Higher White Matter Research Articles

Abstract P321: Is Amyloid Deposition in the Brain of Non-demented Older Adults a Consequence of High Blood Pressure and Arterial Stiffness?

Background: Advances in positron emission tomography imaging using amyloid specific ligands (e.g. PiB-PET) provide in vivo measurement of amyloid deposition in the brain, a hallmark of Alzheimer’s disease (AD) and dementia. Hypertension is believed to promote AD through arterial stiffening and cerebrovascular disease. We hypothesize that vascular measures are associated with amyloid in the brain. Methods: We studied 92 participants aged 83-96 in a follow-up of the Gingko Evaluation of Memory (GEM) Study with measures of: structural MRI of the brain; PiB-PET of brain amyloid deposition; resting blood pressure (BP), ankle brachial index (ABI) and mean arterial pressure (MAP); and vascular stiffness in the central (carotid-femoral ( cf PWV) and heart femoral ( hf PWV), peripheral (femoral-ankle ( fa PWV), and mixed (brachial-ankle ( ba PWV)) vascular beds, using a noninvasive and automated waveform analyzer (Colin Co., Komaki, Japan). Before study entry, all participants underwent ApoE-4 genotyping, detailed neuropsychological battery and adjudication of cognition by committee. Participants with a diagnosis of dementia were excluded from the sub-study. Results: Half (44/92) non-demented older adults in this sub-study were PiB+ for amyloid deposition in the brain. Amyloid deposition was associated with ba PWV, systolic BP and MAP. After adjustment for covariates, one standard deviation increase in ba PWV resulted in a 2-fold increase in the odds of being PiB+. ApoE-4 status was not associated with PWV. Additionally, high white matter disease burden, but not total gray matter volume, was associated with increased cf PWV (p<0.01), hf PWV (p=0.03), SBP (p=0.05) and MAP (p=0.06). Conclusions: The adverse effects of hypertension and vascular stiffness on cerebral small vessel disease is one of the most important hypotheses as to the determinants of amyloid deposition and AD. This is the first report of a possible association between vascular stiffness, BP and in vivo amyloid deposition in non-demented individuals.

Abstract TP301: Warfarin Increases Risk of Future Intracerebral Hemorrhage in Patients Presenting with Isolated Lobar Microbleeds on MRI

BACKGROUND/OBJECTIVES: Lobar microbleeds (LMB) are increasingly identified on brain MRI of older adults, suggesting a diagnosis of cerebral amyloid angiopathy (CAA) in the absence of intracerebral hemorrhage (ICH). Identifying the baseline characteristics and risk of future ICH of these subjects is important to understand their prognosis and safety of antithrombotic use in this setting. METHODS: Baseline characteristics (demographics, risk factors, APOE genotype), markers of CAA severity (LMB counts, white matter hyperintensity volume), and finally outcomes during a mean follow up of 4 years (incidence rate of ICH and case-fatality) were compared between 62 CAA patients without and 747 with ICH diagnosed using Boston criteria upon enrollment. The association between antithrombotic use and risk of incident ICH was explored in patients presenting with isolated LMBs after adjusting for covariates listed above. RESULTS: Female gender (52% vs. 37% p=0.023) and hypertension (67% vs. 53% p=0.025) were more common in patients presenting with ICH, other baseline characteristics did not differ. Patients presenting without ICH had more LMBs (median 10 vs. 1 p<0.001), and higher white matter hyperintensity volume (38cc±32 vs. 27cc ±24 p=0.008) than patients with ICH even after correction for other covariates. Patients without ICH on enrollment had a lower but non-trivial incidence rate of ICH during follow-up (4.8 per 100 person-years vs. 9 per 100 person-years; RR: 0.56, 95%CI 0.27-0.97). The case-fatality rates were similar between these groups (p=0.5). In patients presenting without ICH, the use of Warfarin was an independent predictor of future ICH (p=0.02) in the multivariate model. Patients using either ASA 325mg/day OR Clopidogrel OR ASA/Dipyridamol had higher risk of future ICH (p=.049) but this association did not remain significant in multivariate model. Use of ASA 81mg daily was not a predictor of incident ICH risk. CONCLUSIONS: Patients presenting with LMBs on MRI have a clinical, genetic, and neuroimaging profile suggestive of severe CAA pathology. They have a considerable risk of incident ICH albeit lower than patients who had a prior lobar ICH. The use of warfarin increases the risk of future ICH in patients with isolated LMBs on MRI.

Comparison of MRI based and PET template based approaches in the quantitative analysis of amyloid imaging with PIB-PET

[(11)C]Pittsburgh compound-B (PIB) has been the most widely used positron emission tomography (PET) imaging agent for brain amyloid. Several longitudinal studies evaluating the progression of Alzheimer's disease (AD), and numerous therapeutic intervention studies are underway using [(11)C]PIB PET as an AD biomarker. Quantitative analysis of [(11)C]PIB data requires the definition of regional volumes of interest. This investigation systematically compared two data analysis routes both using a probabilistic brain atlas with 11 bilateral regions. Route 1 used individually segmented structural magnetic resonance images (MRI) for each subject while Route 2 used a standardised [(11)C]PIB PET template. A total of 54 subjects, 20 with probable Alzheimer's disease (AD), 14 with amnestic Mild Cognitive Impairment (MCI) and 20 age-matched healthy controls, were scanned at two imaging centres either in London (UK) or in Turku (Finland). For all subjects structural volumetric MRI and [(11)C]PIB PET scans were acquired. Target-to-cerebellum ratios 40 min to 60 min post injection were used as outcome measures. Regional read outs for grey matter target regions were generated for both routes. Based on a composite neocortical, frontal, posterior cingulate, combined posterior cingulate and frontal cortical regions, scans were categorised into either 'PIB negative' (PIB-) or 'PIB positive' (PIB+) using previously reported cut-off target-to-cerebellar ratios of 1.41, 1.5 and 1.6, respectively. Target-to-cerebellum ratios were greater when defined with a [(11)C]PIB PET template than with individual MRIs for all cortical regions regardless of diagnosis. This difference was highly significant for controls (p<0.001, paired samples t-test), less significant for MCIs and borderline for ADs. Assignment of subjects to raised or normal categories was the same with both routes with a 1.6 cut-off while with lower cut off using frontal cortex, and combined frontal cortex and posterior cingulate demonstrated similar results, while posterior cingulate alone demonstrated significantly higher proportion of controls as amyloid positive by Route 2. Definition of cortical grey matter regions is more accurate when individually segmented MRIs (Route 1) were used rather than a population-based PET template (Route 2). The impact of this difference depends on the grey-to-white matter contrast in the PET images; specifically seen in healthy controls with high white matter and low grey matter uptake. When classifying AD, MCI and control subjects as normal or abnormal using large cortical regions; discordance was found between the MRI and template approach for those few subjects who presented with cortex-to-cerebellum ratios very close to the pre-assigned cut-off. However, posterior cingulate alone demonstrated significant discordance in healthy controls using template based approach. This study, therefore, demonstrates that the use of a [(11)C]PIB PET template (Route 2) is adequate for clinical diagnostic purposes, while MRI based analysis (Route 1) remains more appropriate for clinical research.

Structural Brain Changes in Migraine

A previous cross-sectional study showed an association of migraine with a higher prevalence of magnetic resonance imaging (MRI)-measured ischemic lesions in the brain. To determine whether women or men with migraine (with and without aura) have a higher incidence of brain lesions 9 years after initial MRI, whether migraine frequency was associated with progression of brain lesions, and whether progression of brain lesions was associated with cognitive decline. In a follow-up of the 2000 Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis cohort, a prospective population-based observational study of Dutch participants with migraine and an age- and sex-matched control group, 203 of the 295 baseline participants in the migraine group and 83 of 140 in the control group underwent MRI scan in 2009 to identify progression of MRI-measured brain lesions. Comparisons were adjusted for age, sex, hypertension, diabetes, and educational level. The participants in the migraine group were a mean 57 years (range, 43-72 years), and 71% were women. Those in the control group were a mean 55 years (range, 44-71 years), and 69% were women. MAIN OUTCOME MEASURES Progression of MRI-measured cerebral deep white matter hyperintensities, infratentorial hyperintensities, and posterior circulation territory infarctlike lesions. Change in cognition was also measured. Of the 145 women in the migraine group, 112 (77%) vs 33 of 55 women (60%) in the control group had progression of deep white matter hyperintensities (adjusted odds ratio [OR], 2.1; 95%CI, 1.0-4.1; P = .04). There were no significant associations of migraine with progression of infratentorial hyperintensities: 21 participants (15%) in the migraine group and 1 of 57 participants (2%) in the control group showed progression (adjusted OR, 7.7; 95% CI, 1.0-59.5; P = .05) or new posterior circulation territory infarctlike lesions: 10 of 203 participants (5%) in the migraine group but none of 83 in the control group (P = .07). There was no association of number or frequency of migraine headaches with progression of lesions. There was no significant association of high vs nonhigh deep white matter hyperintensity load with change in cognitive scores (-3.7 in the migraine group vs 1.4 in the control group; 95% CI, -4.4 to 0.2; adjusted P = .07). In a community-based cohort followed up after 9 years, women with migraine had a higher incidence of deep white matter hyperintensities but did not have significantly higher progression of other MRI-measured brain changes. There was no association of migraine with progression of any MRI-measured brain lesions in men.

Markers of cholesterol metabolism in the brain show stronger associations with cerebrovascular disease than Alzheimer's disease.

Cholesterol metabolism is believed to play a role in the development of Alzheimer's disease (AD). Oxysterol metabolites of cholesterol, 24S-hydroxycholesterol (24-OHC, a brain-derived oxysterol) and 27-hydroxycholesterol (27-OHC, a peripherally derived oxysterol) cross the blood brain barrier and have been associated with AD. We investigated whether oxysterols were associated with markers of cerebrovascular disease prior to the onset of cognitive impairment. Oxysterols were quantified in 105 participants (average age: 80 ± 4 years) from the Pittsburgh Cardiovascular Health Study Cognition Study who remained cognitively normal at blood draw in 2002, had MRI in 1992 and 1998, and annual cognitive assessment for incident AD and mild cognitive impairment made by consensus conference between 1998 and 2010. Higher plasma levels of 24-OHC were associated with age, gender, the presence of high grade white matter hyperintensities, and brain infarcts on prior MRI. Participants with higher plasma 24-OHC and a greater ratio of 24-OHC/27-OHC were also more likely to develop incident cognitive impairment over 8 years of follow-up. Higher levels of 24-OHC suggest increased cholesterol metabolism occurring in the brains of participants with cerebrovascular disease prior to the onset of cognitive impairment. Measurement of oxysterols may provide information about cholesterol metabolism and brain disease over the cognitive impairment process.

Cystatin C Predicts Changes in Brain Structure and Cognition in the Elderly (P02.063)

Objective: This study examined the relationships between renal function, measured by cystatin C, and brain small vessel disease (SVD), gray matter (GM) volume and cognition, in cognitively normal elderly subjects. Background Kidney dysfunction is related to neurological disorders, including cerebrovascular and cognitive syndromes. Cystatin C is a measure of kidney function that is considered to be more sensitive than creatinine in the elderly. Previous studies have linked higher cystatin C levels to subclinical brain infarcts and white matter lesions and to a higher incidence of cognitive impairment. Design/Methods: We analyzed demographic, medical, biochemical, neuropsychological, and brain imaging data from 735 cognitively normal subjects from the Cardiovascular Health Cognition Study. The GM volumes were analyzed using Voxel-Based Morphometry. Visual ratings of white matter lesions are used to determine the severity of brain SVD. Results: Elevated cystatin C levels were associated with lower neuropsychological test scores, greater prevalence of brain infarcts, higher white matter grade (WMG), and GM atrophy. Brain SVD was independently associated with higher serum cystatin C concentrations. In adjusted models, cystatin C levels also were significantly associated with GM volume only until body mass index (BMI) and WMG were added to the model. This finding suggests that the statistical effect of cystatin C on GM volume is mediated by these two variables. The VBM analysis found that higher cystatin C levels were associated with lower GM volume. Conclusions: Cystatin C levels are associated with structural brain changes, especially brain SVD and GM volume loss. These findings are consistent with the hypothesis that age-related vascular disease creates a vulnerability state for cognitive decline and dementia, possibly due to a decrease in brain reserve. Disclosure: Dr. Riverol has nothing to disclose. Dr. Becker has nothing to disclose. Dr. Lopez has received personal compensation for activities with Lundbeck and Johnson & Johnson as a consultant. Dr. Raji has nothing to disclose. Dr. Thompson has nothing to disclose. Dr. Carmichael has nothing to disclose. Dr. Gach has nothing to disclose. Dr. Longstreth has nothing to disclose. Dr. Fried has received personal compensation for activities with Pfizer Inc and Bayer Pharmaceuticals as a consultant. Dr. Fried has received personal compensation in an editorial capacity for ACP. Dr. Fried has received research support from Merck & Co., Inc. and Roche Diagnostics. Dr. Tracy has nothing to disclose. Dr. Kuller has nothing to disclose.

Microstructural MR Imaging of Cortical Lesions in Multiple Sclerosis Phenotypes (S21.001)

Objective: We used double inversion recovery (DIR) and diffusion tensor (DT) MRI to quantify tissue damage in cortical lesions (CLs) and the apparently normal cortical gray matter (GM) in patients with MS at different stages of the disease. Background DIR sequences allow the in vivo visualization of a proportion of CLs in MS and their application has demonstrated that CLs occur in all the major disease clinical phenotypes. Design/Methods: Brain DIR, DT MRI and 3D T 1 -weighted scans were acquired from 35 relapsing remitting (RR), 23 secondary progressive (SP), 12 benign (B) MS patients and 41 healthy controls (HC). Diffusivity values in CLs, skeletonised cortical GM, white matter (WM) lesions and normal-appearing (NA) WM were assessed. Results: Compared to HC, MS patients had a significantly lower fractional anisotropy (FA) and higher axial (AD), radial (RD) and mean diffusivity (MD) in the skeletonized cortical GM and NAWM. CLs had higher FA (p=0.02), AD (p=0.01) and MD (p=0.05) vs . HC skeletonized cortical GM, as well as higher FA (p=0.00002) and lower RD (p=0.01) vs . patients9 skeletonized cortical GM. Compared to RRMS, SPMS patients had higher WM lesion volume and more severe damage to the skeletonized cortical GM, NAWM and WM lesions. Damage in the other compartments was similar between SPMS and BMS patients. Compared to SPMS, BMS patients had lower MD, AD and FA of CLs. Damage in the CLs had a high power to discriminate BMS from SPMS (area under the curve: 77-80%), with high specificity (93%), sensitivity (89%) and accuracy (87%). Conclusions: Microstructural diffusivity features of CLs differ from those of WM lesions and are likely to reflect neuronal damage and microglial activation. Their quantification may help in the early identification of RRMS patients at risk of developing a progressive form of disease. Supported by: Partially supported by a grant from FISM/2008/R/13. Disclosure: Dr. Pagani has nothing to disclose. Ms. Rocca has received personal compensation for activities with Bayer Schering Pharma and Biogen Idec as a consultant. Dr. Preziosa has nothing to disclose. Dr. Copetti has nothing to disclose. Dr. Mesaros has received personal compensation for activities with Merck-Serono and Bayer Schering Pharma. Dr. Colombo has nothing to disclose. Dr. Horsfield has received compensation for serving as a Director of Xinapse Systems Ltd.Dr. Horsfield holds stock and/or stock options in Xinapsse Systems Ltd. Dr. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Lassmann has nothing to disclose. Dr. Filippi has received personal compensation for activities with ECTRIMS, MSIF, MS Ireland, US NMSS, Bayer-Schering, Biogen-Dompe AG, Genmab, Merck Serono, Pepgen Corporation, Teva, and Sanofi-Aventis. Dr. Filippi has received research support from Teva, Bayer-Schering and Genmab.

Multivariate pattern classification of gray matter pathology in multiple sclerosis

Univariate analyses have identified gray matter (GM) alterations in different groups of MS patients. While these methods detect differences on the basis of the single voxel or cluster, multivariate methods like support vector machines (SVM) identify the complex neuroanatomical patterns of GM differences. Using multivariate linear SVM analysis and leave-one-out cross-validation, we aimed at identifying neuroanatomical GM patterns relevant for individual classification of MS patients. We used SVM to separate GM segmentations of T1-weighted three-dimensional magnetic resonance (MR) imaging scans within different age- and sex-matched groups of MS patients with either early (n=17) or late MS (n=17) (contrast I), low (n=20) or high (n=20) white matter lesion load (contrast II), and benign MS (BMS, n=13) or non-benign MS (NBMS, n=13) (contrast III) scanned on a single 1.5 T MR scanner. GM patterns most relevant for individual separation of MS patients comprised cortical areas of all the cerebral lobes as well as deep GM structures, including the thalamus and caudate. The patterns detected were sufficiently informative to separate individuals of the respective groups with high sensitivity and specificity in 85% (contrast I), 83% (contrast II) and 77% (contrast III) of cases. The study demonstrates that neuroanatomical spatial patterns of GM segmentations contain information sufficient for correct classification of MS patients at the single case level, thus making multivariate SVM analysis a promising clinical application.

Cerebrovascular disease, beta-amyloid, and cognition in aging

The present study evaluated cerebrovascular disease (CVD), β-amyloid (Aβ), and cognition in clinically normal elderly adults. Fifty-four participants underwent magnetic resonance imaging (MRI), Pittsburgh compound B (PIB)-positron emission tomography (PET) imaging, and neuropsychological evaluation. High white matter hyperintensity burden and/or presence of infarct defined CVD status (CVD−: n = 27; CVD+: n = 27). PIB-positron emission tomography ratios of Aβ deposition were extracted using Logan plotting (cerebellar reference). Presence of high levels of Aβ in prespecified regions determined PIB status (PIB−: n = 33; PIB+: n = 21). Executive functioning and episodic memory were measured using composite scales. CVD and Aβ, defined as dichotomous or continuous variables, were unrelated to one another. CVD+ participants showed lower executive functioning (p = 0.001) when compared with CVD− individuals. Neither PIB status nor amount of Aβ affected cognition (ps ≥ 0.45), and there was no statistical interaction between CVD and PIB on either cognitive measure. Within this spectrum of normal aging CVD and Aβ aggregation appear to be independent processes with CVD primarily affecting cognition.

Vitamin B12, Cognition, and Brain Magnetic Resonance Imaging Measures

BackgroundLow total brain volume (TBV) and high white matter hyperintensity volume (WMHV) have been related to cognitive impairment; vitamin B12 (B12) deficiency has been associated with cognitive decline.ObjectiveTo investigate whether serum markers of B12 nutriture (B12, homocysteine, methylmalonate, cystathionine, 2‐methylcitrate) are related to brain volumes and to cognitive performance in a bi‐racial population sample in four Chicago neighborhoodsDesignCross‐sectional analysis of a prospective bi‐racial study of 121 older adults of the Chicago Health and Aging ProjectOutcome MeasuresMagnetic resonance imaging measures of TBV, WMHV and cerebral infarcts and tests of cognitive performanceResultsBoth serum homocysteine and methylmalonate levels were inversely associated with global cognitive function; only methylmalonate levels were associated with episodic memory and perceptual speed. Homocysteine was related to WMHV and levels of both markers were inversely associated with TBV. The association between homocysteine and TBV was stronger among persons with hypertension.ConclusionsPoor vitamin B12 status as evidenced by elevated homocysteine and methylmalonate levels may be associated with reduced TBV and impairment in several cognitive domains. This common, treatable condition may be important role in cognitive decline with aging.

High White Matter Lesion Load Is Associated with Hippocampal Atrophy in Mild Cognitive Impairment

Background: Mild cognitive impairment (MCI) is a heterogeneous condition suggested as a prodromal state of Alzheimer’s disease (AD) and subcortical vascular dementia (SVD). Recent findings suggest that white matter lesions (WML) may be associated with hippocampal atrophy. The objective of the study was to examine hippocampal and WML volumes in MCI patients and to examine if WML were linked to hippocampal atrophy. Methods: The Gothenburg MCI study is a clinically based longitudinal study with biennial clinical assessments. The participants (n = 166) consist of 92 patients with stable MCI, 30 patients with converting MCI, and 44 healthy controls. WML volumes was measured manually using MRIcron. Automated segmentation of hippocampal and total white matter volumes was performed using FreeSurfer. Results: The patients converting from MCI to dementia had reduced hippocampal volume. Stable MCI patients had fewer WML and converting MCI patients had more WML compared to controls. Hippocampal volume was only correlated to WML volume (ρ = 0.57; p < 0.01) in the quartile (n = 42) with the most WML. Conclusions: Hippocampal atrophy is present in both AD and SVD. Hippocampal volume was associated with WML volume only in the high WML quartile, suggesting that the WML volume must reach a threshold before hippocampal atrophy is seen.

Imaging Reveals Optic Tract Degeneration in Hemianopia

To investigate whether there is transsynaptic degeneration in the human optic tract in hemianopia. To consider how the degeneration varies with duration of hemianopia and location of insult. Seven patients with damage to the primary visual cortex (V1), the lateral geniculate nucleus (LGN), or the optic tract were scanned with structural MRI. The volume and cross-sectional area of the left and right optic tracts were computed based on the intensity values of the T1-weighted image. High values correspond to voxels with high white matter content, and the values decrease as the white matter content drops (indicating degeneration). A laterality index to compare the tract size in the two hemispheres was calculated at different intensity values. The three hemianopic patients with longstanding damage to either V1 or LGN showed laterality indices greater than 0.5 at the highest intensity values, indicating significant optic tract degeneration. Those with recent damage to the optic tract had even higher laterality indices due to direct degeneration. Even 18 months after V1 lesion, there was a significant correlation between the cross-section and volume indices at different intensity thresholds, whereas no control subject showed any correlation. Transsynaptic degeneration had already begun 18 months after lesion. Although there was no visible decrease in volume at this stage, the white matter integrity was compromised. Significant decrease in volume could be visualized at longer durations of hemianopia. This method of objectively assessing structural images provides an effective, noninvasive approach to monitor the timescale of optic tract degeneration.

Statistical analysis of minimum cost path based structural brain connectivity

Diffusion MRI can be used to study the structural connectivity within the brain. Brain connectivity is often represented by a binary network whose topology can be studied using graph theory. We present a framework for the construction of weighted structural brain networks, containing information about connectivity, which can be effectively analyzed using statistical methods. Network nodes are defined by segmentation of subcortical structures and by cortical parcellation. Connectivity is established using a minimum cost path (mcp) method with an anisotropic local cost function based directly on diffusion weighted images. We refer to this framework as Statistical Analysis of Minimum cost path based Structural Connectivity (SAMSCo) and the weighted structural connectivity networks as mcp-networks. In a proof of principle study we investigated the information contained in mcp-networks by predicting subject age based on the mcp-networks of a group of 974 middle-aged and elderly subjects. Using SAMSCo, age was predicted with an average error of 3.7years. This was significantly better than predictions based on fractional anisotropy or mean diffusivity averaged over the whole white matter or over the corpus callosum, which showed average prediction errors of at least 4.8years. Additionally, we classified subjects, based on the mcp-networks, into groups with low and high white matter lesion load, while correcting for age, sex and white matter atrophy. The SAMSCo classification outperformed the classification based on the diffusion measures with a classification accuracy of 76.0% versus 63.2%. We also performed a classification in groups with mild and severe atrophy, correcting for age, sex and white matter lesion load. In this case, mcp-networks and diffusion measures yielded similar classification accuracies of 68.3% and 67.8% respectively. The SAMSCo prediction and classification experiments indicate that the mcp-networks contain information regarding age, white matter lesion load and white matter atrophy, and that in case of age and white matter lesion load the mcp-network based models outperformed the predictions based on diffusion measures.

Characterization of AZD4694, a novel fluorinated Aβ plaque neuroimaging PET radioligand

Positron emission tomography (PET) radioligands that bind selectively to beta-amyloid plaques (Abeta) are promising imaging tools aimed at supporting the diagnosis of Alzheimer's disease and the evaluation of new drugs aiming to modify amyloid plaque load. For extended clinical use, there is a particular need for PET tracers labeled with fluorine-18, a radionuclide with 110 min half-life allowing for central synthesis followed by wide distribution. The development of fluorinated radioligands is, however, challenging because of the lipophilic nature of aromatic fluorine, rendering fluorinated ligands more prone to have high non-specific white matter binding. We have here developed the new benzofuran-derived radioligand containing fluorine, AZD4694 that shows high affinity for beta-amyloid fibrils in vitro (K(d) = 2.3 +/- 0.3 nM). In cortical sections from human Alzheimer's disease brain [(3)H]AZD4694 selectively labeled beta-amyloid deposits in gray matter, whereas there was a lower level of non-displaceable binding in plaque devoid white matter. Administration of unlabeled AZD4694 to rat showed that it has a pharmacokinetic profile consistent with good PET radioligands, i.e., it quickly entered and rapidly cleared from normal rat brain tissue. Ex vivo binding data in aged Tg2576 mice after intravenous administration of [(3)H]AZD4694 showed selective binding to beta-amyloid deposits in a reversible manner. In Tg2576 mice, plaque bound [(3)H]AZD4694 could still be detected 80 min after i.v. administration. Taken together, the preclinical profile of AZD4694 suggests that fluorine-18 labeled AZD4694 may have potential for PET-visualization of cerebral beta-amyloid deposits in the living human brain.

Giant cystic virchow-robin spaces with adjacent white matter signal alteration

Perivascular spaces surround the small arteries and veins as they enter into the brain parenchyma from the subarachnoid spaces. Also called as Virchow-Robin spaces, these are prominent in the basal ganglia and high convexity white matter of the elderly. Occasionally VR spaces may get massively enlarged and may mimic a cystic mass lesion. The typical CSF-like signal intensity of the cysts and location on MRI, in the absence of a neurological abnormality help in the diagnosis of the giant VR spaces and thus biopsy is avoided. Typically there is no significant adjacent brain abnormality; however FLAIR images may sometimes reveal perilesional white matter hyperintensity, which may be an indication of gliosis due to the mass effect of the lesion. Such a signal alteration should not deter one from making a diagnosis of giant Virchow-Robin spaces when the rest of the imaging findings are typical. We describe a case of a 50-year-old female with incidental giant Virchow-Robin spaces in the right hemispheric subcortical white matter with adjacent white matter hyperintense signal intensity on T2-weighted and FLAIR images.

White Matter Damage in Carbon Monoxide Intoxication Assessed in Vivo Using Diffusion Tensor MR Imaging

White matter (WM) injury in carbon monoxide (CO) intoxication is thought to be related to delayed cognitive sequelae. To determine if microstructural changes in WM are responsible for the delayed onset of cognitive symptoms, we performed diffusion tensor imaging (DTI) in patients with CO intoxication. DTI was performed in 14 patients with delayed sequelae after CO intoxication and in 16 sex- and age-matched healthy volunteers. The fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of several WM regions were measured. We also determined the correlation between FA of the selected WM and neuropsychological rating scores for the CO intoxication group. FA of patients with CO intoxication decreased in the corpus callosum, orbitofrontal WM, high frontal WM, parietal WM, and temporal lobes in comparison with the corresponding regions of healthy controls. FA of the WM in the occipital lobe and internal capsule of patients was not significantly different from that in controls. ADCs of all measured WM increased significantly in patients exposed to CO. High correlations were found between the FA of all selected WM and the Mini-Mental State Examination score (gamma = 0.631, P = .016) and the digit span backward task (gamma = 0.759, P = .001). CO intoxication may cause FA decline in associated cortical areas. This observation indicates microstructural WM pathology in CO intoxication, which is related to delayed cognitive encephalopathy.

GLUT1 Deficiency With Delayed Myelination Responding to Ketogenic Diet

Monitoring effects of a ketogenic diet in GLUT1 deficiency syndrome without seizures is difficult. Neuroimaging is considered uninformative. We report the case of a boy with neurodevelopmental delay, severe ataxia, an E54X-mutation in the SLC2A1 gene (previously GLUT1), and neuroimaging abnormalities indicative of delayed myelination. Six months on a ketogenic diet resulted in an improved high subcortical white matter signal on T2-weighted images and a reduced N-acetylaspartate/creatine ratio. We conclude that delayed subcortical myelination may occur in GLUT1 deficiency syndrome as a nonspecific finding reflecting developmental delay. In patients without seizures, cranial magnetic resonance imaging and magnetic resonance spectroscopy may prove useful tools to monitor the response to a ketogenic diet.

Sex differences in regional gray matter in healthy individuals aged 44–48 years: A voxel-based morphometric study

The study examined sex-related differences in regional gray matter (GM) in 44–48 year old healthy individuals. T1-weighted MRI scans were acquired in 411 subjects aged 44–48 from a random community sample and optimized voxel-based morphometry was applied to detect regional GM difference between men and women, correcting for effects of age, years of education, handedness, and total intracranial volume (TIV). Men had larger brain volumes and higher white matter (WM) to TIV ratios compared with women. Women had higher GM to TIV ratios than men. After controlling for age, years of education, handedness, and TIV, there were no significant differences between men and women in the total GM volumes. Regional sex dimorphism was present, with men having more GM volume in midbrain, left inferior temporal gyrus, right occipital lingual gyrus, right middle temporal gyrus, and both cerebellar hemispheres. Women showed more GM in dorsal anterior, posterior and ventral cingulate cortices, and right inferior parietal lobule. Our results suggest sex dimorphism in GM in middle aged healthy individuals, which is not likely to be explained by brain pathology. These differences may provide the structural brain basis for sex differences in certain cognitive functions.

Alcoholic brain damage and dementia viewed by MRI, with special consideration on frontal atrophy and white matter damage in dyslipidemic patients

AbstractLong‐term intake of excessive alcohol causes various forms of brain damage, most of which are now visualized by magnetic resonance imaging (MRI) and proved to be contributing to the early onset of dementia. Bi‐frontal atrophy has a unique position among these various forms of damage because of its lobar conformation localized only to the higher cortex, and because the same kind of atrophy is also seen in dyslipidemic patients like hypercholesterolemia. Multiple logistic regression analysis of 3100 subjects with MRI revealed no other significant group for this finding. Morphological features of this type of atrophy and its rate of progression are described in this paper, and computerized image analysis showed that this atrophy seems to depend mainly on the decrease of white matter. However, a common biochemical factor underlying the frontal atrophy in these two groups has not yet been identified. Importantly, dyslipidemic patients also show some type of T2 high white matter changes, which are not seen in ‘pure’ alcoholics. For dyslipidemic patients, this white matter change, which seems to be the degradation of myelin sheath, is another basis for early dementia. Although the author can propose a new concept of ‘dyslipidemic dementia’ due to frontal atrophy and white matter damage, details of its mechanism and its relation to alcoholism are left to future investigations.

White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study

High white matter grade (WMG) on magnetic resonance imaging (MRI) is a risk factor for dementia, stroke and disability. Higher ventricular size is a marker of brain “atrophy.” In the Cardiovascular Health Study (CHS) ( n = 3245) mean age 75 years, 50% black and 40% men, we evaluated WM and ventricular grade (VG), total, cardiovascular and noncardiovascular mortality and longevity before and after adjusting for numerous determinants of longevity over an approximate 10–12 years of follow-up. A low WMG and VG was a marker for low total, cardiovascular and noncardiovascular mortality and for increased longevity over 10+ years of follow-up. We estimated that a 75-year-old with WMG below median would have about a 5–6 years greater longevity and for VG about 3 years, than above the median even after adjustment for numerous risk factors. Low WMG and VG on MRI is a powerful determinant of long-term survival among older individuals.