The characteristic pattern of functional connectivity density influenced by postmenopausal females in the preclinical stage of dementia.

Subjective cognitive decline (SCD) is considered an early indicator of Alzheimer's disease. Previous evidence suggests that postmenopausal females are at heightened risk for developing dementia. However, the potential effects of gender (i.e. postmenopausal female) on functional connectivity density (FCD) in individuals with SCD are not well understood. A total of 56 healthy controls and 57 subjects with SCD were included. The short-range and long-range FCD (srFCD and lrFCD) mapping of each participant was calculated. The interactive effect of gender × diagnosis on the FCD was explored by two-way analysis of variance. The interaction effect of gender × diagnosis on lrFCD was primarily in the right middle frontal gyrus (MFG). The older males with SCD exhibited significantly enhanced lrFCD in the right MFG relative to other subgroups. The lrFCD of the right MFG was positively associated with cognitive performance in older females with SCD. Cognition-related functional terms were significantly related to the right MFG. Decreased lrFCD of the right MFG in cognitively normal older women may explain why postmenopausal females have a higher risk for progression to dementia than men. Furthermore, this altered pattern could be applied to identify individuals with a high risk for dementia.

Mitochondrial Health, Physical Functioning, and Daily Affect: Bioenergetic Mechanisms of Dementia Caregiver Well-Being.

OBJECTIVE: Chronic stress adversely affects mental and physical well-being. However, health outcomes vary among people experiencing the same stressor. Individual differences in physical and emotional well-being may depend on mitochondrial biology, as energy production is crucial for stress regulation. This study investigated whether mitochondrial respiratory capacity corresponds to individual differences in dementia spousal caregivers' mental and physical health. METHODS: Spousal caregivers of individuals with Alzheimer's disease and related dementias ( N = 102, mean age = 71, 78% female, 83% White) provided peripheral blood samples and completed self-report questionnaires on quality of life, caregiver burden, and a 7-day affect scale. Multiple and mixed linear regressions were used to test the relationship between mitochondrial biology and well-being. RESULTS: Spare respiratory capacity ( b = 12.76, confidence interval [CI] = 5.23-20.28, p = .001), maximum respiratory capacity ( b = 8.45, CI = 4.54-12.35, p < .0001), and ATP-linked respiration ( b = 10.11, CI = 5.05-15.18, p = .0001) were positively associated with physical functioning. At average ( b = -2.23, CI = -3.64 to -0.82, p = .002) and below average ( b = -4.96, CI = -7.22 to 2.70, p < .0001) levels of spare respiratory capacity, caregiver burden was negatively associated with daily positive affect. At above average levels of spare respiratory capacity, caregiver burden was not associated with positive affect ( p = .65). CONCLUSIONS: Findings suggest that higher mitochondrial respiratory capacity is associated with better psychological and physical health-a pattern consistent with related research. These findings provide some of the earliest evidence that cellular bioenergetics are related to well-being.

The Effects of Light Therapy on Sleep, Depression, Neuropsychiatric Behaviors, and Cognition Among People Living With Dementia: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Alterations in the suprachiasmatic nucleus due to underlying pathologies disrupt the circadian rhythms in people living with dementia (PLWD). Circadian rhythms significantly impact sleep, emotional, and cognitive functions, with its synchronization depending on light exposure. We performed a meta-analysis to evaluate the effects of light therapy on sleep, depression, neuropsychiatric behaviors, and cognition among PLWD. METHODS: A systematic search was conducted in Cochrane, ClinicalTrials.gov, Embase, EBSCOhost, Ovid-MEDLINE, PubMed, Scopus, Web of Science, and CINAHL databases. The pooled effect size was calculated using the Hedges' g with random-effects model adopted in comprehensive meta-analysis software. The Cochrane risk of bias (RoB 2.0) tool evaluated the quality of studies, while Cochrane's Q and I² tests assessed heterogeneity. RESULTS: A total of 24 studies with 1,074 participants were included. Light therapy demonstrated small-to-medium effects on improving sleep parameters: total sleep time (Hedges' g = 0.19), wake after sleep onset (Hedges' g = 0.24), sleep efficiency (Hedges' g = 0.31), sleep latency (Hedges' g = 0.35), circadian rhythm (acrophase: Hedges' g = 0.36; amplitude: Hedges' g = 0.43), number of night awakenings (Hedges' g = 0.37), sleep disturbance (Hedges'g = 0.45), and sleep quality (Hedges' g = 0.60). Light therapy showed small-to-medium effect on reducing depression (Hedges' g = -0.46) with medium-to-large effect on cyclical function (Hedges' g = -0.68) and mood-related signs and symptoms (Hedges' g = -0.84) subscales. Light therapy also demonstrated small effect on reducing neuropsychiatric behaviors (Hedges' g = -0.34) with medium-to-large effect on agitation (Hedges' g = -0.65), affective symptom (Hedges' g = -0.70), psychosis (Hedges' g = -0.72), and melancholic behavior (Hedges' g = -0.91) subscales. Additionally, light therapy also improved cognition (Hedges' g = 0.39). CONCLUSION: Light therapy could be used as a supportive therapy to improve sleep, depression, cognition, and neuropsychiatric behaviors among PLWD.

Health Fluctuations in Dementia and its Impact on the Assessment of Health-Related Quality of Life Using the EQ-5D-5L.

OBJECTIVES: To quantify health fluctuations, identify affected health-related quality of life (HRQoL) dimensions, and evaluate if fluctuations affect the HRQoL instruments recall period adherence in people living with dementia (PlwD). METHODS: Caregivers of PlwD completed a daily diary for 14 days, documenting if PlwD's health was better or worse than the day before and the affected HRQoL dimensions. Health fluctuation was categorized into low (0-4 fluctuations in 14 days), moderate (5-8), and high (9-14). Also, caregivers and PlwD completed the EQ-5D-5L (proxy- and self-reported) on days 1, 7, and 14. Subsequently, caregivers were interviewed to determine whether recurrent fluctuations were considered in the EQ-5D-5L assessment of today's health (recall period adherence). RESULTS: Fluctuations were reported for 96% of PlwD, on average, for 7 of the 14 days. Dimensions most frequently triggering fluctuations included memory, mobility, concentration, sleep, pain, and usual activities. Fluctuations were associated with higher EQ-5D-5L health-states variation and nonadherence to the EQ-5D-5L recall period "today." PlwD with moderate to high fluctuation had the highest EQ-5D-5L utility change between day 1 and 14 (0.157 and 0.134) and recall period nonadherence (31% and 26%) compared with PlwD with low fluctuation (0.010; 17%). Recall period nonadherence was higher in PlwD with improved compared with those with deteriorated health in the diary (37% vs 9%). CONCLUSIONS: Health fluctuations frequently occur in dementia and strongly affect HRQoL assessments. Further research is needed to evaluate if more extended recall periods and multiple, consecutive assessments could capture health fluctuations more appropriately in dementia.

Impact of distinct cognitive domains on gait variability in individuals with mild cognitive impairment and dementia.

BACKGROUND: Gait variability is a common feature in neurodegenerative diseases and has been linked to cognitive impairment. Despite this link, the influence of specific cognitive domains, such as memory, visual spatial skills, executive function, and verbal function on gait variability is not well-understood. OBJECTIVE: To investigate the predictive value of these specific cognitive domains on gait variability in people with mild cognitive impairment (MCI) and dementia during preferred and dual task walking. METHOD: One hundred and two participants with either MCI or dementia underwent a comprehensive cognitive assessment and completed preferred and dual-task walking trials on a pressure-sensing walkway. Gait variability was assessed using the PKMAS software. Lower extremity function was evaluated with a self-reported validated scale. RESULTS: Our findings indicate that only visual spatial abilities had a moderate predictive value on gait variability [F (1, 78) = 17.30, p < 0.01, r = 0.43], both in preferred pace walking (70% direct effect) and dual-task walking (90% direct effect) (p's < 0.05). Additionally, lower extremity functional skills had a significant indirect effect (30%) on gait variability in preferred walking contexts. CONCLUSION: For individuals diagnosed with MCI or dementia, increased gait variability may be driven by deficits in visual spatial processing. An increased understanding of the role of visual spatial processing in gait variability can aid in the assessment and management of individuals with MCI or dementia, potentially leading to targeted interventions to improve mobility and safety.

A dynamic computational model of the parallel circuit on the basal ganglia-cortex associated with Parkinson's disease dementia.

The cognitive impairment will gradually appear over time in Parkinson's patients, which is closely related to the basal ganglia-cortex network. This network contains two parallel circuits mediated by putamen and caudate nucleus, respectively. Based on the biophysical mean-field model, we construct a dynamic computational model of the parallel circuit in the basal ganglia-cortex network associated with Parkinson's disease dementia. The simulated results show that the decrease of power ratio in the prefrontal cortex is mainly caused by dopamine depletion in the caudate nucleus and is less related to that in the putamen, which indicates Parkinson's disease dementia may be caused by a lesion of the caudate nucleus rather than putamen. Furthermore, the underlying dynamic mechanism behind the decrease of power ratio is investigated by bifurcation analysis, which demonstrates that the decrease of power ratio is due to the change of brain discharge pattern from the limit cycle mode to the point attractor mode. More importantly, the spatiotemporal course of dopamine depletion in Parkinson's disease patients is well simulated, which states that with the loss of dopaminergic neurons projecting to the striatum, motor dysfunction of Parkinson's disease is first observed, whereas cognitive impairment occurs after a period of onset of motor dysfunction. These results are helpful to understand the pathogenesis of cognitive impairment and provide insights into the treatment of Parkinson's disease dementia.

The relation between cognitive functioning and activities of daily living in normal aging, mild cognitive impairment, and dementia: a meta-analysis.

Literature suggests that dementia and, more generally, cognitive impairment affect the capacity to carry out activities of daily living (ADL) in aging. However, it is important to decipher the weight of specific cognitive domains and neurodegenerative profiles mainly related to ADL difficulties. A meta-analysis was conducted to investigate the nature and strength of the association between cognitive functioning and ADL in healthy older adults, mild cognitive impairment (MCI), and dementia. A comprehensive search of the PubMed, PsycINFO (PROQUEST), and Scopus databases for cross-sectional or longitudinal studies up until December 2022. Our meta-analytic results revealed that: overall, instrumental ADL (IADL) showed a significant association with executive functioning, in particular, abstraction ability/concept formation, set-shifting, and processing speed/complex attention/working memory, regardless of type of participants (i.e., healthy older adults, MCI, and dementia); whereas ADL (both basic ADL, BADL, and IADL) significantly correlated with global cognitive functioning and long-term verbal memory, with a moderator effect of clinical condition (e.g., increasing ES based on the level of cognitive impairment). Moreover, visuospatial and language abilities significantly correlated with ADL, mainly when performance-based tasks were used for ADL assessment. These findings emphasize the importance of neuropsychological assessment in aging to early identify people most at risk of functional decline and shed light on the need to consider specific cognitive abilities in rehabilitation programs.

Associations between accelerometer-measured circadian rest-activity rhythm, brain structural and genetic mechanisms, and dementia.

AIM: Knowledge of how circadian rhythm influences brain health remains limited. We aimed to investigate the associations of accelerometer-measured circadian rest-activity rhythm (CRAR) with incident dementia, cognitive dysfunction, and structural brain abnormalities in the general population and underlying biological mechanisms. METHODS: Fifty-seven thousand five hundred and two participants aged over 60 years with accelerometer data were included to investigate the association of CRAR with incidental dementia. Non-parametric CRAR parameters were utilized, including activity level during active periods of the day (M10), activity level during rest periods of the day (L5), and the relative difference between the M10 and L5 (relative amplitude, RA). Associations of CRAR with cognitive dysfunction and brain structure were studied in a subset of participants. Neuroimaging-transcriptomics analysis was utilized to identify the underlying molecular mechanisms. RESULTS: Over 6.86 (4.94-8.78) years of follow-up, 494 participants developed dementia. The risk of incident dementia was associated with decreasing M10 (hazard ratio [HR] 1.45; 95% conference interval [CI], 1.28-1.64) and RA (HR 1.37; 95% CI, 1.28-1.64), increasing L5 (HR 1.14, 95% CI 1.07-1.21) and advanced L5 onset time (HR 1.12; 95% CI, 1.02-1.23). The detrimental associations were exacerbated by APOE ε4 status and age (>65 years). Decreased RA was associated with lower processing speed (Beta -0.04; SE 0.011), predominantly mediated by abnormalities in subcortical regions and white matter microstructure. The genes underlying CRAR-related brain regional structure variation were enriched for synaptic function. CONCLUSIONS: Our study underscores the potential of intervention targeting at maintaining a healthy CRAR pattern to prevent dementia risk.

The Impact of Dual-Tasks and Disease Severity on Posture, Gait, and Functional Mobility among People Living with Dementia in Residential Care Facilities: A Pilot Study.

Gait speed and timed-up-and-go (TUG) predict cognitive decline, falls, and mortality. Dual-tasks may be useful in cognitive screening among people living with dementia (PWD), but more evidence is needed. This cross-sectional study aimed to compare single- and dual-task performance and determine the influence of dementia severity on dual-task performance and interference. Thirty PWD in two residential care facilities (Age: 81.3 ± 7.1 years; Montreal Cognitive Assessment: 10.4 ± 6.0 points) completed two trials of single- (feet apart) and dual-task posture (feet apart while counting backward), single- (walk 4 m) and dual-task gait (walk 4m while naming words), and single- (timed-up-and-go (TUG)), and dual-task functional mobility (TUG while completing a category task) with APDM inertial sensors. Dual-tasks resulted in greater sway frequency, jerk, and sway area; slower gait speed; greater double limb support; shorter stride length; reduced mid-swing elevation; longer TUG duration; reduced turn angle; and slower turn velocity than single-tasks (ps < 0.05). Dual-task performance was impacted (reduced double limb support, greater mid-swing elevation), and dual-task interference (greater jerk, faster gait speed) was related to moderate-to-severe compared to mild PWD. Moderate-to-severe PWD had poorer dynamic stability and a reduced ability to appropriately select a cautious gait during dual-tasks than those with mild PWD, indicating the usefulness of dual-tasks for cognitive screening.

Associations of Physical Activity and Heart Rate Variability from a Two-Week ECG Monitor with Cognitive Function and Dementia: The ARIC Neurocognitive Study.

Low physical activity (PA) measured by accelerometers and low heart rate variability (HRV) measured from short-term ECG recordings are associated with worse cognitive function. Wearable long-term ECG monitors are now widely used, and some devices also include an accelerometer. The objective of this study was to evaluate whether PA or HRV measured from long-term ECG monitors was associated with cognitive function among older adults. A total of 1590 ARIC participants had free-living PA and HRV measured over 14 days using the Zio® XT Patch [aged 72-94 years, 58% female, 32% Black]. Cognitive function was measured by cognitive factor scores and adjudicated dementia or mild cognitive impairment (MCI) status. Adjusted linear or multinomial regression models examined whether higher PA or higher HRV was cross-sectionally associated with higher factor scores or lower odds of MCI/dementia. Each 1-unit increase in the total amount of PA was associated with higher global cognition (ß = 0.30, 95% CI: 0.16-0.44) and executive function scores (ß = 0.38, 95% CI: 0.22-0.53) and lower odds of MCI (OR = 0.38, 95% CI: 0.22-0.67) or dementia (OR = 0.25, 95% CI: 0.08-0.74). HRV (i.e., SDNN and rMSSD) was not associated with cognitive function. More research is needed to define the role of wearable ECG monitors as a tool for digital phenotyping of dementia.

Effect of an 18-Month Walking Intervention on the Rest-Activity Rhythm of Older Adults With Mild-Moderate Dementia.

The objective of this 18-month walking intervention was to evaluate the effect on rest-activity rhythm (RAR) for older adults with mild-to-moderate dementia (65.8% female; aged M = 82.4 [SD = 6.5]). The intervention group (n = 44) was intended to walk 30 min, five times per week for 18 months. The control group (n = 35) received sedentary activities or usual care. RAR was measured at baseline to after 18 months and five times in between actigraphy outcome variables (interdaily stability, intradaily variability, relative amplitude, activity 10 most active hours, and activity 5 least active hours). Hierarchical mixed model analyses revealed no significant intervention effects (with or without baseline confounders as covariate) on RAR. However, participants in the intervention group were able to significantly increase their daily life activity (activity 10 most active hours) from the onset of the preceding measurement, b = 0.10, t(239.32) = 2.36, p = .019. More research is warranted to study the effect of regular walks on older persons with dementia whose RAR is worst at baseline.

Hypertension-related risk for dementia: A summary review with future directions.

Chronic hypertension, or high blood pressure, is the most prevalent vascular risk factor that accelerates cognitive aging and increases risk for Alzheimer's disease and related dementia. Decades of observational and clinical trials have demonstrated that midlife hypertension is associated with greater gray matter atrophy, white matter damage commiserate with demyelination, and functional deficits as compared to normotension over the adult lifespan. Critically, hypertension is a modifiable dementia risk factor: successful blood pressure control with antihypertensive treatment improves outcomes as compared to uncontrolled hypertension, but does not completely negate the risk for dementia. This suggests that hypertension-related risk for neural and cognitive decline in aging cannot be due to elevations in blood pressure alone. This summary review describes three putative pathways for hypertension-related dementia risk: oxidative damage and metabolic dysfunction; systemic inflammation; and autonomic control of heart rate variability. The same processes contribute to pre-clinical hypertension, and therefore hypertension may be an early symptom of an aging nervous system that then exacerbates cumulative and progressive neurodegeneration. Current evidence is reviewed and future directions for research are outlined, including blood biomarkers and novel neuroimaging methods that may be sensitive to test the specific hypotheses.

Atrial Fibrillation and Dementia: A Report From the AF-SCREEN International Collaboration.

Growing evidence suggests a consistent association between atrial fibrillation (AF) and cognitive impairment and dementia that is independent of clinical stroke. This report from the AF-SCREEN International Collaboration summarizes the evidence linking AF to cognitive impairment and dementia. It provides guidance on the investigation and management of dementia in patients with AF on the basis of best available evidence. The document also addresses suspected pathophysiologic mechanisms and identifies knowledge gaps for future research. Whereas AF and dementia share numerous risk factors, the association appears to be independent of these variables. Nevertheless, the evidence remains inconclusive regarding a direct causal effect. Several pathophysiologic mechanisms have been proposed, some of which are potentially amenable to early intervention, including cerebral microinfarction, AF-related cerebral hypoperfusion, inflammation, microhemorrhage, brain atrophy, and systemic atherosclerotic vascular disease. The mitigating role of oral anticoagulation in specific subgroups (eg, low stroke risk, short duration or silent AF, after successful AF ablation, or atrial cardiopathy) and the effect of rhythm versus rate control strategies remain unknown. Likewise, screening for AF (in cognitively normal or cognitively impaired patients) and screening for cognitive impairment in patients with AF are debated. The pathophysiology of dementia and therapeutic strategies to reduce cognitive impairment warrant further investigation in individuals with AF. Cognition should be evaluated in future AF studies and integrated with patient-specific outcome priorities and patient preferences. Further large-scale prospective studies and randomized trials are needed to establish whether AF is a risk factor for cognitive impairment, to investigate strategies to prevent dementia, and to determine whether screening for unknown AF followed by targeted therapy might prevent or reduce cognitive impairment and dementia.

Prospects for Diminishing the Impact of Nonamyloid Small-Vessel Diseases of the Brain.

Small-vessel diseases (SVDs) of the brain are involved in about one-fourth of ischemic strokes and a vast majority of intracerebral hemorrhages and are responsible for nearly half of dementia cases in the elderly. SVDs are a heavy burden for society, a burden that is expected to increase further in the absence of significant therapeutic advances, given the aging population. Here, we provide a critical appraisal of currently available therapeutic approaches for nonamyloid sporadic SVDs that are largely based on targeting modifiable risk factors. We review what is known about the pathogenic mechanisms of vascular risk factor-related SVDs and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most frequent hereditary SVD, and elaborate on two mechanism-based therapeutic approaches worth exploring in sporadic SVD and CADASIL. We conclude by discussing opportunities and challenges that need to be tackled if efforts to achieve significant therapeutic advances for these diseases are to be successful.

Diet modulates brain network stability, a biomarker for brain aging, in young adults.

Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n = 292, ages 20 to 85 y; n = 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (d-ß-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

Danish and British dementia ITM2b/BRI2 mutations reduce BRI2 protein stability and impair glutamatergic synaptic transmission.

Mutations in integral membrane protein 2B (ITM2b/BRI2) gene cause familial British and Danish dementia (FBD and FDD), autosomal dominant disorders characterized by progressive cognitive deterioration. Two pathogenic mechanisms, which may not be mutually exclusive, have been proposed for FDD and FBD: 1) loss of BRI2 function; 2) accumulation of amyloidogenic mutant BRI2-derived peptides, but the mechanistic details remain unclear. We have previously reported a physiological role of BRI2 in excitatory synaptic transmission at both presynaptic termini and postsynaptic termini. To test whether pathogenic ITM2b mutations affect these physiological BRI2 functions, we analyzed glutamatergic transmission in FDD and FBD knock-in mice, which carry pathogenic FDD and FBD mutations into the mouse endogenous Itm2b gene. We show that in both mutant lines, spontaneous glutamate release and AMPAR-mediated responses are decreased, while short-term synaptic facilitation is increased, effects similar to those observed in Itm2bKO mice. In vivo and in vitro studies show that both pathogenic mutations alter maturation of BRI2 resulting in reduced levels of functional mature BRI2 protein at synapses. Collectively, the data show that FDD and FBD mutations cause a reduction of BRI2 levels and function at synapses, which results in reduced glutamatergic transmission. Notably, other genes mutated in Familial dementia, such as APP, PSEN1/PSEN2, are implicated in glutamatergic synaptic transmission, a function that is altered by pathogenic mutations. Thus, defects in excitatory neurotransmitter release may represent a general and convergent mechanism leading to neurodegeneration. Targeting these dysfunction may offer a unique disease modifying method of therapeutic intervention in neurodegenerative disorders.

A familial Danish dementia rat shows impaired presynaptic and postsynaptic glutamatergic transmission.

Familial British dementia and familial Danish dementia are neurodegenerative disorders caused by mutations in the gene integral membrane protein 2B (ITM2b) encoding BRI2, which tunes excitatory synaptic transmission at both presynaptic and postsynaptic termini. In addition, BRI2 interacts with and modulates proteolytic processing of amyloid-ß precursor protein (APP), whose mutations cause familial forms of Alzheimer's disease (AD) (familial AD). To study the pathogenic mechanisms triggered by the Danish mutation, we generated rats carrying the Danish mutation in the rat Itm2b gene (Itm2bD rats). Given the BRI2/APP interaction and the widely accepted relevance of human amyloid ß (Aß), a proteolytic product of APP, to AD, Itm2bD rats were engineered to express two humanized App alleles and produce human Aß. Here, we studied young Itm2bD rats to investigate early pathogenic changes in these diseases. We found that periadolescent Itm2bD rats not only present subtle changes in human Aß levels along with decreased spontaneous glutamate release and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated responses but also had increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These alterations in excitatory interneuronal communication can impair learning and memory processes and were akin to those observed in adult mice producing rodent Aß and carrying either the Danish or British mutations in the mouse Itm2b gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses across species and early in life. Future studies will determine whether this phenomenon represents an early pathogenic event in human dementia.

Epidemiologic Trends, Social Determinants, and Brain Health: The Role of Life Course Inequalities.

Brain health as expressed in our mental health and occurrence of specific disorders such as dementia and stroke is vitally important to quality of life, functional independence, and risk of institutionalization. Maintaining brain health is, therefore, a societal imperative, and public health challenge, from prevention of acquisition of brain disorders, through protection and risk reduction to supporting those with such disorders through effective societal and system approaches. To identify possible mechanisms that explain the differential effect of potentially modifiable risk factors, and factors that may mitigate risk, a life course approach is needed. This is key to understanding how poor health can accumulate from the earliest life stages. It also allows us to integrate and investigate key material, behavioral, and psychological factors that generate health inequalities within and across communities and societies. This review provides a narrative on how brain health is intimately linked to wider health determinants, thus importance for clinicians and societies alike. There is compelling evidence accumulated from research over decades that socioeconomic status, higher education, and healthy lifestyle extend life and compress major morbidities into later life. Brain health is part of this, but collective action has been limited, partly because of the separation of disciplines and focus on highly reductionist approaches in that clinicians and associated research have focused more on mitigation and early detection of specific diseases. However, clinicians could be part of the drive for better brain health for all society to support life courses that have more protection and less risk. There is evidence of change in such risks for conditions such as stroke and dementia across generations. The evidence points to the importance of starting with parental health and life course inequalities as a central focus.

Evidence and implications of abnormal predictive coding in dementia.

The diversity of cognitive deficits and neuropathological processes associated with dementias has encouraged divergence in pathophysiological explanations of disease. Here, we review an alternative framework that emphasizes convergent critical features of cognitive pathophysiology. Rather than the loss of 'memory centres' or 'language centres', or singular neurotransmitter systems, cognitive deficits are interpreted in terms of aberrant predictive coding in hierarchical neural networks. This builds on advances in normative accounts of brain function, specifically the Bayesian integration of beliefs and sensory evidence in which hierarchical predictions and prediction errors underlie memory, perception, speech and behaviour. We describe how analogous impairments in predictive coding in parallel neurocognitive systems can generate diverse clinical phenomena, including the characteristics of dementias. The review presents evidence from behavioural and neurophysiological studies of perception, language, memory and decision-making. The reformulation of cognitive deficits in terms of predictive coding has several advantages. It brings diverse clinical phenomena into a common framework; it aligns cognitive and movement disorders; and it makes specific predictions on cognitive physiology that support translational and experimental medicine studies. The insights into complex human cognitive disorders from the predictive coding framework may therefore also inform future therapeutic strategies.