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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.

Meta-Analysis of Generalized Additive Models in Neuroimaging Studies

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.

Lifestyle-related risk factors and their cumulative associations with hippocampal and total grey matter volume across the adult lifespan: A pooled analysis in the European Lifebrain consortium.

BACKGROUND: Lifestyle-related risk factors, such as obesity, physical inactivity, short sleep, smoking and alcohol use, have been associated with low hippocampal and total grey matter volumes (GMV). However, these risk factors have mostly been assessed as separate factors, leaving it unknown if variance explained by these factors is overlapping or additive. We investigated associations of five lifestyle-related factors separately and cumulatively with hippocampal and total GMV, pooled across eight European cohorts. METHODS: We included 3838 participants aged 18-90 years from eight cohorts of the European Lifebrain consortium. Using individual person data, we performed cross-sectional meta-analyses on associations of presence of lifestyle-related risk factors separately (overweight/obesity, physical inactivity, short sleep, smoking, high alcohol use) as well as a cumulative unhealthy lifestyle score (counting the number of present lifestyle-related risk factors) with FreeSurfer-derived hippocampal volume and total GMV. Lifestyle-related risk factors were defined according to public health guidelines. RESULTS: High alcohol use was associated with lower hippocampal volume (r = -0.10, p = 0.021), and overweight/obesity with lower total GMV (r = -0.09, p = 0.001). Other lifestyle-related risk factors were not significantly associated with hippocampal volume or GMV. The cumulative unhealthy lifestyle score was negatively associated with total GMV (r = -0.08, p = 0.001), but not hippocampal volume (r = -0.01, p = 0.625). CONCLUSIONS: This large pooled study confirmed the negative association of some lifestyle-related risk factors with hippocampal volume and GMV, although with small effect sizes. Lifestyle factors should not be seen in isolation as there is evidence that having multiple unhealthy lifestyle factors is associated with a linear reduction in overall brain volume.

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.

Brain imaging and treatment response in spasmodic torticollis.

A patient with spasms of the neck, occurring when he turned his head to the left, responded to treatment with benzhexol. Cerebral blood flow imaging demonstrated reduced uptake in the right corpus striatum compared with the left. The study demonstrates the presence of an abnormality in the basal ganglia; it also illustrates response to drug treatment. Cerebral blood flow imaging may be useful in the detection of basal ganglia abnormalities in spasmodic torticollis and assist in the selection of cases which should be targeted for treatment with drugs.

Magnetic resonance imaging and single photon emission tomography in treatment-responsive and treatment-resistant schizophrenia.

BACKGROUND: Patients with schizophrenia differ from controls in several measures of brain structure and function, but it is uncertain how these relate to clinical features of the illness. We dichotomised patient groups by treatment response to test the hypothesis that treatment-resistant patients exhibit more marked biological abnormalities than treatment-responsive patients. METHOD: Twenty treatment-responsive and 20 treatment-resistant patients with schizophrenia, matched for sex, age, and illness duration, were compared by magnetic resonance imaging, single photon emission tomography, and detailed neuropsychological assessment. RESULTS: Brain-imaging variables were not statistically related to treatment response, although poorly responsive patients had lower volumes of most brain structures. Several highly significant differences emerged between patient groups on neuropsychological testing. Episodic memory functioning distinguished patient groups even after we controlled for global cognitive impairment. CONCLUSIONS: Cerebral structure and blood flow have a limited effect on treatment response in schizophrenia, but long-term episodic memory impairment is associated with, and may predict, poor prognosis.

A single photon emission computerised tomography study of regional brain function underlying verbal memory in patients with Alzheimer-type dementia.

Ten patients with Alzheimer-type dementia and nine age-matched normal controls were examined with SPECT, using split-dose 99mTc-labelled exametazime. The baseline condition involved repetition of the word 'yes' or 'no'. The activation condition involved recognition (indicated by a 'yes' or 'no') of words from a previously learned list presented along with distractor words. Patients who performed this task successfully were selected, and efforts were made to match the patients with controls according to their performance on the task, although this was not fully achieved. Uptake of 99mTc-exametazime was estimated at baseline and during the word-recognition task for predetermined regions of interest drawn from a standard neuroanatomical atlas. The baseline task appeared to normalise tracer uptake for frontal, temporal and parietal cortex in the patient group. However, during the recognition task, controls but not patients showed activation effects. These were most prominent in dorsolateral frontal cortex and adjacent anterior cingulate cortex. Among patients, successful performance was correlated with activation of dorsolateral frontal and parietal cortex on the left side. The results confirm the central role of frontal mechanisms in a recognition memory task. The study highlights some of the difficulties of using cognitive challenge tests in clinical groups.

A single photon emission computerised tomography study of regional brain function in elderly patients with major depression and with Alzheimer-type dementia.

The uptake, at rest, of 99mTc-exametazime into different brain regions was compared using SPECT for 20 elderly subjects with major depressive disorder, 20 with Alzheimer-type dementia, and 30 age-matched normal volunteers. Uptake was referred to calcarine-occipital cortex as a reference sensory area. Cross-sectional differences between the three groups were highly statistically significant, but reflected primarily the reductions in cortical uptake in the Alzheimer group. A detailed comparison of depressed patients and controls identified decrements in anterior cingulate, temporal and frontal cortex and in caudate and thalamus in men only. These decrements were correlated with impairment of performance on a trail-making task, but were also associated with continuing treatment with antidepressants or benzodiazepines. However, most depressed patients had quantitatively normal scans for posterior parietal association cortex, and this suggests that SPECT may find a limited role in the differential diagnosis of depression and dementia. The reduced brain function in some depressed patients may parallel the findings from studies of brain structure in elderly depressives; there was between good outcome at 6-18 months and increased tracer uptake in subcortical areas.

Multimodal imaging in Alzheimer's disease. The relationship between MRI, SPECT, cognitive and pathological changes.

Patients with a clinical diagnosis of Alzheimer's disease were studied using MRI, SPECT, and psychometric tests. Significant correlations between focal perfusion deficits and focal cognitive deficits were found. Significant correlations between regional relaxation time of white matter and psychometric tests of diffuse and focal categories were also found. Pathological examination confirmed Alzheimer's disease as the only diagnosis.

The neuropsychiatric sequelae of mercury poisoning. The Mad Hatter's disease revisited.

BACKGROUND: The detailed effects of mercury poisoning on cognitive function, brain anatomy and regional brain function are largely unknown. We report the case of a 38-year-old man who was exposed to toxic levels of inorganic mercury. METHOD: Four years after exposure, the patient was assessed using magnetic resonance imaging (MRI), single-photon emission computerised tomography (SPECT) and detailed neuropsychological evaluation. RESULTS: The patient developed a myriad of physical and psychiatric complaints, including stomatitis, muscle spasm, tremor, skin rash and the psychiatric syndrome known as 'erythism' (Mad Hatter's disease). Neuropsychological evaluation revealed marked and significant deficits of attention concentration, particularly when under time pressure. The MRI scan was unremarkable; however, SPECT revealed hypermetabolism of the posterior cingulate CONCLUSIONS: Mercury poisoning appeared to result in a dysregulation of posterior cingulate cortex, which was associated with attention/concentration deficits and marked anxiety/agitation.

Estimation of premorbid intelligence in schizophrenia.

To determine whether the National Adult Reading Test (NART) would provide a valid estimate of premorbid intelligence in schizophrenia, two schizophrenic samples were recruited, one consisting of 35 patients resident in long-stay wards, the other of 29 patients normally resident in the community. Schizophrenic patients were individually matched for age, sex, and education with a healthy, normal subject. Both schizophrenic samples scored significantly lower on the Wechsler Adult Intelligence Scale (WAIS) than their respective control groups. NART-estimated IQ did not differ significantly between the community-resident schizophrenics and their controls, suggesting that the NART provides a valid means of estimating premorbid intelligence in such a population. NART-estimated IQ was significantly lower in the long-stay sample than in their controls. Although low NART scores in this latter sample could be a valid reflection of low premorbid IQ, the alternative explanation that NART performance was impaired by onset of the disease cannot be ruled out.

Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging study.

BACKGROUND: The aetiology of treatment-resistant major depression is little understood; its apparent intractability may reflect brain abnormality. METHOD: Magnetic resonance images of the brains of 20 subjects with major depression lasting for two years or more were compared with 20 healthy control subjects and 20 other subjects who had completely recovered from depression. Subjects were individually matched for age, gender, years of education and premorbid IQ. Grey matter was segmented from the images, and compared between groups on a voxel-by-voxel basis. RESULTS: Subjects with chronic depression showed reduced grey matter density in the left temporal cortex including the hippocampus. There was also a trend for reduction in the right hippocampus. Left hippocampal grey matter density was correlated with measures of verbal memory, supporting the functional significance of the observed magnetic resonance imaging changes. CONCLUSIONS: Our results potentially challenge the accepted view of depression as a functional and fully reversible illness, implying instead that more permanent brain changes may be associated with chronicity. Confirmatory longitudinal and prospective studies are required to determine whether these differences pre-date the onset of depression or are the result of the chronic illness process or its treatment.

Reduced cortical excitability in depression. Impaired post-exercise motor facilitation with transcranial magnetic stimulation.

BACKGROUND: In healthy controls, preactivation of muscles by exercise results in enhanced motor-evoked potential (MEP) responses to transcranial magnetic stimulation (TMS). AIMS: We tested the hypothesis that medicated, depressed patients would show reduced post-exercise MEP facilitation compared with controls. METHOD: Ten patients with DSM-IV depression (two male, eight female) and ten controls (three male, seven female) participated. MEPs were elicited at rest, then after exercising the contralateral abductor pollicis brevis muscle, using TMS of the primary motor cortex. RESULTS: The mean MEP amplitude recorded after exercise (expressed as a percentage of baseline) was 210% in controls and 130% in patients. There was a significant difference in post-exercise MEP between patients and controls (P = 0.03). CONCLUSIONS: Post-exercise MEP facilitation was demonstrated in controls but not in patients. This supports the hypothesis that the modulation of cortical excitability may be impaired in depression.

Uptake of 99mTc-exametazime shown by single photon emission computed tomography before and after lithium withdrawal in bipolar patients: associations with mania.

BACKGROUND: Early manic relapse following lithium discontinuation offers an important opportunity to investigate the relationship between symptoms, effects of treatment and regional brain activation in bipolar affective disorder. METHOD: Fourteen stable bipolar patients on lithium were examined with neuropsychological measures, clinical ratings and single photon emission computed tomography (SPECT) before and after acute double-blind withdrawal of lithium. Brain perfusion maps were spatially transformed into standard stereotactic space and compared pixel-by-pixel. A parametric analysis was used to examine the change in brain perfusion on lithium withdrawal, and the relationship between symptom severity and brain perfusion separately both between and within subjects. RESULTS: Lithium withdrawal was associated with an important redistribution of brain perfusion, with increases in inferior posterior regions and decreases in limbic areas, particularly anterior cingulate cortex. Seven of the 14 patients developed manic symptoms during the placebo phase, correlating with relative increases in perfusion of superior anterior cingulate and possibly left orbito-frontal cortex. CONCLUSIONS: The important effect of lithium withdrawal on brain perfusion implies that after withdrawal of lithium, the brain develops an abnormal state of activity in limbic cortex. The structures involved did not co-localise with those apparently modulated by manic symptoms.