Changes in MEG resting-state networks are related to cognitive decline in type 1 diabetes mellitus patients

OBJECTIVE: Integrity of resting-state functional brain networks (RSNs) is important for proper cognitive functioning. In type 1 diabetes mellitus (T1DM) cognitive decrements are commonly observed, possibly due to alterations in RSNs, which may vary according to microvascular complication status. Thus, we tested the hypothesis that functional connectivity in RSNs differs according to clinical status and correlates with cognition in T1DM patients, using an unbiased approach with high spatio-temporal resolution functional network.; METHODS: Resting-state magnetoencephalographic (MEG) data for T1DM patients with (n=42) and without (n=41) microvascular complications and 33 healthy participants were recorded. MEG time-series at source level were reconstructed using a recently developed atlas-based beamformer. Functional connectivity within classical frequency bands, estimated by the phase lag index (PLI), was calculated within eight commonly found RSNs. Neuropsychological tests were used to assess cognitive performance, and the relation with RSNs was evaluated.; RESULTS: Significant differences in terms of RSN functional connectivity between the three groups were observed in the lower alpha band, in the default-mode (DMN), executive control (ECN) and sensorimotor (SMN) RSNs. T1DM patients with microvascular complications showed the weakest functional connectivity in these networks relative to the other groups. For DMN, functional connectivity was higher in patients without microangiopathy relative to controls (all p<0.05). General cognitive performance for both patient groups was worse compared with healthy controls. Lower DMN alpha band functional connectivity correlated with poorer general cognitive ability in patients with microvascular complications.; DISCUSSION: Altered RSN functional connectivity was found in T1DM patients depending on clinical status. Lower DMN functional connectivity was related to poorer cognitive functioning. These results indicate that functional connectivity may play a key role in T1DM-related cognitive dysfunction

Cognitive Functioning and Hippocampal Connectivity in Patients With Longstanding Type 1 Diabetes and Apolipoprotein E ε4

OBJECTIVE: While the apolipoprotein E ε4 allele (ApoE-ε4) is related to cognitive and brain decline in the general population, its effect on the brain in type 1 diabetes mellitus (T1DM) remains unclear. Therefore, the aim was to determine the interaction between ApoE-ε4 and T1DM on cognitive performance and hippocampal structure and connectivity as the brain area most vulnerable to ApoE-ε4 effects in adult patients with T1DM. RESEARCH DESIGN AND METHODS: Blood sampling was performed in 104 patients with T1DM and 49 control subjects for ApoE genotyping, neuropsychology, and neuroimaging to determine hippocampal volume and resting-state connectivity. The interaction between T1DM status and ApoE-ε4 presence was investigated and adjusted for age and mean systolic blood pressure. RESULTS: ApoE genotyping could not be performed for three patients with T1DM. Significant interaction effects, indicating a differential effect of ApoE-ε4 between both groups, were found for overall cognitive functioning and for the subdomains of information processing speed and attention. Additionally, interaction effects were present for right hippocampal connectivity with the right posterior cingulate and supramarginal gyri. Subsequent group analysis showed that patients with T1DM with ApoE-ε4 performed worse on these cognitive domains with increased connectivity, relative to their counterparts without ApoE-ε4. In contrast, no cognitive effects, but decreased connectivity, were observed in control subjects with ApoE-ε4. In patients with T1DM, higher right hippocampus connectivity with the posterior cingulate gyrus was related to poorer overall cognitive functioning. CONCLUSIONS: The results may suggest that ApoE-ε4 presence leaves our patients with T1DM more susceptible to cognitive decrements at a younger age, possibly through vascular pathways, warranting further longitudinal studies

Accelerated executive functions decline and gray matter structural changes in middle-aged type 1 diabetes mellitus patients with proliferative retinopathy

Background The aim of the present study was to determine trajectories of cognitive and cortical changes over time in middle‐aged patients with type 1 diabetes mellitus (T1DM) and proliferative retinopathy. Methods Twenty‐five patients and 25 controls underwent neuropsychological assessment and neuroimaging twice in a mean (±SD) of 3.56 ± 0.65 and 3.94 ± 0.91 years, respectively (P = 0.098). Cognitive assessment included the domains of general cognitive ability, memory, information processing speed, executive functions, attention, and motor and psychomotor speed. Symmetrized percentage change in local cortical thickness, surface area, and volume was determined using the FreeSurfer 6 vertex‐wise general linear model method. Analyses were performed uncorrected and corrected for baseline systolic blood pressure and depressive symptoms. Results In patients versus controls, accelerated executive function decline was accompanied by, but not related to, lower left frontal and temporal surface area, left parietal and right frontal thickness, and bilateral frontal and right posterior cingulate volume (family‐wise error [FWE]‐corrected P < 0.05 for all). In patients, lower executive performance was related to loss of right precuneus surface area (PFWE = 0.005). Higher HbA1c during follow‐up was related to executive function decline (r = −0.509, P = 0.016) and loss of left hemisphere surface area (rcorrected analysis = −0.555, P = 0.007). Conclusions After 3.5 years of follow‐up, middle‐aged T1DM patients with proliferative retinopathy, mild focal changes in executive functions, and cortical structure were found, which may indicate accelerated aging

The presence of cerebral white matter lesions and lower skin microvascular perfusion predicts lower cognitive performance in type 1 diabetes patients with retinopathy but not in healthy controls-A longitudinal study

OBJECTIVE: Cognitive impairments in type 1 diabetes may result from hyperglycemia-associated cerebral microangiopathy. We aimed to identify cerebral microangiopathy and skin microvascular dysfunction-as a surrogate marker for generalized microvascular function-as predictors of cognitive performance over time. METHODS: In this prospective cohort study, 25 type 1 diabetes patients with proliferative retinopathy and 25 matched healthy controls underwent neurocognitive testing at baseline and after follow-up (3.8 ± 0.8 years). At baseline, 1.5-T cerebral magnetic resonance imaging was used to detect WML and cerebral microbleeds. Skin capillary perfusion was assessed by means of capillary microscopy. RESULTS: In type 1 diabetes patients, but not in healthy controls, the presence of WML (ß = -0.419; P = 0.037) as well as lower skin capillary perfusion (baseline: ß = 0.753; P < 0.001; peak hyperemia: ß = 0.743; P = 0.001; venous occlusion: ß = 0.675; P = 0.003; capillary recruitment: ß = 0.549; P = 0.022) at baseline was associated with lower cognitive performance over time, independent of age, sex, HbA1c, and severe hypoglycemia. The relationship between WML and lower cognitive performance was significantly reduced after adjusting for capillary perfusion. CONCLUSIONS: These data fit the hypothesis that cerebral microangiopathy is a manifestation of generalized microvascular dysfunction, leading to lower cognitive performance

Altered Eigenvector Centrality is Related to Local Resting-State Network Functional Connectivity in Patients with Longstanding Type 1 Diabetes Mellitus

Introduction: Longstanding type 1 diabetes (T1DM) is associated with microangiopathy and poorer cognition. In the brain, T1DM is related to increased functional resting-state network (RSN) connectivity in patients without, which was decreased in patients with clinically evident microangiopathy. Subcortical structure seems affected in both patient groups. How these localized alterations affect the hierarchy of the functional network in T1DM is unknown. Eigenvector centrality mapping (ECM) and degree centrality are graph theoretical methods that allow determining the relative importance (ECM) and connectedness (degree centrality) of regions within the whole-brain network hierarchy. Methods: Therefore, ECM and degree centrality of resting-state functional MRI-scans was compared between 51 patients with, 53 patients without proliferative retinopathy, and 49 controls, and associated with RSN connectivity, subcortical gray matter volume, and cognition. Results: In all patients versus controls, ECM and degree centrality were lower in the bilateral thalamus and the dorsal striatum, with lowest values in patients without proliferative retinopathy (PFWE<0.05). Increased ECM in this group versus patients with proliferative retinopathy was seen in the bilateral lateral occipital cortex, and in the right lateral cortex versus controls (PFWE<0.05). In all patients, ECM and degree centrality were related to altered visual, sensorimotor, and auditory and language RSN connectivity (PFWE0.05). Conclusion: Our findings suggest reorganization of the hierarchy of the cortical connectivity network in patients without proliferative retinopathy, which is lost with disease progression. Centrality seems sensitive to capture early T1DM-related functional connectivity alterations, but not disease progression

Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia

BACKGROUND: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. METHODS: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). RESULTS: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs =-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs =-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. CONCLUSION: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities

Promoting remyelination in multiple sclerosis-recent advances

We review the current state of knowledge of remyelination in multiple sclerosis (MS), concentrating on advances in the understanding of the pathology and the regenerative response, and we summarise progress on the development of new therapies to enhance remyelination aimed at reducing progressive accumulation of disability in MS. We discuss key target pathways identified in experimental models, as although most identified targets have not yet progressed to the stage of being tested in human clinical trials, they may provide treatment strategies for demyelinating diseases in the future. Finally, we discuss some of the problems associated with testing this class of drugs, where they might fit into the therapeutic arsenal and the gaps in our knowledge