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.

Endosomal-Lysosomal and Autophagy Pathway in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent. OBJECTIVE: To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC). METHODS: Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models. RESULTS: Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD/NHC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2 = 72.8%; LAMP-2: NAD/NHC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2 = 78.7%) and intra-lysosomal proteins (GM2A: NAD/NHC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2 = 87.7%; CTSB: NAD/NHC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2 = 28.5%; CTSZ: NAD/NHC = 535/820, SMD [95% CI] = -0.160 [-0.305, -0.015], I2 = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD/NHC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2 = 27.4%; FLOT1: NAD/NHC = 41/45, SMD [95% CI] = -0.489 [-0.919, -0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD/NHC = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2 = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy. CONCLUSION: Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD.

Biofluid markers of blood-brain barrier disruption and neurodegeneration in Lewy body spectrum diseases: A systematic review and meta-analysis.

BACKGROUND: Mixed evidence supports blood-brain barrier (BBB) dysfunction in Lewy body spectrum diseases. METHODS: We compare biofluid markers in people with idiopathic Parkinson's disease (PD) and people with PD dementia (PDD) and/or dementia with Lewy bodies (DLB), compared with healthy controls (HC). Seven databases were searched up to May 10, 2021. Outcomes included cerebrospinal fluid to blood albumin ratio (Qalb), and concentrations of 7 blood protein markers that also reflect BBB disruption and/or neurodegenerative co-pathology. We further explore differences between PD patients with and without evidence of dementia. Random-effects models were used to obtain standardized mean differences (SMD) with 95% confidence interval. RESULTS: Of 13,949 unique records, 51 studies were meta-analyzed. Compared to HC, Qalb was higher in PD (NPD/NHC = 224/563; SMD = 0.960 [0.227-1.694], p = 0.010; I2 = 92.2%) and in PDD/DLB (NPDD/DLB/NHC = 265/670; SMD = 1.126 [0.358-1.893], p < 0.001; I2 = 78.2%). Blood neurofilament light chain (NfL) was higher in PD (NPD/NHC = 1848/1130; SMD = 0.747 [0.442-1.052], p < 0.001; I2 = 91.9%) and PDD/DLB (NPDD/DLB/NHC = 183/469; SMD = 1.051 [0.678-1.423], p = 0.004; I2 = 92.7%) than in HC. p-tau 181 (NPD/NHC = 276/164; SMD = 0.698 [0.149-1.247], p = 0.013; I2 = 82.7%) was also higher in PD compared to HC. In exploratory analyses, blood NfL was higher in PD without dementia (NPDND/NHC = 1005/740; SMD = 0.252 [0.042-0.462], p = 0.018; I2 = 71.8%) and higher in PDD (NPDD/NHC = 100/111; SMD = 0.780 [0.347-1.214], p < 0.001; I2 = 46.7%) compared to HC. Qalb (NPDD/NPDND = 63/191; SMD = 0.482 [0.189-0.774], p = 0.010; I2<0.001%) and NfL (NPDD/NPDND = 100/223; SMD = 0.595 [0.346-0.844], p < 0.001; I2 = 3.4%) were higher in PDD than in PD without dementia. CONCLUSIONS: Biofluid markers suggest BBB disruption and neurodegenerative co-pathology involvement in common Lewy body diseases. Greater evidence of BBB breakdown was seen in Lewy body disease with cognitive impairment.

Glucose-lowering drugs, cognition, and dementia: The clinical evidence.

Type 2 diabetes mellitus (T2DM) is an important risk factor for dementia. The possibility to mitigate this risk by controlling T2DM is compelling; however, different glucose-lowering drugs have different effects on the brain by virtue of their different mechanisms of action. The clinical and epidemiological data appear mixed, warranting careful critical evaluation of the human studies. Here we examine the evidence in the context of dementia prevention and treatment, both for people with and without T2DM. We discuss the evidence on this scaffold of research directions, identifying methodological complexities in the extant literature (e.g. comparator discrepancies, changes in the therapeutic landscape), and the implications of different outcome measures (e.g. neuropsychological). We consider possible implications of cerebrovascular protection vs. effects on progression of neurodegenerative proteinopathy, and we present a research roadmap for glucose-lowering drugs in cognitive neurology, including neuroimaging, and fluid biomarkers. We conclude that there is great potential to advance personalized strategies to prevent and treat dementia with glucose-lowering drugs.

Gastric acid suppressants and cognitive decline in people with or without cognitive impairment.

INTRODUCTION: Studies suggest associations between proton pump inhibitors (PPIs) and dementia risk; however, many neither considered histamine-2 receptor antagonists (H2RAs) nor baseline cognitive status. METHODS: Participants (National Alzheimer's Coordinating Center Database; 2005-2021) using a PPI or H2RA were compared. Covariate-adjusted Cox regression was used to estimate hazard ratios (HR) for progression from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia over 5 years. In a propensity-score-matched subsample of mild-moderate Alzheimer's disease (AD), mixed-effects negative binomial regression was used to estimate decline in delayed recall memory. RESULTS: Compared to PPI, H2RA use was associated with earlier progression from MCI to dementia (HR = 1.40 [1.09-1.81]; n = 1701), and with faster memory decline in AD over time (rate ratio = 0.76 [0.64-0.92]; n = 628), but not with progression from normal cognition to MCI (HR = 0.94 [0.71-1.24]; n = 2784). DISCUSSION: Compared to PPIs, H2RAs were associated with cognitive decline, specifically among people with pre-existing cognitive impairment.

Leukotriene receptor antagonist use and cognitive decline in normal cognition, mild cognitive impairment, and Alzheimer's dementia.

BACKGROUND: Leukotriene receptor antagonists (LTRAs) alleviate Alzheimer's disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This study aimed to explore the associations between the use of LTRAs (montelukast or zafirlukast) and cognitive performance in people with normal cognition, mild cognitive impairment (MCI), or AD dementia. We hypothesized that LTRA use would be associated with better cognitive performance over time. METHODS: This longitudinal observational study used data from the National Alzheimer's Coordinating Center. Within groups of participants with normal cognition, MCI, or AD dementia, LTRA users were matched 1:3 to non-users using propensity score matching. Cognitive domains including immediate and delayed memory (Wechsler Memory Scale Revised-Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol Substitution Test), and language (animal naming, vegetable naming, and Boston Naming Test) were compared between users and non-users in mixed-effects linear or Poisson regression models. RESULTS: In AD dementia, LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol Substitution Test (Β = 1.466 [0.253, 2.678] symbols/year, n = 442), and language, as measured by animal naming (Β = 0.541 [0.215, 0.866] animals/year, n = 566), vegetable naming (B = 0.309 [0.056, 0.561] vegetables/year, n = 565), and the Boston Naming Test (B = 0.529 [0.005, 1.053] items/year, n = 561). Effect sizes were small but persisted after controlling for a 10% false discovery rate. LTRA use was not associated with changes in memory performance in AD, nor was it associated with changes in cognitive performance in people with normal cognition or MCI. In a post hoc analysis, LTRA use was associated with a slower decline in clinical progression in MCI (B = -0.200 [-0.380, -0.019] points/year, n = 800) and AD dementia (B = -0.321 [-0.597, -0.046] points/year, n = 604) as measured by CDR Sum of Boxes. CONCLUSIONS: The use of LTRAs was associated with preserved function in non-amnestic cognitive domains in AD dementia. The role of leukotrienes and their receptors in cognitive decline warrants further investigation and the leukotriene pathway may represent a target for AD treatment.

Diabetes Mellitus Is Associated With Poor In-Hospital and Long-Term Outcomes in Young and Midlife Stroke Survivors.

Background The incidence of ischemic stroke has increased among adults aged 18 to 64 years, yet little is known about relationships between specific risk factors and outcomes. This study investigates in-hospital and long-term outcomes in patients with stroke aged <65 years with preexisting diabetes mellitus. Methods and Results Consecutive patients aged <65 years admitted to comprehensive stroke centers for acute ischemic stroke between 2003 and 2013 were identified from the Ontario Stroke Registry. Multinomial logistic regression was used to estimate adjusted odds ratio (OR [95% CI]) of in-hospital mortality or direct discharge to long-term or continuing care. Cox proportional hazards regression was used to estimate the adjusted hazards ratio (aHR [95% CI]) of long-term mortality, readmission for stroke/transient ischemic attack, admission to long-term care, and incident dementia. Predefined sensitivity analyses examined stroke outcomes among young (aged 18-49 years) and midlife (aged 50-65 years) subgroups. Among 8293 stroke survivors (mean age, 53.6±8.9 years), preexisting diabetes mellitus was associated with a higher likelihood of in-hospital death (adjusted OR, 1.46 [95% CI, 1.14-1.87]) or direct discharge to long-term care (adjusted OR, 1.65 [95% CI, 1.07-2.54]). Among stroke survivors discharged (N=7847) and followed up over a median of 6.3 years, preexisting diabetes mellitus was associated with increased hazards of death (aHR, 1.68 [95% CI, 1.50-1.88]), admission to long-term care (aHR, 1.57 [95% CI, 1.35-1.82]), readmission for stroke/transient ischemic attack (aHR, 1.37 [95% CI, 0.21-1.54]), and incident dementia (aHR, 1.44 [95% CI, 1.17-1.77]). Only incident dementia was not increased for young stroke survivors. Conclusions Focused secondary prevention and risk factor management may be needed to address poor long-term outcomes for patients with stroke aged <65 years with preexisting diabetes mellitus.

The use of angiotensin-converting enzyme inhibitors vs. angiotensin receptor blockers and cognitive decline in Alzheimer's disease: the importance of blood-brain barrier penetration and APOE ε4 carrier status.

BACKGROUND: The antihypertensive angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) have similar indications and mechanisms of action, but prior work suggests divergence in their effects on cognition. METHODS: Participants in the National Alzheimer's Coordinating Center database with a clinical diagnosis of dementia due to Alzheimer's disease (AD) using an ACE-I or an ARB at any visit were selected. The primary outcome was delayed recall memory on the Wechsler Memory Scale Revised - Logical Memory IIA. Other cognitive domains were explored, including attention and psychomotor processing speed (Trail Making Test [TMT]-A and Digit Symbol Substitution Test [DSST]), executive function (TMT-B), and language and semantic verbal fluency (Animal Naming, Vegetable Naming, and Boston Naming Tests). Random slopes mixed-effects models with inverse probability of treatment weighting were used, yielding rate ratios (RR) or regression coefficients (B), as appropriate to the distribution of the data. Apolipoprotein (APOE) ε4 status and blood-brain barrier (BBB) penetrance were investigated as effect modifiers. RESULTS: Among 1689 participants with AD, ARB use (n = 578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28 years compared with ACE-I use (n = 1111) [RR = 1.094, p = 0.0327]; specifically, users of BBB-crossing ARBs (RR = 1.25, p = 0.002), BBB-crossing ACE-Is (RR = 1.16, p = 0.010), and non-BBB-crossing ARBs (RR = 1.20, p = 0.005) had better delayed recall performance over time compared with non-BBB-crossing ACE-I users. An interaction with APOE ε4 status (drug × APOE × time RR = 1.196, p = 0.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR = 1.200, p = 0.003), but not in carriers (RR = 1.003, p = 0.957). ARB use was also associated with better performance over time on the TMT-A (B = 2.023 s, p = 0.0004) and the DSST (B = 0.573 symbols, p = 0.0485), and these differences were significant among APOE ε4 non-carriers (B = 4.066 s, p = 0.0004; and B = 0.982 symbols, p = 0.0230; respectively). Some differences were seen also in language and verbal fluency among APOE ε4 non-carriers. CONCLUSIONS: Among APOE ε4 non-carriers with AD, ARB use was associated with greater preservation of memory and attention/psychomotor processing speed, particularly compared to ACE-Is that do not cross the blood-brain-barrier.

Associations between brain amyloid accumulation and the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers.

Some studies suggest that angiotensin II type 1 receptor blockers (ARBs) may protect against memory decline more than angiotensin-converting enzyme inhibitors (ACE-Is), but few have examined possible mechanisms. We assessed longitudinal differences between ARB versus ACE-I users in global and sub-regional amyloid-ß accumulation by 18F-florbetapir. In cognitively normal older adults (n= 142), propensity-weighted linear mixed-effects models showed that ARB versus ACE-I use was associated with slower amyloid-ß accumulation in the cortex, and specifically in the caudal anterior cingulate and precuneus, and in the precentral and postcentral gyri. In amyloid-positive participants with Alzheimer's disease dementia or mild cognitive impairment (n = 169), ARB versus ACE-I use was not associated with different rates of amyloid-ß accumulation. Apolipoprotein E ε4 carrier status explained some heterogeneity in the different rates of amyloid-ß accumulation between users of ARBs versus ACE-Is in the study. Replicative studies and clinical trials are warranted to confirm potential benefits of ARBs on rates of amyloid-ß accumulation in the contexts of Alzheimer's disease prevention and treatment.

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.

Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status.

INTRODUCTION: Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs. METHODS: Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised-Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed-effects models with inverse probability treatment weights. RESULTS: In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase-4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers. DISCUSSION: Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some relationships.

Neutrophil activation in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis of protein markers in blood and cerebrospinal fluid.

Inflammation is involved in the pathophysiology of Alzheimer's disease (AD), with multiple inflammatory processes implicated in its risk and progression. This review included original peer-reviewed studies measuring the cerebrospinal fluid or peripheral blood concentrations of protein markers specifically related to neutrophil activity in healthy controls (HC) and in patients with AD or mild cognitive impairment (MCI). A total of 35 studies (NHC = 3095, NAD = 2596, NMCI = 1203) were included. Random-effects meta-analyses were used to estimate between-groups standardized mean differences (SMD) and 95 % confidence intervals. In blood, concentrations of myeloperoxidase (MPO; NAD/NHC = 271/209, SMD = 0.41 [0.20, 0.62]; I2 = 15.7 %) and neutrophil gelatinase associated lipocalin (NGAL; NAD/NHC = 273/185, SMD = 0.30 [0.11, 0.49]; I2 < 0.005 %) were significantly higher in AD relative to HC. Peripheral blood concentrations of NGAL were also higher in MCI compared to HC (NMCI/NHC = 489/145, SMD = 0.39 [0.11, 0.67]; I2 = 38.6 %). None of the protein markers exhibited a significant difference between HC, MCI, or AD groups in the cerebrospinal fluid. The evidence suggests that peripheral neutrophil activation, as indicated by blood concentrations of NGAL and MPO, may be a pathological feature of cognitive impairment due to AD, evident at stages of MCI and AD dementia.

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer's disease.

BACKGROUND: Studies suggest a role of the innate immune system, including the activity of neutrophils, in neurodegeneration related to Alzheimer's disease (AD), but prospective cognitive data remain lacking in humans. We aimed to investigate the predictive relationship between neutrophil-associated inflammatory proteins in peripheral blood and changes in memory and executive function over 1 year in patients with AD. METHODS: Participants with AD were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1ß), and tumor necrosis factor (TNF) were assayed by luminex immunofluorescence multiplex assay at baseline. Confirmatory factor analysis was used to test an underlying neutrophil associated plasma inflammatory factor. Composite z-scores for memory and executive function were generated from multiple tests at baseline and at 1 year. A multiple linear regression model was used to investigate the association of the baseline inflammatory factor with changes in memory and executive function over 1 year. RESULTS: Among AD patients (n = 109, age = 74.8 ± 8.1, 42% women, Mini Mental State Examination [MMSE] = 23.6 ± 1.9), the neutrophil-related inflammatory proteins NGAL (λ = 0.595, p < .001), MPO (λ = 0.575, p < .001), IL-8 (λ = 0.525, p < .001), MIP-1ß (λ = 0.411, p = .008), and TNF (λ = 0.475, p < .001) were found to inform an underlying factor. Over 1 year, this inflammatory factor predicted a decline in executive function (ß = - 0.152, p = 0.015) but not memory (ß = 0.030, p = 0.577) in models controlling for demographics, brain atrophy, white matter hyperintensities, the ApoE ε4 allele, concomitant medications, and baseline cognitive performance. CONCLUSIONS: An inflammatory factor constructed from five neutrophil-related markers in peripheral blood predicted a decline in executive function over 1 year in people with mild AD.

Psychiatric morbidity and cervical cancer screening: a retrospective population-based case-cohort study.

BACKGROUND: Cervical cancer screening reduces disease-specific mortality. This study aimed to estimate whether bipolar disorder or schizophrenia is associated with disparities in cervical cancer screening rates. METHODS: This was a retrospective population-based matched case-cohort study of community-dwelling women aged 19-69 in Ontario using linked health administrative databases. We used odds ratios (ORs), hazards ratios and rate ratios (RRs) adjusted for demographic characteristics and relevant comorbidities to compare cervical cancer screening outcomes between women with a diagnosis of bipolar disorder or schizophrenia to women without that history matched on key demographic characteristics, between 2003 and 2015. RESULTS: In total, 1 245 457 women were identified for inclusion in the analyses, 119 948 with a diagnosis of bipolar disorder or schizophrenia, and 1 125 509 without. Over a median follow-up duration of 12.5 years, women with the exposure were 36% less likely to be screened (OR 0.64, 95% confidence interval [CI] 0.64-0.65) than those without, and they took longer to undergo screening (median 18.98 mo v. 16.63 mo; χ2 = 3718.2, p < 0.001). They were also screened less frequently (median 6.16 yr v. 4.69 yr per screen; RR 0.85, 95% CI 0.84-0.85). These effects were consistent after we excluded the 86 475 women (6.9%) with suspected major depressive disorder, and they were larger for the 59 141 women (4.7%) not attached to a family physician. INTERPRETATION: Women with bipolar disorder or schizophrenia were less likely to undergo cervical cancer screening, their screening was delayed, and they were screened at a lower rate compared to women without this psychiatric history. This practice gap suggests a need to further address barriers to screening, including access to a family physician, among women with bipolar disorder or schizophrenia.