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Subtyping Alzheimer's disease and Parkinson's disease using longitudinal electronic health records.
Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) are clinically heterogeneous, hampering the success of nonselective treatment strategies. Here we apply a transformer-based unsupervised clustering framework to longitudinal electronic health record data from over 100,000 patients across two UK cohorts, Clinical Practice Research Datalink Aurum and UK Biobank, to identify, validate and characterize subtypes of AD and PD. We uncover five reproducible subtypes for each condition, characterized by distinct comorbidity patterns, symptom trajectories, outcomes and genetic profiles. These include a high-mortality AD subtype with motor and cardiovascular features, and a genetically susceptible but clinically resilient PD subtype. We also identify metabolic-inflammatory and vascular-psychiatric phenotypes shared across AD and PD, suggesting cross-disease mechanisms. By integrating routinely collected electronic health record data with genetic analyses, our study provides a scalable framework for early, biologically informed subtyping, laying the groundwork for future targeted interventions in neurodegenerative diseases.
An atlas of age- and sex-related volumetric alterations of grey matter in subcortical regions: The case of 46,111 UK Biobank participants.
Ageing is commonly associated with neuroanatomical changes in brain structure, underscoring the importance of distinguishing normal age-related alterations from those linked to pathological neurodegeneration. Despite this critical need, a standardized benchmark for identifying brain volumetric signatures of ageing remains lacking, and the influence of biological sex on age-related changes in brain volume is not yet fully understood. To address the above-mentioned gaps, we employed T1-weighted MRI images of 46,111 cognitively healthy individuals aged 44-83 from the UK Biobank cohort, and generated comprehensive maps of all the linear and non-linear trajectories of alterations in the grey matter volumes (GMVs) of subcortical regions across males and females. According to our findings, Brainstem, bilateral Amygdala and Hippocampus are the most susceptible subcortical regions to age-related atrophy, with males being generally more prone to such alterations. However, ageing proves to have a dual function as we also observed age-related inflammation in GMVs of Pallidum and Caudate which accelerates during older age and remains consistent across males and females. Our findings guide regenerative strategies and therapeutic interventions by locating subcortical regions most vulnerable to age-related atrophy and inflammation and establish a benchmark for sex-specific typical patterns of subcortical grey matter alterations due to ageing.
Distinct connectivity patterns in clusters of inferior parietal cortex: from a cognitive control hub to modulating cortical areas.
The inferior parietal cortex (IPC) is a complex brain region, composed of the rostral, the middle and the caudal clusters, and functionally connected to several other parts of the brain. Various executive functions are suggested to be governed by the IPC, however, by ignoring the tripartite structure of this region, contradictory research reports abound in the literature. Here, we elaborated on the functional connectivity patterns of the clusters of the IPC, highlighting evidence that only the rostral cluster of this part of the brain is involved in cognitive control, not the entire IPC. We also underscored the unique connectivity profile of the middle and the caudal clusters which are not accommodated by the traditional classification of brain areas as either being task-based or being related to the resting-state functionality of the brain. The middle and the caudal IPC demonstrate negative functional associations with cortical areas involved in general cognitive functions, executive functions, in addition to the precuneus cortex, proportional to cognitive demand, in a modulating manner, while remaining distinct from resting-state related parts of the cortex.
Cognitive demand modulates connectivity patterns of rostral inferior parietal cortex in cognitive control of language.
The inferior parietal cortex (IPC) is involved in different cognitive functions including language. In line with the correlated transmitter receptor-based organization of the IPC, this part of the brain is parcellated into the rostral, the middle and the caudal clusters; however, the tripartite organization of the IPC has not been addressed in studies with a focus on cognitive control of language. Using multiband EPI, in this study we investigated how the rostral IPC contributes to this executive function in bilinguals. In doing so, we focused on the functional connectivity patterns of this part of the cortex with other brain areas in a context characterized with language engagement and disengagement that recruits the neural mechanisms of cognitive control. We found that in switching to L2, which was cognitively less demanding, the right rostral IPC had positive functional connectivity with the anterior division of the cingulate gyrus and the precentral gyrus. However, in switching to L1, which was cognitively more demanding, the right IPC rostral cluster had negative functional coupling with the postcentral gyrus and the precuneus cortex and positive connectivity with the posterior lobe of the cerebellum. In this condition, the left IPC rostral cluster had negative functional coupling with the superior frontal gyrus and the precuneus cortex. Thus, the connectivity patterns of the rostral IPC was influenced by the cognitive demand in an asymmetrical and lateral manner during cognitive control of language.
Connectivity Profile of Middle Inferior Parietal Cortex Confirms the Hypothesis About Modulating Cortical Areas.
According to the correlated transmitter-receptor based structure of the inferior parietal cortex (IPC), this brain area is divided into three clusters, namely, the caudal, the middle and the rostral. Nevertheless, in associating different cognitive functions to the IPC, previous studies considered this part of the cortex as a whole and thus inconsistent results have been reported. Using multiband echo planar imaging (EPI), we investigated the connectivity profile of the middle IPC while forty-five participants performed a task requiring cognitive control. The middle IPC demonstrated functional associations which do not have similarities to a contributing part in the frontoparietal network, in processing cognitive control. At the same time, this cortical area showed negative functional connectivity with both the precuneus cortex, which is resting- state related, and brain areas related to general cognitive functions. That is, the functions of the middle IPC are not accommodated by the traditional categorization of different brain areas i.e. resting state-related or task-related networks and this advanced our hypothesis about modulating cortical areas. Such brain areas are characterized by their negative functional connectivity with parts of the cortex involved in task performance, proportional to the difficulty of the task; yet, their functional associations are inconsistent with the resting state-related cortical areas.
Dual Function of Primary Somatosensory Cortex in Cognitive Control of Language: Evidence from Resting State fMRI.
Resting state functional connectivity can be leveraged to investigate bilingual individual differences in cognitive control of language; however, thus far no report is provided on how the connectivity profiles of brain functional networks at rest point to different language control behavior in bilinguals. In order to address this gap in state-of-the-art research we did a functional connectivity analysis on the resting state data acquired via multiband EPI to investigate three resting state networks of interest namely, the frontoparietal network (FPN), the salience network (SN), and the default mode network (DMN), which are related to cognitive control, between two groups of Dutch-English bilinguals based on how they performed in a language switching task. Results demonstrated that there is the increased coupling of the left primary somatosensory cortex with the dorsolateral prefrontal cortex in the group with better performance in cognitive control of language and the increased coupling of the right primary somatosensory cortex with the inferior parietal cortex in the group with poorer performance in this executive function. As regards these results, we claim that the primary somatosensory cortex has a dual function in coupling with the dorsolateral prefrontal cortex and the inferior parietal cortex in the FPN, and in fact, in what characterizes bilingual individual differences in cognitive control of language in healthy participants. The results of this study provide a model for future research in cognitive control of language and may serve as a reference in clinical neuroscience when bilinguals are diagnosed with dysfunction in cognitive control.
Mapping caudal inferior parietal cortex supports the hypothesis about a modulating cortical area.
The cytoarchitectonically tripartite organization of the inferior parietal cortex (IPC) into the rostral, the middle and the caudal clusters has been generally ignored when associating different functions to this part of the cortex, resulting in inconsistencies about how IPC is understood. In this study, we investigated the patterns of functional connectivity of the caudal IPC in a task requiring cognitive control, using multiband EPI. This part of the cortex demonstrated functional connectivity patterns dissimilar to a cognitive control area and at the same time the caudal IPC showed negative functional associations with both task-related brain areas and the precuneus cortex, which is active during resting state. We found evidence suggesting that the traditional categorization of different brain areas into either task-related or resting state-related networks cannot accommodate the functions of the caudal IPC. This underlies the hypothesis about a new brain functional category as a modulating cortical area proposing that its involvement in task performance, in a modulating manner, is marked by deactivation in the patterns of functional associations with parts of the brain that are recognized to be involved in doing a task, proportionate to task difficulty; however, its patterns of functional connectivity in some other respects do not correspond to the resting state-related parts of the cortex.
White matter hyperintensities classified according to intensity and spatial location reveal specific associations with cognitive performance.
White matter hyperintensities (WMHs) on T2-weighted images are radiological signs of cerebral small vessel disease. As their total volume is variably associated with cognition, a new approach that integrates multiple radiological criteria is warranted. Location may matter, as periventricular WMHs have been shown to be associated with cognitive impairments. WMHs that appear as hypointense in T1-weighted images (T1w) may also indicate the most severe component of WMHs. We developed an automatic method that sub-classifies WMHs into four categories (periventricular/deep and T1w-hypointense/nonT1w-hypointense) using MRI data from 684 community-dwelling older adults from the Whitehall II study. To test if location and intensity information can impact cognition, we derived two general linear models using either overall or subdivided volumes. Results showed that periventricular T1w-hypointense WMHs were significantly associated with poorer performance in the trail making A (p = 0.011), digit symbol (p = 0.028) and digit coding (p = 0.009) tests. We found no association between total WMH volume and cognition. These findings suggest that sub-classifying WMHs according to both location and intensity in T1w reveals specific associations with cognitive performance.
Association of ideal cardiovascular health at age 50 with incidence of dementia: 25 year follow-up of Whitehall II cohort study.
OBJECTIVES: To examine the association between the Life Simple 7 cardiovascular health score at age 50 and incidence of dementia. DESIGN: Prospective cohort study. SETTING: Civil service departments in London (Whitehall II study; study inception 1985-88). PARTICIPANTS: 7899 participants with data on the cardiovascular health score at age 50. EXPOSURES: The cardiovascular health score included four behavioural (smoking, diet, physical activity, body mass index) and three biological (fasting glucose, blood cholesterol, blood pressure) metrics, coded on a three point scale (0, 1, 2). The cardiovascular health score was the sum of seven metrics (score range 0-14) and was categorised into poor (scores 0-6), intermediate (7-11), and optimal (12-14) cardiovascular health. MAIN OUTCOME MEASURE: Incident dementia, identified through linkage to hospital, mental health services, and mortality registers until 2017. RESULTS: 347 incident cases of dementia were recorded over a median follow-up of 24.7 years. Compared with an incidence rate of dementia of 3.2 (95% confidence interval 2.5 to 4.0) per 1000 person years among the group with poor cardiovascular health, the absolute rate differences per 1000 person years were -1.5 (95% confidence interval -2.3 to -0.7) for the group with intermediate cardiovascular health and -1.9 (-2.8 to -1.1) for the group with optimal cardiovascular health. Higher cardiovascular health score was associated with a lower risk of dementia (hazard ratio 0.89 (0.85 to 0.95) per 1 point increment in the cardiovascular health score). Similar associations with dementia were observed for the behavioural and biological subscales (hazard ratios per 1 point increment in the subscores 0.87 (0.81 to 0.93) and 0.91 (0.83 to 1.00), respectively). The association between cardiovascular health at age 50 and dementia was also seen in people who remained free of cardiovascular disease over the follow-up (hazard ratio 0.89 (0.84 to 0.95) per 1 point increment in the cardiovascular health score). CONCLUSION: Adherence to the Life Simple 7 ideal cardiovascular health recommendations in midlife was associated with a lower risk of dementia later in life.
Functional brain imaging and connectivity in dementia
Although several dierent image modalities will be described, neuroimaging studies of brain function in dementia largely fall into two categories: (1) the study of resting blood ow and (2) measurement of brain changes due to a specic task. is chapter starts with a brief description of methods of emission tomography, functional magnetic resonance imaging (fMRI) and diusion tensor imaging (DTI) before describing applications in patients.
Inter- and intra-individual variation in brain structural-cognition relationships in aging.
The sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain structure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age = 69.52 ± 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age = 53.2 ±4.9 years) and late-life (mean age = 67.7 ± 4.9). Using non-negative matrix factorization, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two latent variables describing distinct brain-cognition associations. The first describes variations in 5 structural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid-life performance in fluency and memory, but retention of multiple abilities. Expression of latent variables predicts future cognition 3.2 years later (mean age = 70.87 ± 4.9). This data-driven approach highlights brain-cognition relationships wherein individuals degrees of cognitive decline and maintenance across diverse cognitive functions are both positively and negatively associated with markers of cortical structure.
Innate and adaptive immunity in the development of depression: An update on current knowledge and technological advances.
The inflammation theory of depression, proposed over 20years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced 'omics' technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account.
Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder.
Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d=0.54, p<0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d=0.47, p<0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-α levels and major depression (d=0.40, p=0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1β levels and major depression (d=-0.05, p=0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-α, interleukin-1β and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.
Explaining and understanding in psychopathology.
Psychoanalytical methodology has been described as causal explanation or hermeneutic understanding. This methodological dichotomy has been introduced into psychopathology by Karl Jaspers. Contemporary authors' contributions in the area are discussed. Although these authors accept a role for both methods, they agree with Jaspers that psychoanalysis should be subjected to the logical limitations of hermeneutic analysis. A logical framework for the interaction of explaining with understanding is presented and discussed in relation to psychiatric research.
Further evidence that reading ability is not preserved in Alzheimer's disease.
BACKGROUND: Pre-morbid intelligence level is routinely assessed in Alzheimer's disease using the National Adult Reading Test (NART). This practice is based on the assumption that pronunciation of irregular words remains unaffected by the disease process. Recent reports have suggested that reading ability may become compromised in moderately demented subjects. METHOD: Sixty-eight probably Alzheimer patients were classified into stages of severity (minimal, mild and moderate) using the Mini-Mental State Examination (MMSE). NART and demographic equations were used to estimate pre-morbid ability. RESULTS: A significant correlation emerged between dementia severity and reading ability, NART v. MMSE scores, r = 0.46, P < 0.01. When the total sample was subdivided into moderate, mild and minimal subgroups, significant between-group differences emerged, despite the groups being well matched for age, sex, and years of full-time education. Pre-morbid IQ, as estimated by demographic regression equations, did not correlate with dementia severity. CONCLUSION: NART performance is compromised in moderate Alzheimer disease, and the measure provides a serious underestimate of pre-morbid IQ in patients with an MMSE of 13 or less.
Follow-up study of depression in the elderly. Clinical and SPECT data.
BACKGROUND: Imaging studies in depression of the elderly are often small and highly selective. AIMS: To investigate a large group of elderly depressed patients in order to assess changes in clinical, imaging and neuropsychological variables at follow-up. METHOD: Patients (n = 175, age range 65-91 years) with clinical depression were identified from consecutive local referrals. Clinical interviews, neuropsychological tests and SPECT scans were carried out at referral and at two-year follow-up. RESULTS: Of 84 re-examined patients, 46.5% were well, 9.5% were ill, 33% partially recovered and 11% had developed dementia. Duration of illness before index assessment was the only factor to predict outcome. Thirty-nine patients could be scanned and followed up. There were no differences between patients with good or poor depressive outcome on SPECT. Ten clinically improved patients could be re-examined with SPECT. There were relative increases in right cingulate gyrus and right cerebellum at follow-up. CONCLUSIONS: The patients group was comparable with other studies showing high levels of residual depressive symptoms. Activity changes in limbic cortex are implicated in depression of old age.