Latent profiles of modifiable dementia risk factors in later midlife: relationships with incident dementia, cognition, and neuroimaging outcomes.

In 2020, the Lancet Commission identified 12 modifiable factors that increase population-level dementia risk. It is unclear if these risk factors co-occur among individuals in a clinically meaningful way. Using latent class analysis, we identified profiles of modifiable dementia risk factors in dementia-free adults aged 60-64 years from the UK Biobank. We then estimated associations between these profiles with incident dementia, cognition, and neuroimaging outcomes, and explored the differences across profiles in the effects of a polygenic risk score for Alzheimer's disease on outcomes. In 55,333 males and 63,063 females, three sex-specific latent profiles were identified: cardiometabolic risk, substance use-related risk, and low risk. The cardiometabolic risk profile in both males and females was associated with greater incidence of all-cause dementia (male: OR [95% CI] = 2.33 [2.03, 2.66]; female: OR [95% CI] = 1.44 [1.24, 1.68]), poorer cognitive performance, greater brain atrophy, and greater white matter hyperintensity volume compared to the low risk profile. The substance use-related risk profile in males was associated with poorer cognitive performance and greater white matter hyperintensities compared to the low risk profile, but no difference in all-cause dementia incidence was observed (OR [95% CI] = 1.00 [0.95, 1.06]). In females, the substance use-related risk profile demonstrated increased dementia incidence (OR [95% CI] = 1.58 [1.57, 1.58]) and greater brain atrophy but smaller white matter hyperintensity volume compared to the low risk profile. The polygenic risk score had larger effects among females, and differentially influenced outcomes across profiles; for instance, there were larger effects of the polygenic risk score on atrophy in the cardiometabolic profile vs. the low risk profile among males, and larger effects of the polygenic risk score on loss of white matter integrity in the cardiometabolic profile vs. the low risk profile among females. These results reveal three modifiable dementia risk profiles, their unique cognitive/neuroimaging outcomes, and their interactions with genetic risk for Alzheimer's disease. These differences highlight the need to consider population heterogeneity in risk prediction tools and in planning personalized prevention strategies.

No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes.

BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.

Cardiovascular phenotypes in type 2 diabetes: Latent class analysis of the CANVAS Program and CREDENCE trial.

AIM: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis. METHODS: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes. RESULTS: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05). CONCLUSION: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability.

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound.

The blood-brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer's disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer's disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer's disease pathology (P-tau181, amyloid-ß42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

Investigating the impact of hypertension with and without diabetes on Alzheimer's disease risk: A clinico-pathological study.

INTRODUCTION: Hypertension and diabetes are common cardiovascular risk factors that increase Alzheimer's disease (AD) risk. However, it is unclear whether AD risk differs in hypertensive individuals with and without diabetes. METHODS: Cognitively normal individuals (N = 11,074) from the National Alzheimer's Coordinating Center (NACC) were categorized as having (1) hypertension with diabetes (HTN+/DM+), (2) hypertension without diabetes (HTN+/DM-), or (3) neither (HTN-/DM-). AD risk in HTN+/DM+ and HTN+/DM- was compared to HTN-/DM-. This risk was then investigated in those with AD neuropathology (ADNP), cerebral amyloid angiopathy (CAA), cerebrovascular neuropathology (CVNP), arteriolosclerosis, and atherosclerosis. Finally, AD risk in HTN-/DM+ was compared to HTN-/DM-. RESULTS: Seven percent (N = 830) of individuals developed AD. HTN+/DM+ (hazard ratio [HR] = 1.31 [1.19-1.44]) and HTN+/DM- (HR = 1.24 [1.17-1.32]) increased AD risk compared to HTN-/DM-. AD risk was greater in HTN+/DM+ with ADNP (HR = 2.10 [1.16-3.79]) and CAA (HR = 1.52 [1.09-2.12]), and in HTN+/DM- with CVNP (HR = 1.54 [1.17-2.03]). HTN-/DM+ also increased AD risk (HR = 1.88 [1.30-2.72]) compared to HTN-/DM-. DISCUSSION: HTN+/DM+ and HTN+/DM- increased AD risk compared to HTN-/DM-, but pathological differences between groups suggest targeted therapies may be warranted based on cardiovascular risk profiles. HIGHLIGHTS: AD risk was studied in hypertensive (HTN+) individuals with/without diabetes (DM+/-). HTN+/DM+ and HTN+/DM- both had an increased risk of AD compared to HTN-/DM-. Post mortem analysis identified neuropathological differences between HTN+/DM+ and HTN+/DM-. In HTN+/DM+, AD risk was greater in those with AD neuropathology and CAA. In HTN+/DM-, AD risk was greater in those with cerebrovascular neuropathology.

Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases.

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.

Cytochrome P450-soluble epoxide hydrolase derived linoleic acid oxylipins and cognitive performance in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been reported in T2DM, obesity and cognitive impairment. We examine linoleic acid (LA)-derived CYP450-sEH oxylipins and cognition in T2DM and explore potential differences between obese and nonobese individuals. The study included 51 obese and 57 nonobese participants (mean age 63.0 ± 9.9, 49% women) with T2DM. Executive function was assessed using the Stroop Color-Word Interference Test, FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B. Verbal memory was assessed using the California Verbal Learning Test, second Edition. Four LA-derived oxylipins were analyzed by ultra-high-pressure-LC/MS, and the 12,13-dihydroxyoctadecamonoenoic acid (12,13-DiHOME) considered the main species of interest. Models controlled for age, sex, BMI, glycosylated hemoglobin A1c, diabetes duration, depression, hypertension, and education. The sEH-derived 12,13-DiHOME was associated with poorer executive function scores (F1,98 = 7.513, P = 0.007). The CYP450-derived 12(13)-epoxyoctadecamonoenoic acid (12(13)-EpOME) was associated with poorer executive function and verbal memory scores (F1,98 = 7.222, P = 0.008 and F1,98 = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F1,97 = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F1,97 = 4.126, P = 0.045), predicting executive function such that relationships were stronger in obese individuals. These findings suggest that the CYP450-sEH pathway as a potential therapeutic target for cognitive decline in T2DM. For some markers, relationships may be obesity dependent.

Dynamic relationships between depressive symptoms and insulin resistance over 20 years of adulthood.

BACKGROUND: Bidirectional longitudinal relationships between depression and diabetes have been observed, but the dominant direction of their temporal relationships remains controversial. METHODS: The random-intercept cross-lagged panel model decomposes observed variables into a latent intercept representing the traits, and occasion-specific latent 'state' variables. This permits correlations to be assessed between the traits, while longitudinal 'cross-lagged' associations and cross-sectional correlations can be assessed between occasion-specific latent variables. We examined dynamic relationships between depressive symptoms and insulin resistance across five visits over 20 years of adulthood in the population-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Possible differences based on population group (Black v. White participants), sex and years of education were tested. Depressive symptoms and insulin resistance were quantified using the Center for Epidemiologic Studies Depression (CES-D) scale and the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. RESULTS: Among 4044 participants (baseline mean age 34.9 ± 3.7 years, 53% women, 51% Black participants), HOMA-IR and CES-D traits were weakly correlated (r = 0.081, p = 0.002). Some occasion-specific correlations, but no cross-lagged associations were observed overall. Longitudinal dynamics of these relationships differed by population groups such that HOMA-IR at age 50 was associated with CES-D score at age 55 (ß = 0.076, p = 0.038) in White participants only. Longitudinal dynamics were consistent between sexes and based on education. CONCLUSIONS: The relationship between depressive symptoms and insulin resistance was best characterized by weak correlations between occasion-specific states and enduring traits, with weak evidence that insulin resistance might be temporally associated with subsequent depressive symptoms among White participants later in adulthood.

Sex differences in associations between APOE ε2 and longitudinal cognitive decline.

INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. HIGHLIGHTS: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases.

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.

Associations of white matter hyperintensities with networks of gray matter blood flow and volume in midlife adults: A coronary artery risk development in young adults magnetic resonance imaging substudy.

White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.5 years) and Hi-WMH (mean age = 51 ± 3.7 years) groups of equal size. We constructed group-level covariance networks based on cerebral blood flow (CBF) and gray matter volume (GMV) maps across 74 gray matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no between-group differences in either CBF or GMV covariance networks. In contrast, we found between-group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence that WMH-related network alterations are present at midlife.

Inflammatory markers in type 2 diabetes with vs. without cognitive impairment; a systematic review and meta-analysis.

People with type 2 diabetes mellitus (T2DM) are at increased risk of mild cognitive impairment and dementia. Systemic inflammation has been proposed as a common risk factor. This study aimed to summarize the clinical data pertaining to peripheral blood inflammatory markers. We identified original peer-reviewed articles reporting blood inflammatory marker concentrations in groups of people with a T2DM diagnosis who have cognitive impairment (CI; including mild cognitive impairment, Alzheimer's disease, vascular cognitive impairment) vs. normal cognition (NC). Between-group standardized mean differences (SMD) were summarized in random effects meta-analyses. From 2108 records, data were combined quantitatively from 40 studies. Concentrations of interleukin-6 (IL-6; NCI/NNC = 934/3154, SMD 0.74 95% confidence interval [0.07, 1.42], Z5 = 2.15, p = 0.03; I2 = 98.08%), C-reactive protein (CRP; NCI/NNC = 1610/4363, SMD 0.80 [0.50, 1.11], Z14 = 5.25, p < 0.01; I2 = 94.59%), soluble vascular cell adhesion molecule-1 (sVCAM-1; NCI/NNC = 104/1063, SMD 1.64 95% confidence interval [0.21, 3.07], Z2 = 2.25, p = 0.02; I2 = 95.19%), and advanced glycation end products (AGEs; NCI/NNC = 227/317, SMD 0.84 95% confidence interval [0.41, 1.27], Z2 = 3.82, p < 0.01; I2 = 81.07%) were higher among CI groups compared to NC. Brain derived neurotropic factor (BDNF) concentrations were significantly lower in CI compared to NC (NCI/NNC = 848/2063, SMD -0.67 95% confidence interval [-0.99, -0.35], Z3 = -4.09, p < 0.01; I2 = 89.20%). Cognitive impairment among people with T2DM was associated with systemic inflammation and lower BDNF concentrations. These inflammatory characteristics support an increased inflammatory-vascular interaction associated with cognitive impairment in T2DM. PROSPERO (CRD42020188625).

The complement cascade in Alzheimer's disease: a systematic review and meta-analysis.

Genetic evidence implicates a causal role for the complement pathway in Alzheimer's disease (AD). Since studies have shown inconsistent differences in cerebrospinal fluid (CSF) and peripheral blood complement protein concentrations between AD patients and healthy elderly, this study sought to summarize the clinical data. Original peer-reviewed articles measuring CSF and/or blood concentrations of complement or complement regulator protein concentrations in AD and healthy elderly control (HC) groups were included. Of 2966 records identified, means and standard deviations from 86 studies were summarized as standardized mean differences (SMD) by random effects meta-analyses. In CSF, concentrations of clusterin (NAD/NHC = 625/577, SMD = 0.53, Z8 = 8.81, p < 0.005; I2 < 0.005%) and complement component 3 (C3; NAD/NHC = 299/522, SMD = 0.45, Z3 = 3.21, p < 0.005; I2 = 68.40%) were significantly higher in AD, but differences in C1q, C-reactive protein (CRP), serum amyloid protein (SAP), and factor H concentrations were not significant. In peripheral blood, concentrations of CRP were elevated in AD (NAD/NHC = 3404/3332, SMD = 0.44, Z43 = 3.43, p < 0.005; I2 = 93.81%), but differences between groups in C3, C4, C1-inhibitor, SAP, factor H and clusterin concentrations were not significant, and inconsistent between studies. Of 64 complement pathway proteins or regulators in the quantitative synthesis, trends in C1q, factor B, C4a, and late-stage complement pathway components (e.g. C9) in blood, C4 in CSF, and the membrane attack complex in blood and CSF, might be investigated further. The results collectively support elevated complement pathway activity in AD, which was best characterized by increased CSF clusterin concentrations and less consistently by CSF C3 concentrations. Complement activity related to an AD diagnosis was not reflected consistently by the peripheral blood proteins investigated.

The potential roles of excitatory-inhibitory imbalances and the repressor element-1 silencing transcription factor in aging and aging-associated diseases.

Disruptions to the central excitatory-inhibitory (E/I) balance are thought to be related to aging and underlie a host of neural pathologies, including Alzheimer's disease. Aging may induce an increase in excitatory signaling, causing an E/I imbalance, which has been linked to shorter lifespans in mice, flies, and worms. In humans, extended longevity correlates to greater repression of genes involved in excitatory neurotransmission. The repressor element-1 silencing transcription factor (REST) is a master regulator in neural cells and is believed to be upregulated with senescent stimuli, whereupon it counters hyperexcitability, insulin/insulin-like signaling pathway activity, oxidative stress, and neurodegeneration. This review examines the putative mechanisms that distort the E/I balance with aging and neurodegeneration, and the putative roles of REST in maintaining neuronal homeostasis.

Soluble Epoxide Hydrolase and Diabetes Complications.

Type 2 diabetes mellitus (T2DM) can result in microvascular complications such as neuropathy, retinopathy, nephropathy, and cerebral small vessel disease, and contribute to macrovascular complications, such as heart failure, peripheral arterial disease, and large vessel stroke. T2DM also increases the risks of depression and dementia for reasons that remain largely unclear. Perturbations in the cytochrome P450-soluble epoxide hydrolase (CYP-sEH) pathway have been implicated in each of these diabetes complications. Here we review evidence from the clinical and animal literature suggesting the involvement of the CYP-sEH pathway in T2DM complications across organ systems, and highlight possible mechanisms (e.g., inflammation, fibrosis, mitochondrial function, endoplasmic reticulum stress, the unfolded protein response and autophagy) that may be relevant to the therapeutic potential of the pathway. These mechanisms may be broadly relevant to understanding, preventing and treating microvascular complications affecting the brain and other organ systems in T2DM.

Reciprocal Predictive Relationships between Amyloid and Tau Biomarkers in Alzheimer's Disease Progression: An Empirical Model.

There is an urgent need to understand the relationships between amyloid-ß (Aß) and tau in the progression of Alzheimer's disease to identify treatment targets. Here we examine reciprocal predictions of brain Aß burden quantified by positron emission tomography and CSF concentrations of Aß42 and phosphorylated tau (p-tau). Each biomarker was examined over 48 months in two separate cross-lagged models; one in asymptomatic healthy elderly people (men and women), and one in patients with Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI). The models examine predictions of each biomarker on the progression of the others, considering each previous and concurrent measure. In healthy elderly, lower CSF Aß42 predicted Aß deposition and reciprocally, Aß burden predicted a decrease in CSF Aß42. Lower CSF Aß42 predicted an increase in CSF p-tau, and CSF p-tau predicted Aß deposition. In AD/MCI, lower CSF Aß42 predicted Aß deposition and Aß burden reciprocally predicted CSF Aß42 changes; however, in contrast to healthy elderly, CSF p-tau concentrations did not predict Aß biomarkers, or vice versa. In post hoc models examining cognitive status, CSF Aß42 predicted Mini Mental State Examination (MMSE) scores in healthy elderly, whereas Aß burden and CSF p-tau predicted MMSE scores in AD/MCI. The findings describe reciprocal predictions between Aß and tau biomarkers in healthy elderly and they implicate mechanisms underlying low CSF Aß42 in Alzheimer's disease pathogenesis and progression. In symptomatic Alzheimer's disease, CSF Aß42 and Aß deposition predicted each other; however, Aß and CSF p-tau progressed independently and they independently predicted cognitive decline.SIGNIFICANCE STATEMENT This study offers empirical evidence concerning the hypothesized "amyloid cascade", as it progressed over 4 years in healthy elderly people and in Alzheimer's disease patients. In healthy elderly, CSF amyloid changes predicted amyloid deposition, CSF phosphorylated tau concentrations, and a decline in cognitive status. Phosphorylated tau concentrations specifically predicted amyloid deposition. In Alzheimer's disease patients, although amyloid deposition and CSF amyloid changes continued to "cascade", there was no evidence to suggest that amyloid and tau biomarkers predicted each other, although both amyloid deposition and CSF tau progression predicted cognitive decline independently. Taking advantage of repeated amyloid PET and CSF measures, this dynamic view offers new insight into the progression of Alzheimer's disease biomarkers and their relationships with cognitive decline.

Depression and Diabetes Mellitus Multimorbidity Is Associated With Loss of Independence and Dementia Poststroke.

BACKGROUND AND PURPOSE: Many patients with ischemic stroke present with multiple comorbidities that threaten survival and recovery. This study sought to determine the risks of adverse long-term stroke outcomes associated with multimorbid diabetes mellitus and depression. METHODS: Retrospective analysis of prospectively collected data on consecutive patients without premorbid dementia admitted from the community for a first-ever acute ischemic stroke to comprehensive stroke centers across Ontario, Canada (2003-2013). Premorbid histories of diabetes mellitus and depression were ascertained within 5 years before stroke admission. Adjusted hazard ratios (aHR [95% CI]) of admission to long-term care, incident dementia, readmission for stroke or transient ischemic attack and all-cause mortality, over time among those discharged back into the community poststroke. RESULTS: Among 23 579 stroke admissions, n=20 201 were discharged back into the community. Diabetes mellitus and depression were associated with synergistic hazards of admission to long-term care (X2=5.4; P=0.02) over a median follow-up of 5.6 years. This interaction was observed among women specifically; depression multimorbidity showed particularly high hazards of admission to long-term care (aHRDepression=1.57 [1.24-1.98]) and incident dementia (aHRDepression=1.85 [1.40-2.44]) among women with diabetes mellitus. In the whole cohort, diabetes mellitus and depression were associated individually with long-term care admission (aHRDiabetes=1.20 [1.12-1.29]; aHRDepression=1.19 [1.04-1.37]), incident dementia (aHRDiabetes=1.14 [1.06-1.23]; aHRDepression=1.27 [1.08-1.49]), stroke/transient ischemic attack readmission (aHRDiabetes=1.18 [1.10-1.26]; aHRDepression=1.24 [1.07-1.42]), and all-cause mortality (aHRDiabetes=1.29 [1.23-1.36]; aHRDepression=1.16 [1.05-1.29]). CONCLUSIONS: The risks of dementia and needing long-term care in the years after surviving a stroke were particularly elevated among women when premorbid diabetes mellitus and depression occurred together. Long-term stroke recovery strategies might target high-risk patients with mood and metabolic multimorbidity.

Metabolic and vascular risk factors are associated with reduced cerebral blood flow and poorer midlife memory performance.

Midlife metabolic and vascular risk factors (MVRFs) predict cognitive decline and dementia; however, these risk factors tend to overlap, and the mechanisms underlying their effects on cognitive performance are not well understood. This cross-sectional study investigates the contributions of MVRFs to regional cerebral blood flow (CBF) and verbal learning & memory among middle-aged adults. We used partial least squares (PLS) analysis to create latent risk factor profiles and examine their associations to CBF in 93 regions of interest among 451 participants (age 50.3 ± 3.5 years) of the Coronary Artery Risk Development in Young Adults. This multivariate analysis revealed regional CBF was lower in relation to obesity (higher body mass index and waist circumference), dysregulated glucose homeostasis (higher fasting glucose, oral glucose tolerance, and higher fasting insulin), and adverse fasting lipid profile (lower high-density lipoprotein cholesterol and higher triglycerides). In a sensitivity analysis, we found that significant associations between MVRFs and CBF were prominent in the hypertension-medicated subgroup. In a mediation model, the PLS-based MVRFs profile was associated with memory performance (rey auditory verbal learning test); however, CBF was not a significant mediator of this association. The results describe an adverse midlife metabolic profile that might set the stage for incipient dementia and contribute to widespread changes in CBF.

Hippocampal segmentation for brains with extensive atrophy using three-dimensional convolutional neural networks.

Hippocampal volumetry is a critical biomarker of aging and dementia, and it is widely used as a predictor of cognitive performance; however, automated hippocampal segmentation methods are limited because the algorithms are (a) not publicly available, (b) subject to error with significant brain atrophy, cerebrovascular disease and lesions, and/or (c) computationally expensive or require parameter tuning. In this study, we trained a 3D convolutional neural network using 259 bilateral manually delineated segmentations collected from three studies, acquired at multiple sites on different scanners with variable protocols. Our training dataset consisted of elderly cases difficult to segment due to extensive atrophy, vascular disease, and lesions. Our algorithm, (HippMapp3r), was validated against four other publicly available state-of-the-art techniques (HippoDeep, FreeSurfer, SBHV, volBrain, and FIRST). HippMapp3r outperformed the other techniques on all three metrics, generating an average Dice of 0.89 and a correlation coefficient of 0.95. It was two orders of magnitude faster than some of the tested techniques. Further validation was performed on 200 subjects from two other disease populations (frontotemporal dementia and vascular cognitive impairment), highlighting our method's low outlier rate. We finally tested the methods on real and simulated "clinical adversarial" cases to study their robustness to corrupt, low-quality scans. The pipeline and models are available at: https://hippmapp3r.readthedocs.ioto facilitate the study of the hippocampus in large multisite studies.