Objective: Individuals with type 1 diabetes (T1D) are living longer and developing cognitive and physical impairments. The effect of these impairments on everyday functioning remains poorly understood. We evaluated whether cognitive and physical impairments were associated with functional status in participants from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Research Design and Methods: Participants (n=988) completed cognitive and physical function tests and self-reported ability to complete functional activities across five domains: activities of daily living (ADL), instrumental ADL, leisure and social activities, lower-extremity mobility, and general physical function. Results: Seventy-seven percent of participants (mean age 60 years, diabetes duration 38 years) had neither cognitive nor physical impairments, 23% either, and 7% both. Depressive symptomology was reported by 12%, and subjective cognitive decline by 22%. Participants with vs. without both impairments were more likely to report functional limitations (87% vs. 39%, p<0.001). Cognitive and/or physical impairments, depressive symptomatology, subjective cognitive decline, and neuropathy were associated with higher odds of functional limitations across all domains. Compared to males, females had higher odds of functional limitations, including any, IADL, leisure/social, lower-extremity mobility, and general physical. Higher HbA1c was associated with higher odds of ADL limitations. History of CVD was marginally associated with mobility limitations. Conclusions: Among middle-aged and older adults with T1D, functional limitations were common and associated with cognitive and physical impairments, depressive symptoms, subjective cognitive decline, and neuropathy. Identifying and addressing these factors may help preserve or improve functional status in aging adults with T1D. ARTICLE HIGHLIGHTS · Why did we undertake this study? The impact of cognitive and physical impairments on functioning of individuals with type 1 diabetes (T1D) is unclear. · What is the specific question(s) we wanted to answer? How do cognitive and physical impairments among adults with long-duration T1D affect the ability to perform activities of daily living, instrumental activities of daily living, leisure/social activities, mobility, and general physical function? · What did we find? Participants with cognitive and physical impairments were more likely to report functional limitations than those without. Presence of depressive symptomatology, subjective cognitive decline, and neuropathy were also associated with higher odds of functional limitations. · What are the implications of our findings? Identifying and addressing cognitive and physical impairments, neuropathy, and depressive symptomology may improve functional status for individuals with T1D.

Objective: Adults with type 1 diabetes (T1D) face an increased risk for cognitive decline and dementia. Diabetes-related and vascular risk factors have been linked to cognitive decline using detailed neuropsychological testing; however, it is unclear if cognitive screening batteries can detect cognitive changes associated with aging in T1D. Method: 1,049 participants with T1D (median age 59 years; range 43-74) from the Diabetes Control and Complications Trial (DCCT), and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, completed the NIH Toolbox Cognition Battery (NIHTB-C) and Montreal Cognitive Assessment (MoCA). Neuropsychological assessments, depression, glycated hemoglobin levels (HbA1c), severe hypoglycemia, T1D complications, and vascular risk factors were assessed repeatedly over 32 years to determine associations with current NIHTB-C performance. Available cognitive data was clinically adjudicated to determine cognitive impairment status. Results: NIHTB-C scores had moderate associations (r = 0.36-0.53) with concurrently administered neuropsychological tests. In multivariate models, prior severe hypoglycemic episodes, depression symptoms, nephropathy, lower BMI, and higher HbA1c and LDL cholesterol were associated with poorer NIHTB-C Fluid Cognition Composite scores. The NIHTB-C adequately detected adjudicated cognitive impairment (Area Under the Curve = 0.86; optimal cut score ≤90). The MoCA performed similarly (Area Under the Curve = 0.83; optimal cut score ≤25). Conclusions: The NIHTB-C is sensitive to the cognitive effects of diabetes-related and vascular risk factors, correlated with neuropsychological testing, and accurately detects adjudicated cognitive impairment. These data support its use as a screening test in middle to older aged adults with T1D to determine if referral for detailed neuropsychological assessment is needed.

Over the past decades, life expectancy of people with type 1 diabetes has increased considerably, which brings potential challenges due to the process of aging. Cognitive aging and dementia, as well as reductions in visual acuity, hearing and dexterity, can influence the frequency and quality of daily self-management activities, including medication taking and insulin dosing, glucose self-monitoring, and healthy eating. This can increase the risk for hypo- and hyperglycemic events, which, in turn, may contribute to cognitive decline. Because there is a gap in understanding the barriers and facilitators of self-management in older adults with type 1 diabetes and the relationship to cognitive functioning, the authors 1) review the available literature on cognitive aging and type 1 diabetes, 2) describe what self-management in later adulthood entails and the cognitive functions required for effective self-management behaviors, 3) analyze the interaction between type 1 diabetes, cognition, aging, and self-management behaviors, and 4) describe the barriers and facilitators for self-management throughout the life span and how they may differ for older people. Potential evidence-based practices that could be developed for older adults with type 1 diabetes are discussed. There is need for further studies that clarify the impact of aging on T1D self-management, ultimately to improve diabetes care and quality of life.

Objective: To evaluate associations between plasma biomarkers of brain injury and MRI and cognitive measures in participants with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Research Design and Methods: Plasma amyloidß-40, amyloidß-42, neurofilament light chain (NfL), phosphorylated Tau-181 (pTau-181), and glial fibrillary acidic protein (GFAP) were measured in 373 DCCT/EDIC adults. MRI assessments included total brain and white matter hyperintensity volumes, white matter mean fractional anisotropy, and indices of Alzheimer’s Disease (AD)-like atrophy and predicted brain age. Cognitive measures included memory and psychomotor and mental efficiency tests and assessments of cognitive impairment. Results: Participants were 60 (range 44-74) years old with 38 (30-51) years T1D duration. Higher NfL was associated with an increase in predicted brain age (0.51 years per 20% increase in NfL, p<0.001) and a 19.5% increase in the odds of impaired cognition (p<0.01). Higher NfL and pTau-181 were associated with lower psychomotor and mental efficiency (p<0.001), but not poorer memory. Amyloid-ß measures were not associated with study measures. A 1-percentage increase in mean HbA1c was associated with a 14.6% higher NfL and 12.8% higher pTau-181 (p<0.0001). Conclusions: In this aging T1D cohort, biomarkers of brain injury did not demonstrate an AD-like profile. NfL emerged as a biomarker of interest in T1D due to its association with higher HbA1c, accelerated brain aging on MRI, and cognitive dysfunction. Our study suggests that early neurodegeneration in adults with T1D is likely due to non-AD/non-amyloid mechanisms.

Importance:Little is known about structural brain changes in type 1 diabetes (T1D) and whether there are early manifestations of a neurodegenerative condition like Alzheimer disease (AD) or evidence of premature brain aging. Objective:To evaluate neuroimaging markers of brain age and AD-like atrophy in participants with T1D in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, identify which brain regions are associated with the greatest changes in patients with T1D, and assess the association between cognition and brain aging indices. Design, Setting, and Participants:This cohort study leveraged data collected during the combined DCCT (randomized clinical trial, 1983-1993) and EDIC (observational study, 1994 to present) studies at 27 clinical centers in the US and Canada. A total of 416 eligible EDIC participants and 99 demographically similar adults without diabetes were enrolled in the magnetic resonance imaging (MRI) ancillary study, which reports cross-sectional data collected in 2018 to 2019 and relates it to factors measured longitudinally in DCCT/EDIC. Data analyses were performed between July 2020 and April 2022. Exposure:T1D diagnosis. Main Outcomes and Measures:Psychomotor and mental efficiency were evaluated using verbal fluency, digit symbol substitution test, trail making part B, and the grooved pegboard. Immediate memory scores were derived from the logical memory subtest of the Wechsler memory scale and the Wechsler digit symbol substitution test. MRI and machine learning indices were calculated to predict brain age and quantify AD-like atrophy. Results:This study included 416 EDIC participants with a median (range) age of 60 (44-74) years (87 of 416 [21%] were older than 65 years) and a median (range) diabetes duration of 37 (30-51) years. EDIC participants had consistently higher brain age values compared with controls without diabetes, indicative of approximately 6 additional years of brain aging (EDIC participants: β, 6.16; SE, 0.71; control participants: β, 1.04; SE, 0.04; P < .001). In contrast, AD regional atrophy was comparable between the 2 groups. Regions with atrophy in EDIC participants vs controls were observed mainly in the bilateral thalamus and putamen. Greater brain age was associated with lower psychomotor and mental efficiency among EDIC participants (β, -0.04; SE, 0.01; P < .001), but not among controls. Conclusions and Relevance:The findings of this study suggest an increase in brain aging among individuals with T1D without any early signs of AD-related neurodegeneration. These increases were associated with reduced cognitive performance, but overall, the abnormal patterns seen in this sample were modest, even after a mean of 38 years with T1D.

Key Points We found that development of both albuminuria and reduced eGFR was associated with clinically significant cognitive decline, particularly in the psychomotor and mental efficiency domain. There was also a significant interaction between worsened albuminuria and eGFR, the combination of which augmented cognitive deficits. A more comprehensive longitudinal phenotype of albuminuria showed that regressed albuminuria did not associate with worsened cognitive decline, as opposed to persistent albuminuria. Background Individuals with CKD or type 1 diabetes (T1D) are at risk for cognitive decline, but it is unclear whether these associations are with albuminuria, eGFR, or both. Methods We examined the longitudinal relationships between CKD and change in cognition in 1051 participants with T1D in the Diabetes Control and Complications Trial and its follow-up, the Epidemiology of Diabetes Interventions and Complications study. Albumin excretion rate and eGFR were measured every 1–2 years. Three cognitive domains were assessed repeatedly over a 32-year period: immediate memory, delayed memory, and psychomotor and mental efficiency. Associations between cognitive function and CKD were assessed: ( 1 ) longitudinally and ( 2 ) in models using eGFR and albuminuria measurements over the first 15–20 years with subsequent change in cognitive function over the ensuing 14 years (when decline in cognition was greatest). Results In fully adjusted longitudinal analyses, the magnitude of decline in the psychomotor and mental efficiency domain score was associated with eGFR <60 ml/min per 1.73 m 2 ( β −0.449; 95% confidence interval [CI], −0.640 to −0.259) and sustained albumin excretion rate 30 to <300 mg/24 hours ( β −0.148; 95% CI, −0.270 to −0.026). This was equivalent to a decrease associated with approximately 11 and 4 years of aging, respectively. In analyses focused on changes in cognition between study years 18 and 32, eGFR <60 ml/min per 1.73 m 2 was associated with reduced psychomotor and mental efficiency ( β −0.915; 95% CI, −1.613 to −0.217). Conclusions In T1D, development of CKD was associated with a subsequent reduction on cognitive tasks requiring psychomotor and mental efficiency. These data highlight the need for increased recognition of risk factors for neurologic sequelae in patients with T1D, as well as preventive and treatment strategies to ameliorate cognitive decline.

Objective: Individuals with type 1 diabetes (T1DM) are living to ages when neuropathological changes are increasingly evident. We hypothesized that middle-aged and older adults with long-standing T1DM will show abnormal brain structure in comparison to non-diabetic controls. Research Design and Methods: Magnetic resonance imaging (MRI) was used to compare brain structure among 416 T1DM participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study with 99 demographically similar non-diabetic controls at 26 U.S. and Canadian sites. Assessments included total brain (TBV, primary outcome), gray matter (GMV), white matter (WMV), ventricle and white matter hyperintensity (WMH) volumes and white matter fractional anisotropy (FA). Biomedical assessments included HbA1c and lipid levels, blood pressure, and cognitive assessments of memory and psychomotor and mental efficiency (PME). Among EDIC participants, HbA1c, severe hypoglycemia history, and vascular complications were measured longitudinally. Results: Mean age of EDIC participants and controls was 60 years. T1DM participants showed significantly smaller TBV (1206 ± 1.7 vs. 1229 ± 3.5 cm3, p<0.0001), GMV and WMV, larger ventricle and WMH volumes, but no differences in mean white matter FA versus controls. Structural MRI measures in T1DM were equivalent to controls who are 4 to 9 years older. Lower PME scores were associated with altered brain structure on all MRI measures in T1DM participants. Conclusions: Middle-aged and older adults with T1DM showed brain volume loss and increased vascular injury in comparison to non-diabetic controls, equivalent to 4 to 9 years of brain aging.

BACKGROUND:With improved treatment, individuals with type 1 diabetes are living longer but there is limited information on the effects of type 1 diabetes on cognitive ability as they become older adults. We followed up individuals with type 1 diabetes to identify independent risk factors for cognitive decline as people age. METHODS:1051 participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. Participants completed cognitive assessments at baseline (median age 27 years) and 2, 5, 18, and 32 years later (median age 59). HbA1c levels, frequency of severe hypoglycaemia, non-glycemic risk factors such as elevated blood pressure, and microvascular and macrovascular complications were assessed repeatedly. We examined the effects of these on measures of memory and psychomotor and mental efficiency. These studies are registered with clinicaltrials.gov, NCT00360815 (DCCT) and NCT00360893 (EDIC). FINDINGS:Over 32 years of follow-up, we found substantive declines in memory and psychomotor and mental efficiency. Between 18 and 32 years of follow-up, the decline in psychomotor and mental efficiency was five times larger than the change from baseline to year 18. Independent of the other risk factors and comorbidities, exposure to higher HbA1c levels, more episodes of severe hypoglycaemia, and elevated systolic blood pressure were associated with greater decrements in psychomotor and mental efficiency that was most notable by year 32 (p<0·0001). The combined effect of the presence of these three risk factors is the equivalent to an additional 9·4 years of age. INTERPRETATION:Cognitive function declines with ageing in type 1 diabetes. The association of glycaemia and blood pressure levels with cognitive decline suggests that better management might preserve cognitive function. FUNDING:United States National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease.

DCCT/EDIC participants have been followed for an average of 32 years (N=1,054; mean age 60±7 years; duration T1DM 38±5 years). To evaluate cognitive function in T1DM, mental efficiency and memory were assessed five times during the study. Standardized z-scores were calculated relative to the DCCT baseline evaluation and averaged to obtain three summary domain scores (immediate recall, delayed recall, mental efficiency). Generalized linear mixed models were used. In 2018, mean HbA1c levels were 7.9±0.9% and 46% of participants had experienced ≥1 hypoglycemic coma/seizure. Adjusted for age, sex, and education, cognition declined over time (p<0.0001 each domain). In multivariable analysis, higher mean HbA1c (β±SE, -0.105±0.017 per 1%, p<0.0001), higher mean systolic blood pressure (-0.083±0.013 per 5 mmHg, p<0.0001), and history of coma/seizure (-0.175±0.041 ≥1 vs. none, p<0.0001) were independently associated with declining mental efficiency. Decreased mental efficiency was also associated with microalbuminuria (AER ≥30 mg/hr), lower levels of HDL cholesterol, and higher daily insulin dose (u/kg/day) (each p<0.0001). Biomedical predictors did not influence recall. These findings demonstrate the effects of increasing age, glycemic excursions (chronic hyperglycemia and clinically-significant hypoglycemia), and blood pressure on mental efficiency. Disclosure A.M. Jacobson: None. C.M. Ryan: None. B.H. Braffett: None. R. Gubitosi-Klug: None. G.M. Lorenzi: None. J.A. Luchsinger: Consultant; Self; vTv Therapeutics. V.R. Trapani: None. I. Bebu: None. N. Chaytor: Consultant; Self; Eli Lilly and Company. S.M. Hitt: None. K. Farrell: Stock/Shareholder; Spouse/Partner; Dexcom, Inc., Tandem Diabetes Care. J.M. Lachin: Board Member; Self; Tolerion, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases

Mild to moderate cognitive decrements are a well-known phenomenon associated with diabetes mellitus. In this review, we provide an overview of the cognitive consequences of type 1 and type 2 diabetes based on hallmark studies that follow patients over an extended period of time. In patients with type 1 diabetes, cognitive dysfunction appears soon after diagnosis and can be found in individuals of any age. The magnitude of these effects is generally modest, although their severity is especially pronounced in those with early onset type 1 diabetes (diagnosis before 7 years of age) or those who have developed microvascular disease, such as proliferative retinopathy. Rates of type 2 diabetes have increased dramatically over the past 20 years, in part driven by the world-wide epidemic of obesity, and this form of diabetes is appearing at a progressively younger age. Again, cognition may be disrupted, particularly in those who are in poorer glycemic control, and there is some evidence to suggest that with increasing diabetes duration, the rate of cognitive decline is accelerated and the risk of dementia is increased significantly.

BACKGROUND/OBJECTIVESTo investigate potential mechanisms underlying the well‐established relationship of diabetes and obesity with cognitive decline, among older adults participating in a population‐based study.DESIGN/SETTINGTen‐year population‐based cohort study.PARTICIPANTSA total of 478 individuals aged 65 years and older.MEASUREMENTSWe assayed fasting blood for markers of glycemia (glucose and hemoglobin A1c [HbA1c]), insulin resistance (IR) (insulin and homeostatic model assessment of IR), obesity (resistin, adiponectin, and glucagon‐like peptide‐1), and inflammation (C‐reactive protein). We modeled these indices as predictors of the slope of decline in global cognition, adjusting for age, sex, education, APOE*4 genotype, depressive symptoms, waist‐hip ratio (WHR), and systolic blood pressure, in multivariable regression analyses of the entire sample and stratified by sex‐specific median WHR. We then conducted WHR‐stratified machine‐learning (Classification and Regression Tree [CART]) analyses of the same variables.RESULTSIn multivariable regression analyses, in the entire sample, HbA1c was significantly associated with cognitive decline. After stratifying by median WHR, HbA1c remained associated with cognitive decline in those with higher WHR. No metabolic indices were associated with cognitive decline in those with lower WHR. Cross‐validated WHR‐stratified CART analyses selected no predictors in participants older than 87 to 88 years. Faster cognitive decline was associated, in lower WHR participants younger than 87 years, with adiponectin of 11 or greater; and in higher WHR participants younger than 88 years, with HbA1c of 6.2% or greater.CONCLUSIONSOur population‐based data suggest that, in individuals younger than 88 years with central obesity, even modest degrees of hyperglycemia might independently predispose to faster cognitive decline. In contrast, among those younger than 87 years without central obesity, adiponectin may be a novel independent risk factor for cognitive decline. J Am Geriatr Soc 68:991–998, 2020

The effect of type 1 diabetes on the developing brain is a topic of primary research interest. A variety of potential dysglycaemic insults to the brain can cause cellular and structural injury and lead to altered neuropsychological outcomes. These outcomes might be subtle in terms of cognition but appear to persist into adult life. Age and circumstance at diagnosis appear to play a substantial role in potential CNS injury. A history of diabetic ketoacidosis and chronic hyperglycaemia appear to be more injurious than previously suspected, whereas a history of severe hypoglycaemia is perhaps less injurious. Neurocognitive deficits manifest across multiple cognitive domains, including executive function and speed of information processing. Some evidence suggests that subtle brain injury might directly contribute to psychological and mental health outcomes. Impaired executive function and mental health, in turn, could affect patients' adherence and the ability to make adaptive lifestyle choices. Impaired executive functioning creates a potential feedback loop of diabetic dysglycaemia leading to brain injury, further impaired executive function and mental health, which results in suboptimal adherence, and further dysglycaemia. Clinicians dealing with patients with suboptimal glycaemic outcomes should be aware of these potential issues.

AbstractBackgroundThe diet of most adults is low in fish and, therefore, provides limited quantities of the long-chain, omega-3 fatty acids (LCn-3FAs), eicosapentaenoic and docosahexaenoic acids (EPA, DHA). Since these compounds serve important roles in the brain, we sought to determine if healthy adults with low-LCn-3FA consumption would exhibit improvements in neuropsychological performance and parallel changes in brain morphology following repletion through fish oil supplementation.MethodsIn a randomized, controlled trial, 271 mid-life adults (30–54 years of age, 118 men, 153 women) consuming ⩽300 mg/day of LCn-3FAs received 18 weeks of supplementation with fish oil capsules (1400 mg/day of EPA and DHA) or matching placebo. All participants completed a neuropsychological test battery examining four cognitive domains: psychomotor speed, executive function, learning/episodic memory, and fluid intelligence. A subset of 122 underwent neuroimaging before and after supplementation to measure whole-brain and subcortical tissue volumes.ResultsCapsule adherence was over 95%, participant blinding was verified, and red blood cell EPA and DHA levels increased as expected. Supplementation did not affect performance in any of the four cognitive domains. Exploratory analyses revealed that, compared to placebo, fish oil supplementation improved executive function in participants with low-baseline DHA levels. No changes were observed in any indicator of brain morphology.ConclusionsIn healthy mid-life adults reporting low-dietary intake, supplementation with LCn-3FAs in moderate dose for moderate duration did not affect neuropsychological performance or brain morphology. Whether salutary effects occur in individuals with particularly low-DHA exposure requires further study.

Cognitive impairment, ranging from mild cognitive impairment to dementia, is increasingly recognized as a potential complication of diabetes. The increase in the prevalence of diabetes along with the aging of the population may result in a large increase in the prevalence of cognitive impairment in persons with diabetes. Approximately one-third of the United States adult population has prediabetes or diabetes. However, about one-half of persons age ≥60 years, who are most at risk for cognitive impairment, have prediabetes or diabetes. The association of diabetes and cognitive impairment may reflect a direct effect on the brain of hyperglycemia or the effects of the diabetes-associated comorbidities, such as hypertension, dyslipidemia, or hyperinsulinemia. There is evidence for an effect of diabetes-related processes on both neurodegenerative and vascular processes, thus contributing to both Alzheimer’s-like cognitive impairment, i.e., amnestic, and cerebrovascular-type cognitive impairment characterized by impairment in executive cognitive function.This chapter reviews epidemiologic studies of the association between diabetes and cognitive impairment in large clinical or community-based studies, emphasizing studies in the United States. Type 1 diabetes is, in general, related to modest decrements in cognitive abilities, primarily in executive-frontal abilities. Type 2 diabetes seems to be more strongly related to vascular and non-amnestic forms of cognitive impairment, including non-amnestic mild cognitive impairment and vascular dementia, but it also seems to have a less strong association with amnestic forms of cognitive impairment, including amnestic mild cognitive impairment and Alzheimer’s dementia.The relation of diabetes to cognitive impairment has therapeutic implications. There is conflicting evidence from clinical trials of diabetes interventions examining the effects of better glucose control on cognition and the brain. Lifestyle interventions among persons with diabetes and prediabetes do not seem to be related to better cognitive outcomes in the long term.Despite many studies documenting the association between diabetes and cognitive impairment, the causal nature and the mechanisms of this association have not been fully established and require further study.

Objective: Microvascular pathophysiology that uniquely manifests as white matter (WM) abnormalities is often implicated in type 1 diabetes mellitus (T1DM)-related central nervous system (CNS) complications. This study sought to identify regional WM abnormalities in young adults diagnosed with T1DM and further examine their association with cognitive and emotional dysfunction. Research Design and Methods: Diffusion tensor images (DTI) obtained from 34 young adults with T1DM for >= 15 years (mean duration, 20.9years), and 16 age- and sex-matched healthy control subjects were analyzed using tract-based spatial statistics. Fractional anisotropy (FA) values of the whole brain were analyzed, and their associations with memory function and depressive symptoms were assessed. Results: Whole brain voxel-wise analyses showed that T1DM-related FA reductions were most prominent within the fronto-temporo-parietal regions of the brain. Reduced FA values in the bilateral superior longitudinal fasciculi, at which group differences were most prominent, correlated with lower working memory performance in young adults with T1DM (left, P < .001; right, P = .009). Subsyndromal depressive symptoms were also associated with lower FA values in the right inferior fronto-occipital fasciculus (P = .004). Conclusion: Widespread WM microstructural abnormalities in the fronto-temporo-parietal brain regions, which are associated with emotional and cognitive dysfunction, may be a contributing factor to the neural mechanisms underlying T1DM-related CNS complications, thus affecting the quality of life in young adults with T1DM.

PURPOSE:Inspired by the hypothesis that heterogeneity in the biology of breast cancers at the cellular level may account for cognitive dysfunction symptom variability in survivors, the current study explored relationships between host single-nucleotide polymorphisms (SNPs) in 25 breast cancer-related candidate genes (AURKA, BAG1, BCL2, BIRC5, CCNB1, CD68, CENPA, CMC2, CTSL2, DIAPH3, ERBB2, ESR1, GRB7, GSTM1, MELK, MKI67, MMP11, MYBL2, NDC80, ORC6, PGR, RACGAP1, RFC4, RRM2, and SCUBE2), identified from clinically relevant prognostic multigene-expression profiles for breast cancer, and pretreatment cognitive performance.PATIENTS AND METHODS:The sample (n=220) was comprised of 138 postmenopausal women newly diagnosed with early stage breast cancer and 82 postmenopausal age- and education-matched healthy controls without breast cancer. Cognitive performance was assessed after primary surgery but prior to initiation of adjuvant chemotherapy and/or hormonal therapy using a comprehensive battery of neuropsychological tests encompassing eight cognitive function composite domains: attention, concentration, executive function, mental flexibility, psychomotor speed, verbal memory, visual memory, and visual working memory. In total, 131 SNPs were included in the analysis. Standard and robust multiple linear regression modeling was used to examine relationships between each domain and the presence or absence of one or more minor alleles for each SNP. Genetic risk/protection scores (GRSs) were calculated for each domain to evaluate the collective effect of possession of multiple risk/protective alleles.RESULTS:With the exception of CMC2, MMP11, and RACGAP1, significant (P<0.05) SNP main effect and/or SNP by future prescribed treatment group interactions were observed for every gene between at least one domain and one or more SNPs. All GRSs were found to be significantly (P<0.001) associated with each respective domain score.CONCLUSION:Associations between host SNPs and computed GRSs and variability in pretreatment cognitive function performance support the study hypothesis, and warrant further investigations to identify biomarkers for breast cancer-related cognitive dysfunction.

OBJECTIVE:Psychomotor slowing is a common cognitive complication in type 1 diabetes (T1D), but its neuroanatomical correlates and risk factors are unclear. In nondiabetic adults, smaller gray matter volume (GMV) and presence of white matter hyperintensities are associated with psychomotor slowing. We hypothesize that smaller GMV in prefronto-parietal regions explains T1D-related psychomotor slowing. We also inspect the contribution of microvascular disease and hyperglycemia.METHODS:GMV, white matter hyperintensities (WMH), and glucose levels were measured concurrently with a test of psychomotor speed (Digit Symbol Substitution Test [DSST]) in 95 adults with childhood-onset T1D (mean age/duration = 49/41 years) and 135 similarly aged non-T1D adults. Linear regression models tested associations between DSST and regional GMV, controlling for T1D, sex, and education; a bootstrapping method tested whether regional GMV explained between-group differences in DSST. For the T1D cohort, voxel-based and a priori regions-of-interest methods further tested associations between GMV and DSST, adjusting for WMH, hyperglycemia, and age.RESULTS:Bilateral putamen, but no other regions examined, significantly attenuated DSST differences between the cohorts (bootstrapped unstandardized indirect effects: -3.49, -3.26; 95% confidence interval = -5.49 to -1.80, -5.29 to -1.44, left and right putamen, respectively). Among T1D, DSST was positively associated with GMV of bilateral putamen and left thalamus. Neither WMH, hyperglycemia, age, nor other factors substantially modified these relationships.CONCLUSIONS:For middle-aged adults with T1D and cerebral microvascular disease, GMV of basal ganglia may play a critical role in regulating psychomotor speed, as measured via DSST. Studies to quantify the impact of basal ganglia atrophy concurrent with WMH progression on psychomotor slowing are warranted.

AIM To test associations between statin use and cognitive impairment in adults with childhood-onset type 1 diabetes (T1D). METHODS In 2010-13, n = 108 middle-aged participants from ongoing observational Pittsburgh Epidemiology of Diabetes Complications Study underwent neurocognitive assessment (mean age and T1D duration of 49 and 41 years, respectively). All were diagnosed with childhood-onset (i.e., prior to age 18) T1D between 1950 and 1980 and were seen within one year of diagnosis at Children’s Hospital of Pittsburgh. Self-reported statin use (yes/no and if yes, name of statin) was collected biennially from parent study baseline (1986-1988) to time of neurocognitive testing. Logistic regression models tested associations between statin use groups and cognitive impairment (defined as having two or more cognitive test scores 1.5SD or worse than published norms) while linear regression models tested associations between statin use groups and cognitive domain z-scores (domains: Verbal IQ, memory, executive function, psychomotor speed, and visuo-construction). All models controlled for education and age. To address confounding by indication, models were repeated using a propensity score for statin use. RESULTS Of the 108 participants, 51 reported never using statins. Median duration of statin use among the 57 ever users was 6 years. These 57 ever statin users were split to create two groups (≤ or > median years of statin use): 1-6 years (n = 25), and 7-12 years (n = 32). Compared with never users, using statins 1-6 years tripled the odds of cognitive impairment (OR = 3.16; 95%CI: 0.93-10.72; P = 0.06) and using statins 7-12 years almost quintupled the odds of cognitive impairment (OR = 4.84; 95%CI: 1.63-14.44; P = 0.005). Compared with never users, using statins 1-6 or 7-12 years was related to worse performance in the memory domain (β = -0.52; P = 0.003, and -0.39; P = 0.014, respectively). Adjusting for coronary artery disease, low density lipoprotein cholesterol, and Apo E4 status did not substantially alter results, and none of these covariates were significantly related to cognitive outcomes (all P > 0.05). Propensity score analyses support that associations between poor cognitive outcomes and statin use were not due merely to confounding by indication. CONCLUSION Statin use was associated with cognitive impairment, particularly affecting memory, in these middle-aged adults with childhood-onset T1D, whom at this age, should not yet manifest age-related memory deficits.

Whether, and to what extent, type 1 diabetes (T1D) affects the brains of children and adolescents has been debated for more than 30 years. Early studies found that children and adolescents with T1D were more likely to perform somewhat poorer than their healthy peers on tasks of mental efficiency that required rapid responses and sustained attention, as well as on measures of executive functioning that required problem-solving and planning (1). It was assumed, but not proven, that these between-group differences were a consequence of differences in brain integrity. Only when researchers began using MRI techniques was there unequivocal evidence that diabetes in childhood is accompanied by gross structural changes to the brain, including relative reductions in gray matter density in multiple cortical regions and microstructural abnormalities in major white matter tracts (2,3). Furthermore, these effects were most pronounced in those who developed diabetes early in life and were evident within 2–4 years of disease onset (4–7). One might expect that a significant loss of neurons, accompanied by axonal damage relatively early in life, would lead to increasingly serious cognitive impairment over time in people with diabetes. Interestingly, that does not appear to be the case. Cross-sectional studies of children and young adults with T1D do not show a significant worsening of performance with increasing age or disease duration (8), nor were marked declines in cognition seen in the adolescents and adults participating in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions …

Abstract Intertumor heterogeneity has been proposed as a potential mechanism to account for variability in cognitive performance in women diagnosed with breast cancer. The purpose of this study was to explore associations between variation in pathologic tumor features (PTFs) and variability in preadjuvant therapy cognitive performance in postmenopausal women newly diagnosed with early‐stage breast cancer. Participants (N = 329) completed a comprehensive battery of neuropsychological tests to evaluate cognitive performance after primary surgery but prior to initiation of adjuvant anastrozole±chemotherapy. PTF data were abstracted from medical records. Robust multiple linear regression models were fit to estimate associations between individual PTFs and the cognitive function composite domain scores. All models controlled for age, estimated intelligence, and levels of depressive symptoms, anxiety, fatigue, and pain. Diagnosis of a HER2‐positive tumor contributed to poorer verbal (b = −0.287, P = 0.018), visual (b = −0.270, P = 0.001), and visual working (b = −0.490, P < 0.001) memory performance compared to diagnosis of a HER2‐negative tumor. Similarly, as HER2 immunohistochemistry classification score increased, verbal (b = −0.072, P = 0.093), visual (b = −0.081, P = 0.003), and visual working (b = −0.170, P < 0.001) memory performance score decreased. Associations with performance were also noted between location, focality/centricity, hormone receptor expression, cellular proliferation (i.e., Ki67), and Oncotype DX® Breast Cancer Assay Recurrence Score®.) Our results suggest that certain PTFs related to more aggressive tumor phenotypes or inferior breast cancer prognosis may be implicated in poorer preadjuvant therapy cognitive performance. Follow‐up studies that include a cognitive assessment before primary surgery should be conducted to further delineate the role of intertumor heterogeneity on cognitive performance.