The relation between vascular risk factors and flow in cerebral perforating arteries. A 7 Tesla MRI study.

INTRODUCTION: Cerebral perforating arteries provide blood supply to the deep regions of the brain. Recently, it became possible to measure blood flow velocity and pulsatility in these small arteries. It is unknown if vascular risk factors are related to these measures. METHODS: We measured perforating artery flow with 2D phase contrast 7 Tesla MRI at the level of the centrum semiovale (CSO) and the basal ganglia (BG) in seventy participants from the Heart Brain Connection study with carotid occlusive disease (COD), vascular cognitive impairment (VCI), or no actual cerebrovascular disease. Vascular risk factors included hypertension, diabetes, hyperlipidemia and smoking. RESULTS: No consistent relations were found between any of the vascular risk factors and either flow velocity or flow pulsatility, although there was a relation between lower diastolic blood pressure and higher pulse pressure and higher cerebral perforator pulsatility (p=0,045 and p=0,044, respectively) at the BG level. Results were similar in stratified analyses for patients with and without a history of cardiovascular disease, or only COD or VCI. CONCLUSION: We conclude that, cross-sectionally, cerebral perforating artery flow velocity and pulsatility are largely independent of the presence of common vascular risk factors in a population with a mixed vascular burden.

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy.

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-ß accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters - amplitude, time-to-peak (TTP), and time-to-baseline (TTB) - and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized ß = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (ß = 8.34 × 10-6, 95%CI [1.84 × 10-6, 1.48 × 10-5], p = 0.02, Adj. R2 = 0.25) and TTB (ß = 6.57 × 10-6, 95%CI [1.92 × 10-6, 1.12 × 10-5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.

Aß efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas.

Impairment of vascular pathways of cerebral ß-amyloid (Aß) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aß clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aß within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aß co-deposits. LRP1-mediated Aß transport across the blood-brain barrier and Aß clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aß deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aß pathology.

Chronic kidney disease and cognitive decline in patients with type 2 diabetes at elevated cardiovascular risk.

AIMS: We addressed the question whether chronic kidney disease (CKD) may contribute to cognitive decline in type 2 diabetes. METHODS: Participants with type 2 diabetes with elevated cardiovascular risk or CKD from cognition substudies of two large trials were studied prospectively (CARMELINA: n = 2666, mean ± SD age 68.1 ± 8.7 years, CAROLINA: n = 4296; 64.7 ± 9.4 years). Estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) at baseline were related to cognitive performance (Mini-Mental State Examination (MMSE) and attention and executive functioning score (A&E)) in linear regression analyses, adjusted for demographics, cardiovascular risk factors and treatment, at baseline and follow-up. RESULTS: CKD at baseline was more common in CARMELINA than CAROLINA (eGFR<60 in 72.6 % and 19.6 %, macroalbuminuria in 35.0 % and 4.1 %, respectively). Baseline eGFR was related to A&E in CARMELINA (b = 0.02 per 10 ml/min/1.73m2, 95%CI [0.01,0.03]). Baseline UACR was related to A&E in CAROLINA (b = -0.01 per doubling of UACR mg/g, 95%CI [-0.02,-0.002]). Baseline UACR predicted decline in A&E in CAROLINA (median 6.1 years follow-up; b = -0.01, 95%CI [-0.03,-0.0001] per doubling of UACR mg/g). CONCLUSIONS: eGFR and UACR were associated with A&E in two cohorts with type 2 diabetes, enriched for CKD and cardiovascular disease. The small effect size estimates indicate limited impact of kidney dysfunction on cognition in this setting. GOV IDENTIFIERS: NCT01897532 NCT01243424.

The association of circulating amylin with ß-amyloid in familial Alzheimer's disease.

INTRODUCTION: This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aß) in early Alzheimer's disease (AD). METHODS: Evidence of amylin-AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats. RESULTS: Amylin-Aß cross-seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aß42 concentrations. AD risk and amylin gene are not correlated. Suppressed amylin secretion protected APP/PS1 rats against AD-associated effects. In contrast, hypersecretion or intravenous injection of human amylin in APP/PS1 rats exacerbated AD-like pathology through disruption of CSF-brain Aß exchange and amylin-Aß cross-seeding. DISCUSSION: These findings strengthened the hypothesis of circulating amylin-AD interaction and suggest that modulation of blood amylin levels may alter Aß-related pathology/symptoms.

Zooming in on cerebral small vessel function in small vessel diseases with 7T MRI: Rationale and design of the "ZOOM@SVDs" study.

Background: Cerebral small vessel diseases (SVDs) are a major cause of stroke and dementia. Yet, specific treatment strategies are lacking in part because of a limited understanding of the underlying disease processes. There is therefore an urgent need to study SVDs at their core, the small vessels themselves. Objective: This paper presents the rationale and design of the ZOOM@SVDs study, which aims to establish measures of cerebral small vessel dysfunction on 7T MRI as novel disease markers of SVDs. Methods: ZOOM@SVDs is a prospective observational cohort study with two years follow-up. ZOOM@SVDs recruits participants with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL, N = 20), sporadic SVDs (N = 60), and healthy controls (N = 40). Participants undergo 7T brain MRI to assess different aspects of small vessel function including small vessel reactivity, cerebral perforating artery flow, and pulsatility. Extensive work-up at baseline and follow-up further includes clinical and neuropsychological assessment as well as 3T brain MRI to assess conventional SVD imaging markers. Measures of small vessel dysfunction are compared between patients and controls, and related to the severity of clinical and conventional MRI manifestations of SVDs. Discussion: ZOOM@SVDs will deliver novel markers of cerebral small vessel function in patients with monogenic and sporadic forms of SVDs, and establish their relation with disease burden and progression. These small vessel markers can support etiological studies in SVDs and may serve as surrogate outcome measures in future clinical trials to show target engagement of drugs directed at the small vessels.

Vascular Risk Factors of Hippocampal Subfield Volumes in Persons without Dementia: The Medea 7T Study.

BACKGROUND: Vascular risk factors have been associated with risk of Alzheimer's disease (AD) and volume loss of the hippocampus, but the associations with subfields of the hippocampus are understudied. Knowing if vascular risk factors contribute to hippocampal subfield atrophy may improve our understanding of vascular contributions to neurodegenerative diseases. OBJECTIVE: To investigate the associations between age, sex, and vascular risk factors with hippocampal subfields volumes on 7T MRI in older persons without dementia. METHODS: From the Medea 7T study, 283 participants (67±9 years, 68% men) without dementia had 7T brain MRI and hippocampal subfield segmentation. Subfields were automatically segmented on the 3D T2-weighted 7T images with ASHS software. Using linear mixed models, we estimated adjusted associations of age, sex, and vascular risk factors with z-scores of volumes of the entorhinal cortex (ERC), subiculum (SUB), Cornu Ammonis (CA)1, CA2, CA3, CA4, and dentate gyrus (DG), and tail as multivariate correlated outcomes. RESULTS: Increasing age was associated with smaller volumes in all subfields, except CA4/DG. Current smoking was associated with smaller ERC and SUB volumes; moderate alcohol use with smaller CA1 and CA4/DG, obesity with smaller volumes of ERC, SUB, CA2, CA3, and tail; and diabetes mellitus with smaller SUB volume. Sex, former smoking, and hypertension were not associated with subfield volumes. When formally tested, no risk factor affected the subfield volumes differentially. CONCLUSION: Several vascular risk factors were associated with smaller volumes of specific hippocampal subfields. However, no statistical evidence was found that subfields were differentially affected by these risk factors.

Oxidative stress and endothelial dysfunction are associated with reduced cognition in type 2 diabetes.

OBJECTIVE: Type 2 diabetes is associated with cognitive dysfunction, but the mechanisms are unknown. We assessed the relationships of biomarkers of oxidation, endothelial function and inflammation with cognition in participants of the CAROLINA® trial (CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes). METHODS: Baseline circulating biomarkers of oxidation (8-iso-prostaglandin F2α), endothelial function (asymmetric dimethylarginine, endothelin-1) and inflammation (C-reactive protein, interleukin-6, tumour necrosis factor-α), based on linear regression, were related to cognition on five domains, as measured with an automated battery. RESULTS: In 37 patients (mean age 66.7 ± 8.7 years, median HbA1c 6.9%/52 mmol/mol), 8-iso-prostaglandin F2α was associated with reduced mental flexibility and attention (standardised regression coefficients -0.47, -0.34), whereas asymmetric dimethylarginine was associated with reduced psychomotor speed and attention (standardised regression coefficients -0.39, -0.34). No significant associations were observed between biomarkers of inflammation and cognition. CONCLUSION: Elevated biomarkers of oxidation and endothelial function are associated and may play a role in reduced psychomotor speed, mental flexibility and attention in type 2 diabetes.

Treatment of Diabetes in Older Adults: An Endocrine Society* Clinical Practice Guideline.

OBJECTIVE: The objective is to formulate clinical practice guidelines for the treatment of diabetes in older adults. CONCLUSIONS: Diabetes, particularly type 2, is becoming more prevalent in the general population, especially in individuals over the age of 65 years. The underlying pathophysiology of the disease in these patients is exacerbated by the direct effects of aging on metabolic regulation. Similarly, aging effects interact with diabetes to accelerate the progression of many common diabetes complications. Each section in this guideline covers all aspects of the etiology and available evidence, primarily from controlled trials, on therapeutic options and outcomes in this population. The goal is to give guidance to practicing health care providers that will benefit patients with diabetes (both type 1 and type 2), paying particular attention to avoiding unnecessary and/or harmful adverse effects.

Depressive symptoms and quality of life after screening for cognitive impairment in patients with type 2 diabetes: observations from the Cog-ID cohort study.

OBJECTIVES: To assess changes in depressive symptoms and health-related quality of life (HRQOL) after screening for cognitive impairment in people with type 2 diabetes. DESIGN: A prospective cohort study, part of the Cognitive Impairment in Diabetes (Cog-ID) study. SETTING: Participants were screened for cognitive impairment in primary care. People suspected of cognitive impairment (screen positives) received a standardised evaluation at a memory clinic. PARTICIPANTS: Participants ≥70 years with type 2 diabetes were included in Cog-ID between August 2012 and September 2014, the current study includes 179 patients; 39 screen positives with cognitive impairment, 56 screen positives without cognitive impairment and 84 participants not suspected of cognitive impairment during screening (screen negatives). OUTCOME MEASURES: Depressive symptoms and HRQOL assessed with the Center for Epidemiologic Studies Depression Scale (CES-D), 36-Item Short-Form Health Survey, European Quality of Life-5 Dimensions questionnaire and the EuroQol Visual Analogue Scale. Outcomes were assessed before the screening, and 6 and 24 months after screening. An analysis of covariance model was fitted to assess differences in score changes among people diagnosed with cognitive impairment, screen negatives and screen positives without cognitive impairment using a factor group and baseline score as a covariate. RESULTS: Of all participants, 60.3% was male, mean age was 76.3±5.0 years, mean diabetes duration 13.0±8.5 years. At screening, participants diagnosed with cognitive impairment had significantly more depressive symptoms and a worse HRQOL than screen negatives. Scores of both groups remained stable over time. Screen positives without cognitive impairment scored between the other two groups at screening, but their depressive symptoms decreased significantly during follow-up (mean CES-D: -3.1 after 6 and -2.1 after 24 months); their HRQOL also tended to improve. CONCLUSIONS: Depressive symptoms are common in older people with type 2 diabetes. Screening for and a subsequent diagnosis of cognitive impairment will not increase depressive symptoms.

Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia.

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins. METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells ex vivo. RESULTS: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type 2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury, and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats. INTERPRETATION: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. Ann Neurol 2017;82:208-222.

Heterogeneous histopathology of cortical microbleeds in cerebral amyloid angiopathy.

OBJECTIVE: To investigate the histopathologic substrate of microbleeds detected on 7T postmortem MRI in autopsy cases with severe cerebral amyloid angiopathy (CAA) and Alzheimer pathology. METHODS: Five decedents (mean age at death 79.6 ± 5.7 years) with documented severe CAA and Alzheimer pathology on standard neuropathologic examination were selected from a local database. Formalin-fixed coronal brain slices were scanned at 7T MRI, including high-resolution T2- and T2*-weighted sequences. Representative microbleeds from each case were sampled for histopathologic analysis, including the presence of blood, blood breakdown products, and markers of ischemic tissue injury. RESULTS: On MRI, we identified >300 cortical and 4 subcortical microbleeds. Two out of 15 sampled cortical microbleeds corresponded histologically to erythrocytes (suggestive of recent hemorrhages), 4 to vasculopathies (fibrinoid necrosis in 3 and a cavernoma) without substantial parenchymal tissue injury, and 9 to accumulations of iron-positive siderophages without erythrocytes (suggestive of old hemorrhages) combined with mild to moderate degrees of chronic ischemic tissue injury. CONCLUSIONS: This study provides evidence for heterogeneous pathologic substrates and possibly different pathophysiologic mechanisms underlying MRI-observed cortical microbleeds in the context of advanced CAA and Alzheimer disease.

Bayesian model selection for pathological neuroimaging data applied to white matter lesion segmentation.

In neuroimaging studies, pathologies can present themselves as abnormal intensity patterns. Thus, solutions for detecting abnormal intensities are currently under investigation. As each patient is unique, an unbiased and biologically plausible model of pathological data would have to be able to adapt to the subject's individual presentation. Such a model would provide the means for a better understanding of the underlying biological processes and improve one's ability to define pathologically meaningful imaging biomarkers. With this aim in mind, this work proposes a hierarchical fully unsupervised model selection framework for neuroimaging data which enables the distinction between different types of abnormal image patterns without pathological a priori knowledge. Its application on simulated and clinical data demonstrated the ability to detect abnormal intensity clusters, resulting in a competitive to improved behavior in white matter lesion segmentation when compared to three other freely-available automated methods.

Severe diabetic retinal disease and dementia risk in type 2 diabetes.

BACKGROUND: Persons with type 2 diabetes are at an increased risk of dementia compared to those without, but the etiology of this increased risk is unclear. OBJECTIVE: Cerebral microvascular disease may mediate the link between diabetes and dementia. Given the anatomical and physiological similarities between cerebral and retinal microvessels, we examined the longitudinal association between diabetic retinal disease and dementia in patients with type 2 diabetes. METHODS: Longitudinal cohort study of 29,961 patients with type 2 diabetes aged ≥60 years. Electronic medical records were used to collect diagnoses and treatment of severe diabetic retinal disease (i.e., diabetic proliferative retinopathy and macular edema) between 1996-1998 and dementia diagnoses for the next ten years (1998-2008). The association between diabetic retinal disease and dementia was evaluated by Cox proportional hazard models adjusted for sociodemographics, as well as diabetes-specific (e.g., diabetes duration, pharmacotherapy, HbA1c, hypoglycemia, hyperglycemia) and vascular (e.g., vascular disease, smoking, body mass index) factors. RESULTS: 2,008 (6.8%) patients had severe diabetic retinal disease at baseline and 5,173 (17.3%) participants were diagnosed with dementia during follow-up. Those with diabetic retinal disease had a 42% increased risk of incident dementia (demographics adjusted Hazards Ratio (HR) = 1.42, 95% Confidence Interval (CI) 1.27, 1.58); further adjustment for diabetes-specific (HR 1.29; 95% CI 1.14, 1.45) and vascular-related disease conditions (HR 1.35; 95% CI 1.21, 1.52) attenuated the relation slightly. CONCLUSION: Diabetic patients with severe diabetic retinal disease have an increased risk of dementia. This may reflect a causal link between microvascular disease and dementia.

Symptom Checklist 90-Revised in neurological outpatients.

The Symptom Checklist 90-Revised (SCL-90-R) is an international, widely used, self-report questionnaire of multidimensional complaints with normative data for healthy control subjects and psychiatric patients. The questionnaire is also often used in neurological patients. Little is known about the amount and pattern of complaints in this group, and normative data are lacking. We therefore analyzed self-reported symptoms on the SCL-90-R of a neurological population (N = 600). Moreover, we compared the answer patterns of five subgroups: neurodegenerative disease, cerebrovascular disease, epilepsy, brain tumor, and traumatic brain injury. Neurological outpatients scored significantly higher in comparison with normative data from healthy control subjects, with most pronounced scores on Inadequacy of Thinking and Acting, Depression, and Somatization (p < .01, effect sizes 1.69, 0.83, and 0.83). No differences between the various pathologies were found. Although it is difficult to determine whether the complaints arise directly from the neurological disease or more indirectly from psychiatric disturbances accompanying the disease, simply comparing a neurological patient to normative data for healthy control subjects can lead to inappropriate classifications. Complaints of our patients should not be directly interpreted as psychopathology. A two-step procedure in which scores on the SCL-90-R are first compared to healthy control subjects and secondly to neurological patients can be helpful in the interpretation.

Midlife risk score for the prediction of dementia four decades later.

OBJECTIVE: The objective of this study was to obtain external validation of the only available midlife dementia risk score cardiovascular risk factors , aging and dementia study (CAIDE) constituting age, education, hypertension, obesity, and hyperlipidemia in a larger, more diverse population. Our second aim was to improve the CAIDE risk score by additional midlife risk factors. METHODS: This retrospective cohort study was conducted in an integrated health care delivery system. A total of 9480 Kaiser Permanente members who participated in a health survey study (age range, 40-55 years) from 1964 to 1973 were included in this study. Dementia diagnoses from primary care and medical specialist visits were collected from January 1, 1994 to January 16, 2006, using International Classification of Diseases 9 codes 290.0, 290.1 for "possible dementia," and 331.0 and 290.4 for "specialist confirmed dementia." Risk model prediction and validation were examined with the C statistic, net reclassification improvement, and integrated discrimination improvement. Dementia risk per sum score was calculated with Kaplan-Meier estimates. RESULTS: A total of 2767 participants (25%) were diagnosed with any type of dementia, of which 1011 diagnoses (10.7%) were specialist-confirmed diagnoses. Average time between midlife examination and end of follow-up was 36.1 years. The CAIDE risk score replicated well with a C statistic of 0.75, quite similar to the original CAIDE C statistic of 0.78. The CAIDE score also predicted well within different race strata. Other midlife risk factors (central obesity, depressed mood, diabetes mellitus, head trauma, lung function, and smoking) did not improve predictability. The risk score allowed stratification of participants into those with 40-year low (9%) and high (29%) dementia risk. CONCLUSIONS: A combination of modifiable vascular risk factors in midlife is highly predictive of the likelihood of dementia decades later. Possible dementia prevention strategies should point to a life course perspective on maintaining vascular health.

Cerebral microinfarcts: a systematic review of neuropathological studies.

Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 µm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment.

Intensive multifactorial treatment and cognitive functioning in screen-detected type 2 diabetes--the ADDITION-Netherlands study: a cluster-randomized trial.

AIM: To assess whether an intensive multifactorial treatment can reduce cognitive decrements and cognitive decline in screen-detected type 2 diabetes. METHODS: The multinational ADDITION-study, a cluster-randomized parallel group trial in patients with screen-detected type 2 diabetes, compared the effectiveness of intensive multifactorial treatment (IT; lifestyle advice and strict regulation of metabolic parameters) with routine care (RC) on cardiovascular outcome. In The Netherlands randomization was stratified according to practice organization. Allocation was concealed from patients. The present study assessed the effect of IT on cognition through two neuropsychological assessments (NPA) on two occasions. The assessments took place three and six years after the start of the intervention. Non-diabetic controls served as reference group. The first NPA was performed in 183 patients (IT: 97; RC: 86) and 69 controls. The second NPA was performed in 135 patients (IT: 71; RC: 64) and 55 controls. Primary outcome was a composite score, including the domains memory, information-processing speed and attention and executive function. Comparisons between the treatment groups were performed with multi-level analyses. RESULTS: The first NPA showed no differences between the treatment groups (mean difference composite z-score: 0.00; 95%-CI -0.16 to 0.16; IT vs RC). Over the next three years cognitive decline in the diabetic groups was within the range of the reference group and did not differ between the treatment arms (difference decline between diabetic groups -0.12; -0.24 to 0.01; IT vs RC). CONCLUSIONS: Six years of IT in screen-detected type 2 diabetes had no benefit on cognitive functioning over RC.