Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis.

Importance: The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. Objectives: To assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group. Data Source and Study Selection: Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece). Data Extraction and Synthesis: Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines. Main Outcomes and Measures: The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group. Results: The analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses. Conclusions and Relevance: This individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

Genetically Predicted Blood Pressure and Cognition in Midlife: A UK Biobank Study.

BACKGROUND: This UK Biobank study uses a mendelian randomization approach to mitigate the variability and confounding that has affected previous analyses of the relationship between measured blood pressure (BP) and cognition and thus delineate the true association between the two. METHODS: Systolic BP (SBP) and diastolic BP polygenic risk scores (PRSs) were calculated using summary statistics from the International Consortium of Blood Pressure-Genome Wide Association Study (n=299 024). Adjusted nonlinear mixed-effects regression models were used, including a natural splines term for BP-PRS with outcomes of fluid intelligence, reaction time (RT), and composite attention score. Moderating effects of age, sex, and antihypertensive use were assessed in separate models. RESULTS: There were 448 575 participants (mean age, 56.3 years; age range, 37-72 years) included in the analysis after genetic and neurological disease exclusions. Genetic propensity for high SBP had an approximately linear association with worsened fluid intelligence (P=0.0018). This relationship was significantly moderated by age (P<0.0001). By contrast, genetic propensity for high and low SBP and diastolic BP predicted worse attention function (P=0.0099 and P=0.0019), with high PRSs predicting worse function than low PRSs. Genetic propensity for low SBP and diastolic BP was associated with considerably worse RTs, while for high SBP-PRSs, the RT plateaued (P<0.0001). The relationships between RT and the PRSs were significantly moderated by sex (P<0.0001) and antihypertensive use (P<0.0001). CONCLUSIONS: Genetic propensity for high and low BP impacts on midlife cognition in subtle ways and differentially affects cognitive domains. While a genetic propensity to low BP may preserve nontimed tests in midlife, it may come at a trade-off with worsened attention scores and RT.

Understanding and managing the long-term cognitive consequences of traumatic brain injuries.

This editorial critically evaluates the current data on traumatic brain injuries and their effects on cognitive function. It discusses management strategies and clinical considerations to improve patient outcomes in light of these findings.

Machine learning prediction will be part of future treatment of depression.

Machine learning (ML) is changing the way that medicine is practiced. While already clinically utilised in diagnostic radiology and outcome prediction in intensive care unit, ML approaches in psychiatry remain nascent. Implementing ML algorithms in psychiatry, particularly in the treatment of depression, is significantly more challenging than other areas of medicine in part because of the less demarcated disease nosology and greater variability in practice. Given the current exiguous capacity of clinicians to predict patient and treatment outcomes in depression, there is a significantly greater need for better predictive capability. Early studies have shown promising results. ML predictions were significantly better than chance within the sequenced treatment alternatives to relieve depression (STAR*D) trial (accuracy 64.6%, p < 0.0001) and combining medications to enhance depression outcomes (COMED) randomised Controlled Trial (RCT) (accuracy 59.6%, p = 0.043), with similar results found in larger scale, retrospective studies. The greater flexibility and dimensionality of ML approaches has been demonstrated in studies incorporating diverse input variables including electroencephalography scans, achieving 88% accuracy for treatment response, and cognitive test scores, achieving up to 72% accuracy for treatment response. The predicting response to depression treatment (PReDicT) trial tested ML informed prescribing of antidepressants against standard therapy and found there was both better outcomes for anxiety and functional endpoints despite the algorithm only having a balanced accuracy of 57.5%. Impeding the progress of ML algorithms in psychiatry are pragmatic hurdles, including accuracy, expense, acceptability and comprehensibility, and ethical hurdles, including medicolegal liability, clinical autonomy and data privacy. Notwithstanding impediments, it is clear that ML prediction algorithms will be part of depression treatment in the future and clinicians should be prepared for their arrival.

Lifetime Traumatic Brain Injury and Cognitive Domain Deficits in Late Life: The PROTECT-TBI Cohort Study.

Traumatic brain injury (TBI) causes cognitive impairment but it remains contested regarding which cognitive domains are most affected. Further, moderate-severe TBI is known to be deleterious, but studies of mild TBI (mTBI) show a greater mix of negative and positive findings. This study examines the longer-term cognitive effects of TBI severity and number of mTBIs in later life. We examined a subset (n = 15,764) of the PROTECT study, a cohort assessing risk factors for cognitive decline (ages between 50 and 90 years). Participants completed cognitive assessments annually for 4 years. Cognitive tests were grouped using a principal components analysis (PCA) into working memory, episodic memory, attention, processing speed, and executive function. Lifetime TBI severity and number were retrospectively recalled by participants using the Brain Injury Screening Questionnaire (BISQ). Linear mixed models (LMMs) examined the effect of severity of head injury (non-TBI head strike, mTBI, and moderate-severe TBI) and number of mTBI at baseline and over time. mTBI was considered as a continuous and categorical variable (groups: 0 mTBI, 1 mTBI, 2 mTBIs, 3 mTBIs, and 4+ mTBIs). Of the participants 5725 (36.3%) reported at least one mTBI and 510 (3.2%) at least one moderate-severe TBI, whereas 3711 (23.5%) had suffered at worst a non-TBI head strike and 5818 (32.9%) reported no head injuries. The participants had suffered their last reported head injury an average (standard deviation, SD) of 29.6 (20.0) years prior to the study. Regarding outcomes, there was no worsening in longitudinal cognitive trajectories over the study duration but at baseline there were significant cognitive deficits associated with TBI. At baseline, compared with those without head injury, individuals reporting at least one moderate-severe TBI had significantly poorer attention (B = -0.163, p < 0.001), executive scores (B = -0.151, p = 0.004), and processing speed (B = -0.075, p = 0.033). Those who had suffered at least a single mTBI also demonstrated significantly poorer attention scores at baseline compared with the no head injury group (B = -0.052, p = 0.001). Compared with those with no mTBI, those in the 3 mTBI group manifested poorer baseline executive function (B = -0.149, p = 0.025) and attention scores (B = -0.085, p = 0.015). At baseline, those who had suffered four or more mTBIs demonstrated poorer attention (B = -0.135, p < 0.001), processing speed (B = -0.072, p = 0.009), and working memory (B = -0.052, p = 0.036), compared with those reporting no mTBI. TBI is associated with fixed, dose, and severity-dependent cognitive deficits. The most sensitive cognitive domains are attention and executive function, with approximately double the effect compared with processing speed and working memory. Post-TBI cognitive rehabilitation should be targeted appropriately to domain-specific effects. Significant long-term cognitive deficits were associated with three or more lifetime mTBIs, a critical consideration when counseling individuals post-TBI about continuing high-risk activities.

Genetic Therapies for Alzheimer's Disease: A Scoping Review.

Effective, disease modifying therapies for Alzheimer's disease (AD) remain a quandary, following a panoply of expensive failures in human clinical trials. Given the stagnation in therapeutics, alternative approaches are needed. Recent successes of genetic therapies in other neurodegenerative diseases may highlight the way forward. This scoping review explores suggested targets of genetic therapy in AD, with a focus on vector-based approaches in pre-clinical and clinical trials. Putative targets of genetic therapies tested in pre-clinical trials include amyloid pathway intermediates and enzymes modulation, tau protein downregulation, APOE4 downregulation and APOE2 upregulation, neurotrophin expression (nerve growth factor (NGF) and brain-derived neurotrophic factor), and inflammatory cytokine alteration, among several other approaches. There have been three completed human clinical trials for genetic therapy in AD patients, all of which upregulated NGF in AD patients, showing some mixed evidence of benefit. Several impediments remain to be surpassed before genetic therapies can be successfully applied to AD, including the challenge of delivering monogenic genetic therapies for complex polygenic disorders, risks in the dominant delivery method (intracranial injection), stability of genetic therapies in vivo, poor translatability of pre-clinical AD models, and the expense of genetic therapy production. Genetic therapies represent an exciting opportunity within the world of AD therapeutics, but clinical applications likely remain a long term, rather than short term, possibility.

Hypertension and Alzheimer's disease: is the picture any clearer?

PURPOSE OF REVIEW: The relationship between hypertension and Alzheimer's disease (AD) is complex and varies across the lifespan. Studies have suggested that midlife hypertension is a risk factor for AD, although studies of late life hypertension have suggested that it either has no effect or a weak protective effect. RECENT FINDINGS: Animal models of induced and spontaneous hypertension have found that AD pathological change (ß-amyloid plaques and tau tangles) occurs within weeks of a hypertensive insult. Human imaging and autopsy studies indicate that midlife and late life hypertension are associated with increased AD pathological change. Meta-analyses of longitudinal studies indicate that midlife rather than late life hypertension is a risk factor for AD. New areas of research have suggested that rather than mean blood pressure (BP), it is the negative BP trajectories or the variability of BP that contributes to AD. In a number of meta-analyses of antihypertensive medications and their effect on AD, there were weak associations between improved AD outcomes and treatment. SUMMARY: The combined analysis of animal, human clinical/pathological, epidemiological and drug trial data indicates that hypertension increases the risk of AD and treatment of hypertension may be an appropriate preventive measure.

Does Antihypertensive Use Moderate the Effect of Blood Pressure on Cognitive Decline in Older People?

BACKGROUND: While midlife hypertension is deleterious, late-life hypertension has been associated with better cognitive outcomes in several studies. Many questions remain, including the relative benefit or harm of a blood pressure (BP) target and antihypertensive therapy of <120 in very old individuals. METHODS: The Sydney Memory and Aging Study (n = 1015) comprises a cohort of 70- to 90-year-olds, who were followed biennially for 8 years. Global cognition was assessed with a battery of 10 neuropsychological tests. Blood pressure was measured at Waves 1 and 2 and classified into 3 systolic groupings: group 1 (≤120 mmHg), group 2 (121-140 mmHg), and group 3 (>140 mmHg). Multiple regression, linear mixed modeling, and Cox regression examined the effect of BP and antihypertensives. RESULTS: There were no overall significant differences in global cognition or dementia between the disparate BP groups. However, in those not taking antihypertensives, the systolic BP (SBP) > 140 mmHg group had a significantly worse global cognitive trajectory compared to SBP ≤ 120 mmHg (b = -0.067, 95% CI [-0.129, -0.006], p = .030). Within the SBP ≤ 120 mmHg group those taking antihypertensives had significantly worse global cognition trajectories compared to those not taking antihypertensives even when controlling for past history of hypertension (b = -0.077, 95% CI [-0.147, -0.007], p = .030). CONCLUSIONS: Untreated hypertension in old age is related to worse global cognitive decline. However, ongoing treatment at new recommendations of lower SBP targets may be related to poorer cognitive decline and should be considered carefully in older populations.

Understanding the professional satisfaction of hospital trainees in Australia.

CONTEXT: Ensuring that specialty trainees are professionally satisfied is not only important from the point of view of trainee well-being, but is also critical if health systems are to retain doctors. Despite this, little systematic research in specialist trainees has identified policy-amenable factors correlated with professional satisfaction. This study examined factors associated with trainee professional satisfaction in a national Australian cohort. METHODS: This study used 2008-2015 data from the Medicine in Australia: Balancing Employment and Life (MABEL) survey, a national study of doctor demographics, characteristics and professional and personal satisfaction. Our study examined specialist trainees using a repeat cross-sectional method pooling first responses across all waves. A multivariate logistic regression analysis was used to assess correlates with professional satisfaction. RESULTS: The three factors most strongly correlated with professional satisfaction were feeling well supported and supervised by consultants (odds ratio [OR] 2.59, 95% confidence interval [CI] 2.42-2.77), having sufficient study time (OR 1.54, 95% CI 1.40-1.70) and self-rated health status (OR 1.65, 95% CI 1.53-1.80). Those working >56 hours per week were significantly less professionally satisfied (OR 0.76, 95% CI 0.70-0.84) compared with those working the median work hours (45-50 hours per week). Those earning in the lower quintiles, those earlier in their training and those who had studied at overseas universities were also significantly less likely to be satisfied. CONCLUSIONS: Our study suggests that good clinical supervision and support, appropriate working hours and supported study time directly impact trainee satisfaction, potentially affecting the quality of clinical care delivered by trainees. Furthermore, the needs of junior trainees, overseas graduates and those working >56 hours per week should be given particular consideration when developing well-being and training programmes.

Midlife Hypertension and Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Hypertension is an established risk factor for stroke and vascular dementia but recent meta-analyses examining the association between Alzheimer's disease (AD) and hypertension have found no significant association. These meta-analyses included short term studies starting in late life which may have obscured the real effect of midlife hypertension. OBJECTIVE: To examine the association of AD with midlife hypertension, by including only studies with a sufficiently long follow up duration. METHODS: Relevant studies were found by searches of MEDLINE, EMBASE, and PubMed. Study outcomes were grouped by measures of blood pressure and definition of hypertension (e.g., systolic hypertension > 140 mmHg or > 160 mmHg). We assessed pooled effect estimates using random effects models and heterogeneity of pooled estimates through the I2 statistic. RESULTS: Literature search found 3,426 publications of which 7 were eligible studies. There was a significant association between systolic hypertension (>160 mm Hg) and AD (HR 1.25, 95CI 1.06 - 1.47, p = 0.0065). Similarly, for systolic hypertension > 140 mm Hg, there was a smaller but still significant association (HR 1.18, 95CI 1.02 - 1.35, p = 0.021). For diastolic hypertension, all four studies found no significant associations between diastolic hypertension and AD, and these data could not be pooled due to heterogeneity in reporting. CONCLUSIONS: Our study found that midlife stage 1 and stage 2 systolic hypertension is associated with increased risk of AD by 18 and 25%, respectively, although no association was found for diastolic hypertension. It is likely that assertive control of systolic hypertension starting in midlife is important to preventing AD.

Partial empty sella in a woman with cerebral venous sinus thrombosis: A rare presentation of polycythaemia rubra vera.

We report the case of a 59 year old woman who presented with a six week history of worsening bifrontal headache. On CT brain the only abnormal finding was a partially empty sella potentially indicative of increased intracranial pressure. MRI found a large cerebral venous sinus thrombosis in the superior sagittal sinus. Blood tests and a bone marrow biopsy revealed a diagnosis of JAK2 positive primary polycythaemia rubra vera. The lack of sensitivity and specificity of CT in the diagnosis of CVST should engender a low threshold for MRI in patients with risk factors and/or non-diagnostic abnormalities on initial CT. Management of this dual pathology involves both the immediate treatment of the thrombus with heparin bridging to warfarin and the long treatment for polycythaemia involving repeat venesections and cytoreductive therapy.

HIV brain latency as measured by CSF BcL11b relates to disrupted brain cellular energy in virally suppressed HIV infection.

OBJECTIVE: We investigated whether HIV brain latency was associated with brain injury in virally suppressed HIV infection. DESIGN: Observational cross-sectional and longitudinal study. METHODS: The study included 26 virally suppressed HIV-infected men (61.5% with HIV-associated neurocognitive disorder) who undertook cerebrospinal fluid (CSF) analyses at baseline. They also completed a proton magnetic resonance spectroscopy (1H MRS) and neuropsychological assessments at baseline and 18 months. To quantify whether there was residual brain HIV transcription, we measured CSF HIV-tat. As an HIV brain latency biomarker, we used concentrations of CSF BcL11b - a microglia transcription factor that inhibits HIV transcription. Concurrently, we assessed neuroinflammation with CSF neopterin, neuronal injury with CSF neurofilament light-chain (NFL), and in-vivo neurochemistry with 1H MRS of N-acetyl aspartate (NAA), choline (Cho), creatine, myo-inositol (MI), glutamine/glutamate (Glx) in the frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate nucleus area. RESULTS: Baseline adjusted regression models for neopterin, NFL, and tat showed that a higher CSF BcL11b was consistently associated with lower FWM creatine (when adjusted for neopterin: ß = -0.30, P = 0.15; when adjusted for NFL: ß = -0.47, P = 0.04; and when adjusted for tat: ß = -0.47, P = 0.02). In longitudinal analyses, we found no time effect, but a consistent BcL11b altering effect on FWM creatine. The effect reached a significant moderate effect size range when corrected for CSF NFL (ß = -0.36, P = 0.02) and CSF tat (ß = -0.34, P = 0.02). CONCLUSIONS: Reduced frontal white matter total creatine may indicate subclinical HIV brain latency-related injury. H MRS may offer a noninvasive option to measure HIV brain latency.

Bcl11b-A Critical Neurodevelopmental Transcription Factor-Roles in Health and Disease.

B cell leukemia 11b (Bcl11b) is a zinc finger protein transcription factor with a multiplicity of functions. It works as both a genetic suppressor and activator, acting directly, attaching to promoter regions, as well as indirectly, attaching to promoter-bound transcription factors. Bcl11b is a fundamental transcription factor in fetal development, with important roles for the differentiation and development of various neuronal subtypes in the central nervous system (CNS). It has been used as a specific marker of layer V subcerebral projection neurons as well as striatal interneurons. Bcl11b also has critical developmental functions in the immune, integumentary and cardiac systems, to the extent that Bcl11b knockout mice are incompatible with extra-uterine life. Bcl11b has been implicated in a number of disease states including Huntington's disease, Alzheimer's disease, HIV and T-Cell malignancy, amongst others. Bcl11b is a fascinating protein whose critical roles in the CNS and other parts of the body are yet to be fully explicated. This review summarizes the current literature on Bcl11b and its functions in development, health, and disease as well as future directions for research.

Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases.

The kynurenine pathway (KP) of tryptophan metabolism has emerged in recent years as a key regulator of the production of both neuroprotective (e.g. kynurenic and picolinic acid, and the essential cofactor NAD+) and neurotoxic metabolites (e.g. quinolinic acid, 3-hydroxykynurenine). The balance between the production of the two types of metabolites is controlled by key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO-1), and in turn, molecular signals such as interferon-γ (IFN-γ), which activate the KP metabolism of tryptophan by this enzyme, as opposed to alternative pathways for serotonin and melatonin production. Dysregulated KP metabolism has been strongly associated with neurological diseases in recent years, and is the subject of increasing efforts to understand how the metabolites are causative of disease pathology. Concurrent with these endeavours are drug development initiatives to use inhibitors to block certain enzymes in the pathway, resulting in reduced levels of neurotoxic metabolites (e.g. quinolinic acid, an excitotoxin and N-Methyl-d-Aspartate (NMDA) receptor agonist), while in turn enhancing the bioavailability of the neuroprotective metabolites such as kynurenic acid. Neurodegenerative diseases often have a substantial autoimmune or inflammatory component; hence a greater understanding of how KP metabolites influence the inflammatory cascade is required. Additionally, challenges exist in diseases like multiple sclerosis (MS) and motor neurone disease (MND), which do not have reliable biomarkers. Clinical diagnosis can often be prolonged in order to exclude other diseases, and often diagnosis occurs at an advanced state of disease pathology, which does not allow a lengthy time for patient assessment and intervention therapies. This review considers the current evidence for involvement of the KP in several neurological diseases, in biomarkers of disease and also the parallels that exist in KP metabolism with what is known in other diseases such as HIV, Alzheimer's disease/dementia, infection, immune privilege and cardiovascular disease. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.

Bcl11b: A New Piece to the Complex Puzzle of Amyotrophic Lateral Sclerosis Neuropathogenesis?

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, neurodegenerative disease of the human motor system. The pathogenesis of ALS is a topic of fascinating speculation and experimentation, with theories revolving around intracellular protein inclusions, mitochondrial structural issues, glutamate excitotoxicity and free radical formation. This review explores the rationale for the involvement of a novel protein, B-cell lymphoma/leukaemia 11b (Bcl11b) in ALS. Bcl11b is a multifunctional zinc finger protein transcription factor. It functions as both a transactivator and genetic suppressor, acting both directly, binding to promoter regions, and indirectly, binding to promoter-bound transcription factors. It has essential roles in the differentiation and growth of various cells in the central nervous system, immune system, integumentary system and cardiovascular system, to the extent that Bcl11b knockout mice are incompatible with extra-uterine life. It also has various roles in pathology including the suppression of latent retroviruses, thymic tumourigenesis and neurodegeneration. In particular its functions in neurodevelopment, viral latency and T-cell development suggest potential roles in ALS pathology.