Author Correction: Predicting cognitive decline in a low-dimensional representation of brain morphology

Accumulating evidence suggests insulin and insulin signaling may be involved in the pathophysiology of Alzheimer disease (AD). The relationship between insulin-mediated glucoregulation and brain structure has not been assessed in individuals with AD. Nondemented (Clinical Dementia Rating [CDR] 0, n = 31) and early stage AD (CDR 0.5 and 1, n = 31) participants aged 65 years and older had brain MRI to determine whole brain and hippocampal volume and 3-hour IV glucose tolerance tests to determine glucose and insulin area under the curve (AUC). Linear regression models were used to assess the relationship of insulin and glucose with brain volume, cognition, and dementia severity. In early AD, insulin and glucose AUCs were related to whole brain (insulin beta = 0.66, p < 0.001; glucose beta = 0.45, p < 0.01) and hippocampal volume (insulin beta = 0.42, p < 0.05; glucose beta = 0.46, p < 0.05). These relationships were independent of age, sex, body mass index, body fat, cardiorespiratory fitness, physical activity, cholesterol, and triglycerides. Insulin AUC, but not glucose, was associated with cognitive performance in early AD (beta = 0.40, p = 0.04). Insulin AUC was associated with dementia severity (Pearson r = -0.40, p = 0.03). Glucose and insulin were not related to brain volume or cognitive performance in nondemented individuals. Increased peripheral insulin is associated with reduced Alzheimer disease (AD)-related brain atrophy, cognitive dysfunction, and dementia severity, suggesting that insulin signaling may play a role in the pathophysiology of AD.

The effects of air pollution on sleep and dementia remain unclear. The objective of this study was to investigate the effects of air pollution on cognitive function as mediated by the sleep cycle. A cross-sectional study design was conducted to recruit 4866 subjects on which PSG had been performed. Fifty of them were further given a cognitive function evaluation by the MMSE and CASI as well as brain images by CT and MRI. Associations of 1-year air pollution parameters with sleep parameters, cognitive function, and brain structure were examined. We observed that O3 was associated with a decrease in arousal, an increase in the N1 stage, and a decrease in the N2 stage of sleep. NO2 was associated with an increase in the N1 stage, a decrease in the N2 stage, and an increase in REM. PM2.5 was associated with a decrease in the N1 stage, increases in the N2 and N3 stages, and a decrease in REM. The N1 and N2 stages were associated with cognitive decline, but REM was associated with an increase in cognitive function. The N1 stage was a mediator of the effects of PM2.5 on the concentration domain of the MMSE. O3 was associated with an increase in the pars orbitalis volume of the left brain. NO2 was associated with increases in the rostral middle frontal volume, supramarginal gyrus volume, and transverse temporal volume of the left brain, and the pars opercularis volume of the right brain. PM2.5 was associated with increases in the pars triangularis volume of the left brain and the fusiform thickness of the right brain. In conclusion, we observed that air pollution was associated with cognitive decline by mediating effects on the sleep cycle with changes in the brain structure in controlling executive, learning, and language functions in adults.

As persons with human immunodeficiency virus (PWH) live longer, interactions between human immunodeficiency virus (HIV), aging, and structural brain integrity become increasingly vital for understanding cognitive disorders. This study analyzed the effects of aging, HIV serostatus, and viral load on cognition and brain volumes in a large cohort of persons without HIV (PWOH), PWH with undetectable virus (PWHU) (HIV RNA ≤50 copies/mL), and PWH with detectable virus (PHWD) (HIV RNA >50 copies/mL). Cross-sectional and longitudinal data were included. Cognitive composites (NPZ4) and brain volumes were obtained from 259 PWOH, 264 PWHU, and 84 PWHD with a total of 841 sessions. A series of generalized additive mixed models explored group differences in the relationship between age and cognition, age and regional brain volumes, and interactions between age and brain volumes on cognition. PWOH and PWHU exhibited similar change in cognitive performance with age, while PWHD exhibited a steeper decline compared to both. While both PWH groups had significantly smaller regional brain volumes compared to PWOH, the slopes of volume loss with age were similar across all groups except in the lentiform regions. Smaller brain volumes and increased age interacted for greater cognitive decline in PWHD. PWH who achieve viral suppression do not exhibit accelerated decline in cognition or brain volumes compared to PWOH, while PWHD may be at an increased risk for accelerated cognitive decline. These findings highlight the clinical importance of managing viral load in aging PWH and suggest that once viral suppression is achieved, changes to brain integrity are not accelerated compared to PWOH.

Type 2 diabetes (diabetes) is characterized by accelerated cognitive decline and higher dementia risk. Controversy exists regarding the impact of metformin, which is associated with both increased and decreased dementia rates. The objective of this study was to determine the association of metformin use with incident dementia and cognitive decline over 6 years in participants with diabetes compared with those not receiving metformin and those without diabetes. A prospective observational study was conducted of N = 1,037 community-dwelling older participants without dementia aged 70-90 years at baseline (the Sydney Memory and Ageing Study). Exclusion criteria were dementia, major neurological or psychiatric disease, or progressive malignancy. Neuropsychological testing measured cognitive function every 2 years; a battery of tests measured executive function, memory, attention/speed, language, and visuospatial function individually. These were used to determine the measure of global cognition. Incident dementia was ascertained by a multidisciplinary panel. Total brain, hippocampal, and parahippocampal volumes were measured by MRI at baseline and 2 years (n = 526). Data were analyzed by linear mixed modeling, including the covariates of age, sex, education, BMI, heart disease, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Of n = 1,037, 123 had diabetes; 67 received metformin (DM+MF) and were demographically similar to those who did not (DM-noMF) and participants without diabetes (no-DM). DM+MF had significantly slower global cognition and executive function decline compared with DM-noMF. Incident dementia was significantly higher in DM-noMF compared with DM+MF (odds ratio 5.29 [95% CI 1.17-23.88]; P = 0.05). Older people with diabetes receiving metformin have slower cognitive decline and lower dementia risk. Large randomized studies in people with and without diabetes will determine whether these associations can be attributed to metformin.

Cognitive decline is a grave complication in aging people with type 1 diabetes (T1D). We previously reported that compared to individuals without diabetes, those with long-duration T1D, the Joslin “Medalists” cohort, have impaired cognitive function, similar to people with type 2 diabetes (T2D). We further reported that Medalists (n=52), with T1D≥50 years, mean age of 71 years, mean HbA1c of 6.8 %, a good lipid profile and controlled hypertension, had significantly lower brain volumes compared to age-matched controls (n=20) on brain MRI (Alzheimer Disease Neuroimaging Initiative-3 protocol), but no significant differences in neurovascular lesions. In this study, we demonstrate that among Medalists, reduced total and regional brain volumes were cross-sectionally associated (p&amp;lt;0.05) with female sex, worse psychomotor function and visual acuity, longer diabetes duration and higher inflammatory cytokines, but not with glycemic control (HbA1c, continuous glucose monitoring indices, advanced glycation end-products) or history of hypoglycemia. Interestingly, worse cognitive function and lower brain volumes, in addition to diabetic retinopathy, correlated selectively with thinning of the outer retinal nuclear layer (ONL, composed of photoreceptors) as assessed by Optical Coherence Tomography. Mediation analysis showed that psychomotor function mediated 58 % of the association between visual acuity and brain volume, and 44 % of the association between ONL thickness and brain volume. In a longitudinal subset (n=48), where Medalists had 2 or more cognitive visits with an average follow-up time of 4.8 years between visits, worse baseline visual acuity was associated with decline in psychomotor function over 3-5 years of follow-up. These findings suggest that future studies should investigate a potentially novel therapeutic approach of targeting improvement in visual acuity to prevent cognitive decline in people with long-duration T1D. Disclosure H. Shah: None. M. Desalvo: None. A. Haidar: None. S. Jangolla: None. M. Yu: None. R. Roque: None. N.A. Ziemniak: None. E.R. Viebranz: None. I. Wu: None. W. Fickweiler: None. T. Chokshi: None. T. Billah: None. L. Ning: None. A. Adam: None. J.K. Sun: Research Support; Optovue, Boehringer-Ingelheim, Novo Nordisk, Roche Pharmaceuticals. Other Relationship; Roche Pharmaceuticals. Research Support; Physical Sciences, Inc, Boston Micromachines. Y. Rathi: None. M.B. Feany: None. G.L. King: None. Funding NIH/NIDDK (3P30DK036836-34S1); The Beatson Foundation

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington’s disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington’s disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington’s disease and their effect on brain structure.

Association of liver disease with brain volume loss, cognitive decline, and plasma neurodegenerative disease biomarkers

Type 2 diabetes mellitus (T2DM) is associated with diseases of the brain, kidney, and vasculature. However, the relationship between T2DM, chronic kidney disease, brain alterations, and cognitive function after stroke is unknown. We aimed to evaluate the inter-relationship between T2DM, impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort. The TABASCO (Tel Aviv brain acute stroke cohort) is a prospective cohort of stroke/transient ischemic attack survivors. The volume and white matter integrity, ischemic lesions, and brain and hippocampal volumes were measured at baseline using 3-T MRI. Cognitive tests were performed on 507 patients, who were diagnosed as having mild cognitive impairment, dementia, or being cognitively intact after 24 months. At baseline, T2DM and impaired renal function (estimated creatinine clearance [eCCl] <60 mL/min) were associated with smaller brain and hippocampal volumes, reduced cortical thickness, and worse white matter microstructural integrity. Two years later, both T2DM and eCCl <60 mL/min were associated with poorer cognitive scores, and 19.7% of the participants developed cognitive decline (mild cognitive impairment or dementia). Multiple analysis, controlling for age, sex, education, and apolipoprotein E4, showed a significant association of both T2DM and eCCl <60 mL/min with cognitive decline. Having both conditions doubled the risk compared with patients with T2DM or eCCl <60 mL/min alone and almost quadrupled the risk compared with patients without either abnormality. T2DM and impaired renal function are independently associated with abnormal brain structure, as well as poorer performance in cognitive tests, 2 years after stroke. The presence of both conditions quadruples the risk for cognitive decline. T2DM and lower eCCl have an independent and additive effect on brain atrophy and the risk of cognitive decline. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01926691.

BackgroundType 2 diabetes mellitus (T2DM) is known to be associated with cognitive decline and brain structural changes. This study systematically reviews and estimates human brain volumetric differences and atrophy associated with T2DM.MethodsPubMed, PsycInfo and Cochrane Library were searched for brain imaging studies reporting on brain volume differences between individuals with T2DM and healthy controls. Data were examined using meta-analysis, and association between age, sex, diabetes characteristics and brain volumes were tested using meta-regression.ResultsA total of 14,605 entries were identified; after title, abstract and full-text screening applying inclusion and exclusion criteria, 64 studies were included and 42 studies with compatible data contributed to the meta-analysis (n=31,630; mean age 71.0 years; 44.4% male; 26,942 control; 4,688 diabetes). Individuals with T2DM had significantly smaller total brain volume, total grey matter volume, total white matter volume and hippocampal volume (approximately 1% to 4%); meta-analyses of smaller samples focusing on other brain regions and brain atrophy rate in longitudinal investigations also indicated smaller brain volumes and greater brain atrophy associated with T2DM. Meta-regression suggests that diabetes-related brain volume differences start occurring in early adulthood, decreases with age and increases with diabetes duration.ConclusionT2DM is associated with smaller total and regional brain volume and greater atrophy over time. These effects are substantial and highlight an urgent need to develop interventions to reduce the risk of T2DM for brain health.

Objective: Adherence to the Mediterranean- DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs) or brain atrophy. Methods: We aimed to evaluate, cross-sectionally and longitudinally, whether consumption of a diet consist with the MIND diet was associated with larger brain volumes, fewer SBIs and fewer atrophy in the community-based Framinham Heart Study. We included 1,904 participants (mean age 69 (SD, 9)) who completed a brain MRI and a validated food frequency questionnaire (FFQ). The MIND diet consists of 10 healthy and five unhealthy components (range: 0-15). A cumulative MIND diet score was calculated by averaging across three FFQs (exams 5 (1991-1995), 6 (1995-1998), and 7 (1998-2001)). From the total study population, 86 % completed all three FFQs. Brain MRI was performed proximal to exam 7 and again after a mean of 7 years (SD, 1.1) (n=1,317). Total brain volume (TBV), hippocampal volume (HPV), white matter hyperintensity volume (WMHV), expressed as a percentage of total cranial volume, and presence of SBIs were assessed from MRI scans. We used multivariable linear (TBV, HPV and WMHV) and logistic (SBIs) regressions for the cross-sectional analyses, and we analyzed the annualized change of TBV and HPV as atrophy measures using multivariable linear regression. Results: In cross-sectional analyses, higher MIND diet scores were significantly associated with larger TBV (β±SE, +0.09±0.04; p=0.03) after adjustment for basic demographic factors, total daily energy intake, and APOE e4 allele status, but was not associated with HPV (+0.001±0.001; p=0.09), WMHV (-0.01±0.01; p=0.27), SBIs (OR (95%CI), +1.01, 0.92:1.10; p=0.61) or atrophy (TBV, -0.001±0.01; p=0.88; HPV, -0.0003±0.001; p=0.62). After additional adjustments for cardiovascular risk factors the association with TBV was attenuated (+0.05±0.04; p=0.17). Significant interactions were observed for HPV by APOE ε4 status and BMI in the basic model. After stratification by APOE ε4 status, higher MIND diet scores were significantly associated with higher HPV among APOE ε4 non-carriers (+0.002±0.001; p=0.01) but not carriers (n=412). After stratification by BMI, higher adherence to the MIND diet was associated with larger HPV among participants with a BMI above 25 (+0.002±0.001; p=0.01), but not among participants with a BMI below 25. Conclusions: Higher adherence to the MIND diet was not independently associated with brain volume measures, SBIs or brain atrophy in our community cohort as the associations appeared to be mediated by cardiovascular risk factors. In addition, we observed that adherence to the diet was associated with larger brain volume measures in sub groups. Replication is needed to confirm our findings.

DEVELOPMENT OF A PROGRAM FOR QUICK BRAIN VOLUMETRY

Cognitive decline, related at least in part to reduced processing speed and lower working memory, is a major problem in paediatric and adult patients with sickle cell anaemia (SCA)1,2 and affects quality of life. Multiple studies investigating the association between quantitative and qualitative neuroimaging findings and cognition have had mixed results. Hence, the aetiology of cognitive decline in this population is not clearly understood. Cerebral atrophy on magnetic resonance imaging is noted in the literature but few studies have investigated the association between brain volumes and cognition. White matter microstructural integrity and white matter hyperintensities have been associated with reduced processing speed index (PSI).3 However no study has investigated the association between white matter volumes and PSI in the SCA population. Total subcortical volumes have also been noted to be lower in SCA children and adults. Only one study has investigated the association between total subcortical volumes and working memory index (WMI) in adults.4 Moreover, several studies in the past have noted age related decline in total brain volume as well neurodevelopmental delay in grey matter volume growth.5,6 Most of the developmental trajectory data in the literature comes from longitudinal data sets with limited samples and without control groups. Hence, for the purpose of this study, we investigated the association between regional brain volumes (white matter volumes and total subcortical volumes) and cognition (processing speed index and working memory index) in 129 SCA patients aged 8 – 64 years (66 male) and 50 controls (21 males). Participants were enrolled in two studies - the Sleep Asthma Cohort (SAC) and the Prevention of Morbidity in SCA (POMS) trial. We hypothesized that white matter volumes would predict processing speed index and total subcortical volumes would predict working memory index in SCA patients as well as controls. We also hypothesized that the developmental trajectories for regional brain volumes and cognitive variables would differ between patients and controls. Separate multiple linear regression models for males and females revealed that WMV predicted processing speed index(p=.019) and total subcortical volumes predicted working memory index (p=.025) in male patients only. Age (p=.003) and socioeconomic status (p=.03) also independently predicted PSI in male patients. Individual subcortical regions predicting WMI were statistically significant for left and right thalamus only in male patients. Haemoglobin and age emerged as the best predictors of cognitive decline in patients. Comparison of developmental trajectories between patients and controls revealed that only processing speed was significantly delayed at 8 years. The rate of development for all variables was lower in SCA patients and age-related decline was accelerated in patients as compared to controls. We speculate that early cerebral haemodynamic compromise may contribute to long term cognitive decline in patients. We also highlight that male SCA patients are particularly vulnerable to SCA disease severity. Hence, timely intervention to stabilise haemoglobin levels, especially in males, should be considered. Limitations include lack of stratification by SCI and age (adults and children separately) and the possibility that we were underpowered to detect effects in females.

BackgroundChronic pain affects one in five older adults and is linked to increased risk for Alzheimer’s disease (AD) dementia. Few studies have investigated associations between chronic pain and AD biomarkers, especially chronic pain at moderate‐to‐severe levels considered clinically significant.MethodWe included 2487 participants without baseline dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). At baseline, participants were categorized by absence/presence of moderate‐to‐severe chronic pain, defined as persistent/recurring pain with onset >3 months prior. For sensitivity analyses, we categorized people based on the absence/presence of chronic pain at mild levels. Cognitive outcomes included the Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB), episodic memory, and executive function (minimal n = 1328, mean follow‐up‐years=1.49, SD=2.78). AD biomarkers included cerebrospinal fluid levels of Aβ42, total tau, and phosphorylated tau (minimal n = 1057, mean follow‐up‐years=.53, SD=1.24); and structural MRI (AD structural brain signature, hippocampal volume, entorhinal cortical thickness, and whole brain volume, minimal n = 2136, mean follow‐up‐years=1.11, SD=2.28). Mixed‐effects models assessed differences in baseline levels and change in each outcome between pain groups, and mediation analyses explored Aβ and neurodegeneration pathways. Covariates included baseline age, sex, APOE ε4 status, depressive symptoms, and opioid use (intracranial volume for structural MRI outcomes).ResultModerate‐to‐severe chronic pain relative to mild or none was associated with accelerated decline in global cognition (increase in CDR‐SB: b=.05), memory, executive function (b=‐.04), and whole brain volume (b=‐.02), and faster accumulation of Aβ pathology (CSF Aβ42 decline: b=‐.07, all p’s < .05). It was not associated with neurodegeneration in AD brain signature regions, hippocampal volume, or entorhinal cortex (all ps>.05). Accumulation of Aβ pathology (absolute b’s range=.03 to .05) and whole brain volume loss (absolute b’s range=.001‐.002) mediated associations of moderate‐to‐severe chronic pain with cognitive decline, with Aβ also mediating moderate‐to‐severe chronic pain’s association with brain volume loss (b=‐.01, all ps<.05). Mild chronic pain relative to none did not significantly relate to cognitive or biomarker outcomes (all ps>.05).ConclusionModerate‐to‐severe chronic pain contributes to accelerated cognitive decline and general neurodegeneration, primarily via Aβ. These findings highlight the need to consider moderate‐to‐severe chronic pain, rather than just presence/absence of chronic pain in AD risk assessments and interventions.

(Reprinted with permission from American Psychiatric Association, http://psychiatryonline.org/guidelines).

Background: Stroke survivors are at high risk of dementia, associated with increasing age and vascular burden and with pre-existing cognitive impairment, older age. Brain atrophy patterns are recognised as signatures of neurodegenerative conditions, but the natural history of brain atrophy after stroke remains poorly described. We sought to determine whether stroke survivors who were cognitively normal at time of stroke had greater total brain (TBV) and hippocampal volume (HV) loss over 3 years than controls. We examined whether stroke survivors who were cognitively impaired (CI) at 3 months following their stroke had greater brain volume loss than cognitively normal (CN) stroke participants over the next 3 years.Methods: Cognition And Neocortical Volume After Stroke (CANVAS) study is a multi-centre cohort study of first-ever or recurrent adult ischaemic stroke participants compared to age- and sex-matched community controls. Participants were followed with MRI and cognitive assessments over 3 years and were free of a history of cognitive impairment or decline at inclusion. Our primary outcome measure was TBV change between 3 months and 3 years; secondary outcomes were TBV and HV change comparing CI and CN participants. We investigated associations between group status and brain volume change using a baseline-volume adjusted linear regression model with robust standard error.Results: Ninety-three stroke (26 women, 66.7 ± 12 years) and 39 control participants (15 women, 68.7 ± 7 years) were available at 3 years. TBV loss in stroke patients was greater than controls: stroke mean (M) = 20.3 cm3 ± SD 14.8 cm3; controls M = 14.2 cm3 ± SD 13.2 cm3; [adjusted mean difference 7.88 95%CI (2.84, 12.91) p-value = 0.002]. TBV decline was greater in those stroke participants who were cognitively impaired (M = 30.7 cm3; SD = 14.2 cm3) at 3 months (M = 19.6 cm3; SD = 13.8 cm3); [adjusted mean difference 10.42; 95%CI (3.04, 17.80), p-value = 0.006]. No statistically significant differences in HV change were observed.Conclusions: Ischaemic stroke survivors exhibit greater neurodegeneration compared to stroke-free controls. Brain atrophy is greater in stroke participants who were cognitively impaired early after their stroke. Early cognitive impairment was associated greater subsequent atrophy, reflecting the combined impacts of stroke and vascular brain burden. Atrophy rates could serve as a useful biomarker for trials testing interventions to reduce post-stroke secondary neurodegeneration.Clinical Trail Registration: http://www.clinicaltrials.gov, identifier: NCT02205424.