary biology. Although exquisite fossil and geological records provide insight in rare cases, most groups lack high-quality fossil records. Consequently, biologists typically rely on molecular phylogenies to study the diversity dynamics of clades, usually by correlating changes in diversification rate with environmental or trait shifts. However, inferences drawn from molecular phylogenies can be limited owing to the challenge of accounting for extinct species, making it difficult to accurately determine the underlying diversity dynamics that produce them. Here, using a geologically informed model of the relationship between changing island area and species richness for the Hawaiian archipelago, we infer the rates of species richness change for 14 endemic groups over their entire evolutionary histories without the need for fossil data, or molecular phylogenies. We find that these endemic clades underwent evolutionary radiations characterized by initially increasing rates of species accumulation, followed by slow-downs. In fact, for most groups on most islands, their time of evolutionary expansion has long past, and they are now undergoing previously unrecognized long-term evolutionary decline. Our results show how landscape dynamism can drive evolutionary dynamics over broad timescales, including driving species loss that is not readily detected using molecular phylogenies, or without a rich fossil record. We anticipate that examination of other clades where the relationship between environmental change and species richness change can be quantified will reveal that many other living groups have also experienced similarly complex evolutionary trajectories, including long-term and ongoing evolutionary decline.

Artificial intelligence for dementia prevention.

INTRODUCTION: A wide range of modifiable risk factors for dementia have been identified. Considerable debate remains about these risk factors, possible interactions between them or with genetic risk, and causality, and how they can help in clinical trial recruitment and drug development. Artificial intelligence (AI) and machine learning (ML) may refine understanding. METHODS: ML approaches are being developed in dementia prevention. We discuss exemplar uses and evaluate the current applications and limitations in the dementia prevention field. RESULTS: Risk-profiling tools may help identify high-risk populations for clinical trials; however, their performance needs improvement. New risk-profiling and trial-recruitment tools underpinned by ML models may be effective in reducing costs and improving future trials. ML can inform drug-repurposing efforts and prioritization of disease-modifying therapeutics. DISCUSSION: ML is not yet widely used but has considerable potential to enhance precision in dementia prevention. HIGHLIGHTS: Artificial intelligence (AI) is not widely used in the dementia prevention field. Risk-profiling tools are not used in clinical practice. Causal insights are needed to understand risk factors over the lifespan. AI will help personalize risk-management tools for dementia prevention. AI could target specific patient groups that will benefit most for clinical trials.

Trans-ethnic genomic informed risk assessment for Alzheimer's disease: An International Hundred K+ Cohorts Consortium study.

BACKGROUND: As a collaboration model between the International HundredK+ Cohorts Consortium (IHCC) and the Davos Alzheimer's Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for Alzheimer's disease (AD). METHODS: The GIRA model was created to include polygenic risk score calculated from the AD genome-wide association study loci, the apolipoprotein E haplotypes, and non-genetic covariates including age, sex, and the first three principal components of population substructure. RESULTS: We validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD. CONCLUSIONS: As the initial effort by the IHCC to leverage existing large-scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA for AD with the potential of identifying individuals at high risk of developing AD for future clinical applications.

Hearing and dementia: from ears to brain.

The association between hearing impairment and dementia has emerged as a major public health challenge, with significant opportunities for earlier diagnosis, treatment and prevention. However, the nature of this association has not been defined. We hear with our brains, particularly within the complex soundscapes of everyday life: neurodegenerative pathologies target the auditory brain, and are therefore predicted to damage hearing function early and profoundly. Here we present evidence for this proposition, based on structural and functional features of auditory brain organization that confer vulnerability to neurodegeneration, the extensive, reciprocal interplay between 'peripheral' and 'central' hearing dysfunction, and recently characterized auditory signatures of canonical neurodegenerative dementias (Alzheimer's disease, Lewy body disease and frontotemporal dementia). Moving beyond any simple dichotomy of ear and brain, we argue for a reappraisal of the role of auditory cognitive dysfunction and the critical coupling of brain to peripheral organs of hearing in the dementias. We call for a clinical assessment of real-world hearing in these diseases that moves beyond pure tone perception to the development of novel auditory 'cognitive stress tests' and proximity markers for the early diagnosis of dementia and management strategies that harness retained auditory plasticity.

Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome.

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65-1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016-19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: -0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

Primary progressive aphasia: ReADing the clinical GRANularity.

Primary progressive aphasia remains a diagnostic challenge despite (or even because of) the increasing availability of ancillary tests and biomarkers. We present a 67-year-old man with apparently sporadic logopenic aphasia and positive Alzheimer biomarkers who was subsequently found also to have a pathogenic mutation in the progranulin gene. This was signalled by early atypical features (mild expressive agrammatism and behavioural change, rapid clinical deterioration) around the core logopenic aphasia syndrome. Each of the canonical progressive aphasia syndromes has a 'halo' of less typical variants that may herald alternative or additional pathologies. The accurate diagnosis of primary progressive aphasia depends on careful clinical analysis to direct investigations appropriately.

Ethnic and Socioeconomic Associations with Multiple Sclerosis Risk.

OBJECTIVE: Epidemiological research in multiple sclerosis (MS) has mainly been performed in socioeconomically and ethnically limited populations; influences on MS risk have not been studied in prospectively collected non-White populations. We set out to study the influence of previously described MS risk factors in an ethnically diverse population. METHODS: A nested case-control study was created using primary care records of >1 million individuals, >50% of whom identify as Black, Asian, and Minority Ethnic (BAME). MS cases were compared to an age- and sex-matched control cohort (1:4), and to a large unmatched cohort. Odds ratios (ORs) of disease were determined according to exposure of interest, and a multivariate model including all exposures was created. Potential pairwise interactions were considered where both indicated a significant effect. RESULTS: A total of 1,344 confirmed MS cases were included. MS OR in blacks aged <40 years was 1.15 (95% confidence interval [CI] = 0.81-1.62) compared to whites. MS odds in BAME current (OR = 1.71, 95% CI = 1.24-2.31) and ex-smokers (OR = 2.83, 95% CI = 2.14-3.72) were considerably higher than in Whites (OR = 1.09, 95% CI = 0.88-1.34; OR = 1.44, 95% CI = 1.19-1.74, respectively). Prior infectious mononucleosis was associated with increased odds of MS in Blacks (OR = 4.94, 95% CI = 1.23-17.89). An increase in MS odds was seen in the least-deprived quintile (OR = 2.46, 95% CI = 1.40-4.24), but no effect across deprived quintiles was seen. INTERPRETATION: This cohort provides novel data on factors potentially driving MS susceptibility in a diverse population, one-third of whom live in poverty. Environmental exposures have differential risk across ethnicity. ANN NEUROL 2020;87:599-608.

Primary Progressive Aphasia: Toward a Pathophysiological Synthesis.

PURPOSE OF REVIEW: The term primary progressive aphasia (PPA) refers to a diverse group of dementias that present with prominent and early problems with speech and language. They present considerable challenges to clinicians and researchers. RECENT FINDINGS: Here, we review critical issues around diagnosis of the three major PPA variants (semantic variant PPA, nonfluent/agrammatic variant PPA, logopenic variant PPA), as well as considering 'fragmentary' syndromes. We next consider issues around assessing disease stage, before discussing physiological phenotyping of proteinopathies across the PPA spectrum. We also review evidence for core central auditory impairments in PPA, outline critical challenges associated with treatment, discuss pathophysiological features of each major PPA variant, and conclude with thoughts on key challenges that remain to be addressed. New findings elucidating the pathophysiology of PPA represent a major step forward in our understanding of these diseases, with implications for diagnosis, care, management, and therapies.

Suspecting dementia: canaries, chameleons and zebras.

The early and accurate diagnosis of dementia is more important than ever before but remains challenging. Dementia is increasingly the business of neurologists and, with ageing populations worldwide, will become even more so in future. Here we outline a practical, symptom-led, bedside approach to suspecting dementia and its likely diagnosis, inspired by clinical experience and based on recognition of characteristic syndromic patterns. We show how clinical intuition reflects underlying signature profiles of brain involvement by the diseases that cause dementia and suggest next steps that can be taken to define the diagnosis. We propose 'canaries' that provide an early warning signal of emerging dementia and highlight the 'chameleons' that disguise or mimic this, as well as the 'zebras' that herald a rare (and sometimes curable) diagnostic opportunity.

The functional neuroanatomy of emotion processing in frontotemporal dementias.

Impaired processing of emotional signals is a core feature of frontotemporal dementia syndromes, but the underlying neural mechanisms have proved challenging to characterize and measure. Progress in this field may depend on detecting functional changes in the working brain, and disentangling components of emotion processing that include sensory decoding, emotion categorization and emotional contagion. We addressed this using functional MRI of naturalistic, dynamic facial emotion processing with concurrent indices of autonomic arousal, in a cohort of patients representing all major frontotemporal dementia syndromes relative to healthy age-matched individuals. Seventeen patients with behavioural variant frontotemporal dementia [four female; mean (standard deviation) age 64.8 (6.8) years], 12 with semantic variant primary progressive aphasia [four female; 66.9 (7.0) years], nine with non-fluent variant primary progressive aphasia [five female; 67.4 (8.1) years] and 22 healthy controls [12 female; 68.6 (6.8) years] passively viewed videos of universal facial expressions during functional MRI acquisition, with simultaneous heart rate and pupillometric recordings; emotion identification accuracy was assessed in a post-scan behavioural task. Relative to healthy controls, patient groups showed significant impairments (analysis of variance models, all P < 0.05) of facial emotion identification (all syndromes) and cardiac (all syndromes) and pupillary (non-fluent variant only) reactivity. Group-level functional neuroanatomical changes were assessed using statistical parametric mapping, thresholded at P < 0.05 after correction for multiple comparisons over the whole brain or within pre-specified regions of interest. In response to viewing facial expressions, all participant groups showed comparable activation of primary visual cortex while patient groups showed differential hypo-activation of fusiform and posterior temporo-occipital junctional cortices. Bi-hemispheric, syndrome-specific activations predicting facial emotion identification performance were identified (behavioural variant, anterior insula and caudate; semantic variant, anterior temporal cortex; non-fluent variant, frontal operculum). The semantic and non-fluent variant groups additionally showed complex profiles of central parasympathetic and sympathetic autonomic involvement that overlapped signatures of emotional visual and categorization processing and extended (in the non-fluent group) to brainstem effector pathways. These findings open a window on the functional cerebral mechanisms underpinning complex socio-emotional phenotypes of frontotemporal dementia, with implications for novel physiological biomarker development.

Big data, machine learning and artificial intelligence: a neurologist's guide.

Modern clinical practice requires the integration and interpretation of ever-expanding volumes of clinical data. There is, therefore, an imperative to develop efficient ways to process and understand these large amounts of data. Neurologists work to understand the function of biological neural networks, but artificial neural networks and other forms of machine learning algorithm are likely to be increasingly encountered in clinical practice. As their use increases, clinicians will need to understand the basic principles and common types of algorithm. We aim to provide a coherent introduction to this jargon-heavy subject and equip neurologists with the tools to understand, critically appraise and apply insights from this burgeoning field.

Frontotemporal Dementia: A Clinical Review.

Frontotemporal dementias are a clinically, neuroanatomically, and pathologically diverse group of diseases that collectively constitute an important cause of young-onset dementia. Clinically, frontotemporal dementias characteristically strike capacities that define us as individuals, presenting broadly as disorders of social behavior or language. Neurobiologically, these diseases can be regarded as "molecular nexopathies," a paradigm for selective targeting and destruction of brain networks by pathogenic proteins. Mutations in three major genes collectively account for a substantial proportion of behavioral presentations, with far-reaching implications for the lives of families but also potential opportunities for presymptomatic diagnosis and intervention. Predicting molecular pathology from clinical and radiological phenotypes remains challenging; however, certain patterns have been identified, and genetically mediated forms of frontotemporal dementia have spearheaded this enterprise. Here we present a clinical roadmap for diagnosis and assessment of the frontotemporal dementias, motivated by our emerging understanding of the mechanisms by which pathogenic protein effects at the cellular level translate to abnormal neural network physiology and ultimately, complex clinical symptoms. We conclude by outlining principles of management and prospects for disease modification.

Variable impact of late-Quaternary megafaunal extinction in causing ecological state shifts in North and South America.

Loss of megafauna, an aspect of defaunation, can precipitate many ecological changes over short time scales. We examine whether megafauna loss can also explain features of lasting ecological state shifts that occurred as the Pleistocene gave way to the Holocene. We compare ecological impacts of late-Quaternary megafauna extinction in five American regions: southwestern Patagonia, the Pampas, northeastern United States, northwestern United States, and Beringia. We find that major ecological state shifts were consistent with expectations of defaunation in North American sites but not in South American ones. The differential responses highlight two factors necessary for defaunation to trigger lasting ecological state shifts discernable in the fossil record: (i) lost megafauna need to have been effective ecosystem engineers, like proboscideans; and (ii) historical contingencies must have provided the ecosystem with plant species likely to respond to megafaunal loss. These findings help in identifying modern ecosystems that are most at risk for disappearing should current pressures on the ecosystems' large animals continue and highlight the critical role of both individual species ecologies and ecosystem context in predicting the lasting impacts of defaunation currently underway.

The sea as deathtrap: comment on a paper by miller and wiens.

Miller & Wiens (2017) claim that low marine as compared with terrestrial diversity results from more frequent extinctions and insufficient time for diversification in marine clades. Their data on marine amniotes are unrepresentative of marine diversity, their analysis of clade dynamics is flawed, and they ignore previously proposed explanations for the diversity difference.