Prediction of Cognitive Recovery After Stroke: The Value of Diffusion-Weighted Imaging-Based Measures of Brain Connectivity.

BACKGROUND AND PURPOSE: Prediction of long-term recovery of a poststroke cognitive disorder (PSCD) is currently inaccurate. We assessed whether diffusion-weighted imaging (DWI)-based measures of brain connectivity predict cognitive recovery 1 year after stroke in patients with PSCD in addition to conventional clinical, neuropsychological, and imaging variables. METHODS: This prospective monocenter cohort study included 217 consecutive patients with a clinical diagnosis of ischemic stroke, aged ≥50 years, and Montreal Cognitive Assessment score below 26 during hospitalization. Five weeks after stroke, patients underwent DWI magnetic resonance imaging. Neuropsychological assessment was performed 5 weeks and 1 year after stroke and was used to classify PSCD as absent, modest, or marked. Cognitive recovery was operationalized as a shift to a better PSCD category over time. We evaluated 4 DWI-based measures of brain connectivity: global network efficiency and mean connectivity strength, both weighted for mean diffusivity and fractional anisotropy. Conventional predictors were age, sex, level of education, clinical stroke characteristics, neuropsychological variables, and magnetic resonance imaging findings (eg, infarct size). DWI-based measures of brain connectivity were added to a multivariable model to assess additive predictive value. RESULTS: Of 135 patients (mean age, 71 years; 95 men [70%]) with PSCD 5 weeks after ischemic stroke, 41 (30%) showed cognitive recovery. Three of 4 brain connectivity measures met the predefined threshold of P<0.1 in univariable regression analysis. There was no added value of these measures to a multivariable model that included level of education and infarct size as significant predictors of cognitive recovery. CONCLUSIONS: Current DWI-based measures of brain connectivity appear to predict recovery of PSCD but at present have no added value over conventional predictors.

Histopathology of diffusion-weighted imaging-positive lesions in cerebral amyloid angiopathy.

Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI-ex vivo MRI-histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions post-mortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI-/T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls (p = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute microinfarcts post-mortem, which may benefit future histopathological investigations on the etiology of microinfarcts.

Extent to Which Network Hubs Are Affected by Ischemic Stroke Predicts Cognitive Recovery.

Background and Purpose- It is uncertain what determines the potential for cognitive recovery after ischemic stroke. The extent to which strategic areas of the brain network, so-called hubs, are affected by the infarct could be a key factor. We developed a lesion impact score, which estimates the damage to network hubs by integrating information on infarct size with healthy brain network topology. We verified whether the lesion impact score indeed reflects global network disturbances in patients and assessed if it could predict cognitive recovery. Methods- Seventy-five ischemic stroke patients without signs of a prestroke cognitive disorder were included, all with evidence of a cognitive disorder during hospitalization. A brain magnetic resonance imaging and neuropsychological assessment were performed 5 weeks (±1 week) after stroke. Neuropsychological testing was repeated after 1 year to assess cognitive recovery. Brain networks were reconstructed from diffusion-weighted data and consisted of 90 gray matter regions (ie, network nodes). A standard brain network map, indicating the hub-score of each node, was obtained from network data of 44 cognitively healthy adults. For each patient, we calculated the lesion impact score by multiplying the percentage of node volume affected by the infarct with the node's corresponding hub-score. The patients' maximum lesion impact score was used as outcome predictor. Results- A higher lesion impact score in patients, indicating an increasing infarct size in nodes with a higher hub-score, was related to lower global brain network efficiency (ß=-0.528 [-0.776 to -0.277]; P<0.001), independent of age, brain volume, infarct volume, and white matter hyperintensity severity. A lower lesion impact score, however, was an independent predictor of cognitive recovery 1 year after stroke (odds ratio=0.434 [0.193-0.978]; P=0.044). Conclusions- We introduced a lesion impact score that combines information on infarct size and network topology to predict long-term recovery after stroke. This score can potentially be used in a clinical setting, also without availability of high-resolution diffusion-weighted magnetic resonance imaging.

Cerebral Cortical Microinfarcts on Magnetic Resonance Imaging and Their Association With Cognition in Cerebral Amyloid Angiopathy.

Background and Purpose- We aimed to explore the association between presence of cerebral cortical microinfarcts (CMIs) on magnetic resonance imaging and other small-vessel disease neuroimaging biomarkers in cerebral amyloid angiopathy (CAA) and to analyze the role of CMIs on individual cognitive domains and dementia conversion. Methods- Participants were recruited from an ongoing longitudinal research cohort of eligible CAA patients between March 2006 and October 2016. A total of 102 cases were included in the analysis that assessed the relationship of cortical CMIs to CAA neuroimaging markers. Ninety-five subjects had neuropsychological tests conducted within 1 month of magnetic resonance imaging scanning. Seventy-five nondemented CAA patients had cognitive evaluation data available during follow-up. Results- Among 102 patients enrolled, 40 patients had CMIs (39%) on magnetic resonance imaging. CMIs were uniformly distributed throughout the cortex without regional predilection ( P=0.971). The presence of CMIs was associated with lower total brain volume (odds ratio, 0.85; 95% CI, 0.74-0.98; P=0.025) and presence of cortical superficial siderosis (odds ratio, 2.66; 95% CI, 1.10-6.39; P=0.029). In 95 subjects with neuropsychological tests, presence of CMIs was associated with impaired executive function (ß, -0.23; 95% CI, -0.44 to -0.02; P=0.036) and processing speed (ß, -0.24; 95% CI, -0.45 to -0.04; P=0.020). Patients with CMIs had a higher cumulative dementia incidence compared with patients without CMIs ( P=0.043), whereas only baseline total brain volume (hazard ratio, 0.76; 95% CI, 0.62-0.92; P=0.006) independently predicted dementia conversion. Conclusions- Magnetic resonance imaging-detected CMIs in CAA correlated with greater overall disease burden. The presence of CMIs was associated with worse cognitive performance, whereas only total brain atrophy independently predicted dementia conversion.

Microstructural White Matter Abnormalities and Cognitive Impairment After Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- Aneurysmal subarachnoid hemorrhage (aSAH) may have detrimental effects on white matter microstructure, which may in turn explain the cognitive impairments that occur often after aSAH. We investigated (1) whether the white matter microstructure is altered in patients with aSAH compared with patients with an unruptured intracranial aneurysm and (2) whether these abnormalities are associated with cognitive impairment 3 months after ictus. Methods- Forty-nine patients with aSAH and 22 patients with an unruptured intracranial aneurysm underwent 3T brain magnetic resonance imaging, including a high-resolution diffusion tensor imaging sequence. Patients with aSAH were scanned 2 weeks and 6 months after ictus. Microstructural white matter alterations were quantified by the fractional anisotropy and mean diffusivity (MD). Cognition was evaluated 3 months after ictus. Results- Patients with aSAH had higher white matter MD 2 weeks after ictus than patients with an unruptured intracranial aneurysm (mean difference±SEM, 0.3±0.01×10-3 mm2/s; P≤0.01), reflecting an abnormal microstructure. After 6 months, the MD had returned to the level of the unruptured intracranial aneurysm group. No between-group differences in fractional anisotropy were found (-0.01±0.01; P=0.16). Higher MD at 2 weeks was associated with cognitive impairment after 3 months (odds ratio per SD increase in MD, 2.6; 95% CI, 1.1-6.7). The association between MD and cognitive impairment was independent of conventional imaging markers of aSAH-related brain injury (ie, cerebral infarction, hydrocephalus, total amount of subarachnoid blood, total brain volume, or white matter hyperintensity severity). Conclusions- Patients with aSAH have temporary white matter abnormalities in the subacute phase that are associated with cognitive impairment at 3 months after ictus.

Parietal Involvement in Constructional Apraxia as Measured Using the Pentagon Copying Task.

Deficits in copying ("constructional apraxia") is generally defined as a multifaceted deficit. The exact neural correlates of the different types of copying errors are unknown. To assess whether the different categories of errors on the pentagon drawing relate to different neural correlates, we examined the pentagon drawings of the MMSE in persons with subjective cognitive complaints, mild cognitive impairment, or early dementia due to Alzheimer's disease. We adopted a qualitative scoring method for the pentagon copy test (QSPT) which categorizes different possible errors in copying rather than the dichotomous categories "correct" or "incorrect." We correlated (regional) gray matter volumes with performance on the different categories of the QSPT. Results showed that the total score of the QSPT was specifically associated with parietal gray matter volume and not with frontal, temporal, and occipital gray matter volume. A more fine-grained analysis of the errors reveals that the intersection score and the number of angles share their underlying neural correlates and are associated with specific subregions of the parietal cortex. These results are in line with the idea that constructional apraxia can be attributed to the failure to integrate visual information correctly from one fixation to the next, a process called spatial remapping.

Intracerebral hemorrhage and cognitive impairment.

Vascular cognitive impairment and vascular dementia are composed of cognitive deficits resulted from a range of vascular lesions and pathologies, including both ischemic and hemorrhagic. However the contribution of spontaneous intracerebral hemorrhage presumed due to small vessel diseases on cognitive impairment is underestimated, in contrast to the numerous studies about the role of ischemic vascular disorders on cognition. In this review we summarize recent findings from clinical studies and appropriate basic science research to better elucidate the role and possible mechanisms of intracerebral hemorrhage in cognitive impairment and dementia. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Relationship between white matter connectivity loss and cortical thinning in cerebral amyloid angiopathy.

Patients with cerebral amyloid angiopathy (CAA) show loss of white matter connectivity and cortical thinning on MRI, primarily in posterior brain regions. Here we examined whether a potential causal relationship exists between these markers of subcortical and cortical brain injury by examining whether changes in cortical thickness progress in tandem with changes in their underlying connections. Thirty-one patients with probable CAA with brain MRI at two time points were included (follow-up time: 1.3 ± 0.4 years). Brain networks were reconstructed using diffusion MRI-based fiber tractography. Of each network node, we calculated the change in fractional anisotropy-weighted connectivity strength over time and the change in cortical thickness. The association between change in connectivity strength and cortical thickness was assessed with (hierarchical) linear regression models. Our results showed that decline in posterior network connectivity over time was strongly related to thinning of the occipital cortex (ß = 0.65 (0.35-0.94), P < 0.001), but not to thinning of the other posterior or frontal cortices. However, at the level of individual network nodes, we found no association between connectivity strength and cortical thinning of the corresponding node (ß = 0.009 ± 0.04, P = 0.80). Associations were independent of age, sex, and other brain MRI markers of CAA. To conclude, CAA patients with greater progressive loss of posterior white matter connectivity also have greater progression of occipital cortical thinning, but our results do not support a direct causal relationship between them. The association can be better explained by a shared underlying mechanism, which may form a potential target for future treatments. Hum Brain Mapp 38:3723-3731, 2017. © 2017 Wiley Periodicals, Inc.

Microbleed and microinfarct detection in amyloid angiopathy: a high-resolution MRI-histopathology study.

Cerebral amyloid angiopathy is a common neuropathological finding in the ageing human brain, associated with cognitive impairment. Neuroimaging markers of severe cerebral amyloid angiopathy are cortical microbleeds and microinfarcts. These parenchymal brain lesions are considered key contributors to cognitive impairment. Therefore, they are important targets for therapeutic strategies and may serve as surrogate neuroimaging markers in clinical trials. We aimed to gain more insight into the pathological basis of magnetic resonance imaging-defined microbleeds and microinfarcts in cerebral amyloid angiopathy, and to explore the pathological burden that remains undetected, by using high and ultra-high resolution ex vivo magnetic resonance imaging, as well as detailed histological sampling. Brain samples from five cases (mean age 85 ± 6 years) with pathology-proven cerebral amyloid angiopathy and multiple microbleeds on in vivo clinical magnetic resonance imaging were subjected to high-resolution ex vivo 7 T magnetic resonance imaging. On the obtained high-resolution (200 µm isotropic voxels) ex vivo magnetic resonance images, 171 microbleeds were detected compared to 66 microbleeds on the corresponding in vivo magnetic resonance images. Of 13 sampled microbleeds that were matched on histology, five proved to be acute and eight old microhaemorrhages. The iron-positive old microhaemorrhages appeared approximately four times larger on magnetic resonance imaging compared to their size on histology. In addition, 48 microinfarcts were observed on ex vivo magnetic resonance imaging in three out of five cases (two cases exhibited no microinfarcts). None of them were visible on in vivo 1.5 T magnetic resonance imaging after a retrospective analysis. Of nine sampled microinfarcts that were matched on histology, five were confirmed as acute and four as old microinfarcts. Finally, we explored the proportion of microhaemorrhage and microinfarct burden that is beyond the detection limits of ex vivo magnetic resonance imaging, by scanning a smaller sample at ultra-high resolution, followed by serial sectioning. At ultra-high resolution (75 µm isotropic voxels) magnetic resonance imaging we observed an additional 48 microbleeds (compared to high resolution), which proved to correspond to vasculopathic changes (i.e. morphological changes to the small vessels) instead of frank haemorrhages on histology. After assessing the serial sections of this particular sample, no additional haemorrhages were observed that were missed on magnetic resonance imaging. In contrast, nine microinfarcts were found in these sections, of which six were only retrospectively visible at ultra-high resolution. In conclusion, these findings suggest that microbleeds on in vivo magnetic resonance imaging are specific for microhaemorrhages in cerebral amyloid angiopathy, and that increasing the resolution of magnetic resonance images results in the detection of more 'non-haemorrhagic' pathology. In contrast, the vast majority of microinfarcts currently remain under the detection limits of clinical in vivo magnetic resonance imaging.

Progression of Brain Network Alterations in Cerebral Amyloid Angiopathy.

BACKGROUND AND PURPOSE: We recently showed that cerebral amyloid angiopathy (CAA) is associated with functionally relevant brain network impairments, in particular affecting posterior white matter connections. Here we examined how these brain network impairments progress over time. METHODS: Thirty-three patients with probable CAA underwent multimodal brain magnetic resonance imaging at 2 time points (mean follow-up time: 1.3±0.4 years). Brain networks of the hemisphere free of intracerebral hemorrhages were reconstructed using fiber tractography and graph theory. The global efficiency of the network and mean fractional anisotropies of posterior-posterior, frontal-frontal, and posterior-frontal network connections were calculated. Patients with moderate versus severe CAA were defined based on microbleed count, dichotomized at the median (median=35). RESULTS: Global efficiency of the intracerebral hemorrhage-free hemispheric network declined from baseline to follow-up (-0.008±0.003; P=0.029). The decline in global efficiency was most pronounced for patients with severe CAA (group×time interaction P=0.03). The decline in global network efficiency was associated with worse executive functioning (ß=0.46; P=0.03). Examination of subgroups of network connections revealed a decline in fractional anisotropies of posterior-posterior connections at both levels of CAA severity (-0.006±0.002; P=0.017; group×time interaction P=0.16). The fractional anisotropies of posterior-frontal and frontal-frontal connections declined in patients with severe but not moderate CAA (group×time interaction P=0.007 and P=0.005). Associations were independent of change in white matter hyperintensity volume. CONCLUSIONS: Brain network impairment in patients with CAA worsens measurably over just 1.3-year follow-up and seem to progress from posterior to frontal connections with increasing disease severity.

Small vessel disease and cognitive impairment: The relevance of central network connections.

Central brain network connections greatly contribute to overall network efficiency. Here we examined whether small vessel disease (SVD) related white matter alterations in central brain network connections have a greater impact on executive functioning than alterations in non-central brain network connections. Brain networks were reconstructed from diffusion-weighted MRI scans in 72 individuals (75 ± 8 years) with cognitive impairment and SVD on MRI. The centrality of white matter connections in the network was defined using graph theory. The association between the fractional anisotropy (FA) of central versus non-central connections, executive functioning, and markers of SVD was evaluated with linear regression and mediation analysis. Lower FA in central network connections was more strongly associated with impairment in executive functioning than FA in non-central network connections (r = 0.41 vs. r = 0.27; P < 0.05). Results were consistent across varying thresholds to define the central subnetwork (>50%-10% connections). Higher SVD burden was associated with lower FA in central as well as non-central network connections. However, only central network FA mediated the relationship between white matter hyperintensity volume and executive functioning [change in regression coefficient after mediation (95% CI): -0.15 (-0.35 to -0.02)]. The mediation effect was not observed for FA alterations in non-central network connections [-0.03 (-0.19 to 0.04)]. These findings suggest that the centrality of network connections, and thus their contribution to global network efficiency, appears to be relevant for understanding the relationship between SVD and cognitive impairment. Hum Brain Mapp 37:2446-2454, 2016. © 2016 Wiley Periodicals, Inc.

Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = -0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging markers of small-vessel disease. These findings suggest that reduced structural brain network efficiency might mediate the relationship between advanced cerebral amyloid angiopathy and neurologic dysfunction and that such large-scale brain network measures may represent useful outcome markers for tracking disease progression.

The effect of lacunar infarcts on white matter tract integrity.

BACKGROUND AND PURPOSE: Lacunar infarcts may cause disturbances of the white matter (WM) structure remote from the primary lesion. Here, we used diffusion MRI and tractography to (1) spatially characterize microstructural abnormalities along WM tracts containing a lacunar infarct and (2) relate abnormalities in remote parts of the affected WM tract to cognitive outcome. METHODS: In 17 participants with a lacunar infarct, we reconstructed the affected WM tract using fiber tractography. The corresponding nonlesioned tract in the contralateral hemisphere served as a control tract. Diffusion parameters (fractional anisotropy and mean diffusivity) were plotted along the tract and related to measures of memory, executive functioning and information processing speed. RESULTS: Diffusion abnormalities remote from the lacune were present in the affected tract compared with the control tract up to 2 cm from the lacune (9% to 17% decrease in fractional anisotropy, 11% to 27% increase in mean diffusivity; P<0.05). The severity of these abnormalities attenuated with increasing distance to the primary lesion. Furthermore, the degree of remote WM disturbances was related to worse cognitive functioning on all 3 domains, independent of the size of the lacune (r=0.6-0.8; P<0.05). CONCLUSIONS: Lacunar infarcts are associated with abnormalities in the affected WM tract that extend centimeters beyond the lesion visible on conventional MRI. These secondary WM abnormalities may contribute to the cognitive deficits observed in patients with subcortical infarcts.

Impact of thresholding on the consistency and sensitivity of diffusion MRI-based brain networks in patients with cerebral small vessel disease.

INTRODUCTION: Thresholding of low-weight connections of diffusion MRI-based brain networks has been proposed to remove false-positive connections. It has been previously established that this yields more reproducible scan-rescan network architecture in healthy subjects. In patients with brain disease, network measures are applied to assess inter-individual variation and changes over time. Our aim was to investigate whether thresholding also achieves improved consistency in network architecture in patients, while maintaining sensitivity to disease effects for these applications. METHODS: We applied fixed-density and absolute thresholding on brain networks in patients with cerebral small vessel disease (SVD, n = 86; ≈24 months follow-up), as a clinically relevant exemplar condition. In parallel, we applied the same methods in healthy young subjects (n = 44; scan-rescan interval ≈4 months) as a frame of reference. Consistency of network architecture was assessed with dice similarity of edges and intraclass correlation coefficient (ICC) of edge-weights and hub-scores. Sensitivity to disease effects in patients was assessed by evaluating interindividual variation, changes over time, and differences between those with high and low white matter hyperintensity burden, using correlation analyses and mixed ANOVA. RESULTS: Compared to unthresholded networks, both thresholding methods generated more consistent architecture over time in patients (unthresholded: dice = .70; ICC: .70-.78; thresholded: dice = .77; ICC: .73-.83). However, absolute thresholding created fragmented nodes. Similar observations were made in the reference group. Regarding sensitivity to disease effects in patients, fixed-density thresholds that were optimal in terms of consistency (densities: .10-.30) preserved interindividual variation in global efficiency and node strength as well as the sensitivity to detect effects of time and group. Absolute thresholding produced larger fluctuations of interindividual variation. CONCLUSIONS: Our results indicate that thresholding of low-weight connections, particularly when using fixed-density thresholding, results in more consistent network architecture in patients with longer rescan intervals, while preserving sensitivity to disease effects.

Does Loss of Integrity of the Cingulum Bundle Link Amyloid-ß Accumulation and Neurodegeneration in Alzheimer's Disease?

BACKGROUND: Alzheimer's disease is characterized by the accumulation of amyloid-ß (Aß) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aß deposition and local neurodegeneration. OBJECTIVE: Here, we test the hypothesis that the cingulum bundle links Aß deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. METHODS: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aß-PET scan, T1-weighted and diffusion-weighted MRI were included. Aß load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. RESULTS: We found at most a weak association between cingulate Aß and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aß or MTL volume (added R2 <0.01). Various sensitivity analyses (Aß-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. CONCLUSION: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aß deposition and MTL atrophy.

Corpus callosum lesions are associated with worse cognitive performance in cerebral amyloid angiopathy.

The impact of vascular lesions on cognition is location dependent. Here, we assessed the contribution of small vessel disease lesions in the corpus callosum to vascular cognitive impairment in cerebral amyloid angiopathy, as a model for cerebral small vessel disease. Sixty-five patients with probable cerebral amyloid angiopathy underwent 3T magnetic resonance imaging, including a diffusion tensor imaging scan, and neuropsychological testing. Microstructural white-matter integrity was quantified by fractional anisotropy and mean diffusivity. Z-scores on individual neuropsychological tests were averaged into five cognitive domains: information processing speed, executive functioning, memory, language and visuospatial ability. Corpus callosum lesions were defined as haemorrhagic (microbleeds or larger bleeds) or ischaemic (microinfarcts, larger infarcts and diffuse fluid-attenuated inversion recovery hyperintensities). Associations between corpus callosum lesion presence, microstructural white-matter integrity and cognitive performance were examined with multiple regression models. The prevalence of corpus callosum lesions was confirmed in an independent cohort of memory clinic patients with and without cerebral amyloid angiopathy (n = 82). In parallel, we assessed corpus callosum lesions on ex vivo magnetic resonance imaging in cerebral amyloid angiopathy patients (n = 19) and controls (n = 5) and determined associated tissue abnormalities with histopathology. A total number of 21 corpus callosum lesions was found in 19/65 (29%) cerebral amyloid angiopathy patients. Corpus callosum lesion presence was associated with reduced microstructural white-matter integrity within the corpus callosum and in the whole-brain white matter. Patients with corpus callosum lesions performed significantly worse on all cognitive domains except language, compared with those without corpus callosum lesions after correcting for age, sex, education and time between magnetic resonance imaging and neuropsychological assessment. This association was independent of the presence of intracerebral haemorrhage, whole-brain fractional anisotropy and mean diffusivity, and white-matter hyperintensity volume and brain volume for the domains of information processing speed and executive functioning. In the memory clinic patient cohort, corpus callosum lesions were present in 14/54 (26%) patients with probable and 2/8 (25%) patients with possible cerebral amyloid angiopathy, and in 3/20 (15%) patients without cerebral amyloid angiopathy. In the ex vivo cohort, corpus callosum lesions were present in 10/19 (53%) patients and 2/5 (40%) controls. On histopathology, ischaemic corpus callosum lesions were associated with tissue loss and demyelination, which extended beyond the lesion core. Together, these data suggest that corpus callosum lesions are a frequent finding in cerebral amyloid angiopathy, and that they independently contribute to cognitive impairment through strategic microstructural disruption of white-matter tracts.

Accelerated cognitive decline in patients with type 2 diabetes: MRI correlates and risk factors.

BACKGROUND: Type 2 diabetes mellitus is associated with an increased risk of cognitive decline and dementia. We examined brain imaging correlates and vascular and metabolic risk factors of accelerated cognitive decline in patients with type 2 diabetes. METHODS: Cognitive functioning and brain volume as well as metabolic and vascular risk factors were assessed twice in 68 patients with no dementia with type 2 diabetes with a 4-year interval. Thirty-eight control participants served as a reference group. Volumetric measurements of the total brain, lateral ventricles and white-matter hyperintensities were performed on 1.5T magnetic resonance imaging scans. A regression-based index score was calculated on the basis of the reference group to assess changes in cognitive performance over time, adjusted for age, sex and estimated intelligence quotient. Brain volumes were compared between patients with and without accelerated cognitive decline. Logistic regression analyses were used to identify baseline risk factors for accelerated cognitive decline within the diabetes group. RESULTS: Accelerated cognitive decline was found in 17 (25%) patients with type 2 diabetes and was associated with a greater increase in ventricular volume [mean difference (95% confidence interval): 0.23% (0.08-0.38); p = 0.003] and white-matter hyperintensities volume [0.16% (0.05-0.27); p = 0.006] over the 4-year period. There were no specific vascular or metabolic risk factors associated with accelerated cognitive decline. CONCLUSIONS: Accelerated cognitive decline in patients with type 2 diabetes was associated with progressive changes on brain magnetic resonance imaging, comprising both vascular damage and global atrophy. Exploration of vascular and metabolic risk factors revealed no specific determinants of accelerated cognitive decline.

Dementia risk score predicts cognitive impairment after a period of 15 years in a nondemented population.

BACKGROUND/AIM: Cardiovascular risk factors play an important role in the development of cognitive impairment and dementia. We examined whether a previously designed dementia risk score based on midlife vascular risk profiles also predicts cognitive impairment 15 years later. METHODS: 322 individuals without dementia from the population-based Hoorn study (aged 50-64 years) underwent a medical examination at baseline and a detailed cognitive assessment 15 years later. The relation between the risk score and late-life cognitive impairment in each of 6 domains was analyzed with logistic regression analysis. RESULTS: The risk score was significantly related to impairment on the domains information-processing speed (p = 0.04), visuoconstruction (p = 0.04) and abstract reasoning (p = 0.02). Participants with a risk score of 9 points or more had a markedly increased risk of late-life impairment in the domains information-processing speed (OR 3.07, 95% CI 1.37-6.90; p = 0.007) and abstract reasoning (OR 3.97, 95% CI 1.07-14.71; p = 0.04). CONCLUSION: A previously designed risk score for dementia also predicts late-life cognitive impairment. Because such impairment can lead to complaints and functional consequences, also in individuals who do not progress to dementia, identification of individuals at risk is important and can help to target preventive strategies.

Cognitive dysfunction in patients with type 2 diabetes.

People with diabetes mellitus are at increased risk of cognitive dysfunction and dementia. This review explores the nature and severity of cognitive changes in patients with type 2 diabetes. Possible risk factors such as hypo- and hyperglycemia, vascular risk factors, micro- and macrovascular complications, depression and genetic factors will be examined, as well as findings from brain imaging and autopsy studies. We will show that type 2 diabetes is associated with modest cognitive decrements in non-demented patients that evolve only slowly over time, but also with an increased risk of more severe cognitive deficits and dementia. There is a dissociation between these two 'types' of cognitive dysfunction with regard to affected age groups and course of development. Therefore, we hypothesize that the mild and severe cognitive deficits observed in patients with type 2 diabetes reflect separate processes, possibly with different risk factors and aetiologies.

Microvascular determinants of cognitive decline and brain volume change in elderly patients with type 2 diabetes.

BACKGROUND/AIMS: The present study examined the relationship between microvascular complications and cognitive decline and the development of structural brain abnormalities over a period of 4 years in patients with type 2 diabetes mellitus (T2DM). METHODS: Sixty-eight elderly patients with T2DM had 2 cognitive assessments with a 4-year interval. Two MRI scans, performed at the same time as the cognitive assessments, were available from 55 patients. Changes in cognitive performance over time were expressed as a regression-based index (RBI). Automated volumetric measurements of total brain, lateral ventricles and white matter hyperintensities were performed. The relationship between baseline microvascular complications [diabetic retinopathy, peripheral neuropathy or albuminuria (micro- or macroalbuminuria)] and cognition and brain volumes was examined with linear regression analyses adjusted for age and sex (for cognition also for IQ). RESULTS: At baseline, diabetic retinopathy was present in 18% of patients, peripheral neuropathy in 36%, albuminuria in 15%. Retinopathy or neuropathy were not significantly associated with baseline cognition or brain volumes, or changes in these measures over time. Albuminuria was associated with a lower composite RBI score, indicating accelerated cognitive decline (adjusted mean difference between patients with or without albuminuria: -0.58, 95% CI -0.85 to -0.31, p < 0.001). CONCLUSION: Albuminuria predicted accelerated cognitive decline in patients with T2DM, but other microvascular complications were unrelated to accelerated cognitive decline or brain MRI abnormalities.