Complex spatial and temporally defined myelin and axonal degeneration in Huntington disease.

Although much prior work has focused on the basal ganglia and cortical pathology that defines Huntington's disease (HD), recent studies have also begun to characterize cerebral white matter damage (Rosas et al., 2006; Dumas et al., 2012; Poudel et al., 2014). In this study, we investigated differences in the large fascicular bundles of the cerebral white matter of gene-positive HD carriers, including pre-manifest individuals and early symptomatic patients, using recently developed diffusion tractography procedures. We examined eighteen major fiber bundles in 37 patients with early HD (average age 55.2 ±â€¯11.5, 14 male, 23 female), 31 gene-positive, motor negative pre-symptomatic HD (PHD) (average age 48.1 ±â€¯11.5, 13 male, 18 female), and 38 healthy age-matched controls (average age 55.7 ±â€¯8.6, 14 male, 24 female), using the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. We calculated the mean fractional anisotropy (FA) and the mean radial (RD) and axial diffusivities (AD) for each fiber bundle. We also evaluated the relationships between diffusion measures, cognition and regional cortical thinning. We found that early changes in RD of select tracts in PHD subjects were associated with impaired performance on neuropsychological tests, suggesting that early changes in myelin might underlie early cognitive dysfunction. Finally, we found that increases in AD of select tracts were associated with regionally select cortical thinning of areas known to atrophy in HD, including the sensorimotor, supramarginal and fusiform gyrus, suggesting that AD may be reflecting pyramidal cell degeneration in HD. Together, these results suggest that white matter microstructural changes in HD reflect a complex, clinically relevant and dynamic process.

SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans.

Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness and psychiatric phenotypes linked to suicide in trauma-exposed veterans. About 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine-guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD) and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylation(adj)). Specifically, DNA methylation(adj) was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation(adj) and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylation(adj) of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.

Tract-based analysis of white matter degeneration in Alzheimer's disease.

Although much prior work has focused on the known cortical pathology that defines Alzheimer's disease (AD) histologically, recent work has additionally demonstrated substantial damage to the cerebral white matter in this condition. While there is large evidence of diffuse damage to the white matter in AD, it is unclear whether specific white matter tracts exhibit a more accelerated pattern of damage and whether the damage is associated with the classical neurodegenerative changes of AD. In this study, we investigated microstructural differences in the large fascicular bundles of the cerebral white matter of individuals with AD and mild cognitive impairment (MCI), using recently developed automated diffusion tractography procedures in the Alzheimer's disease Neuroimaging Initiative (ADNI) dataset. Eighteen major fiber bundles in a total of 36 individuals with AD, 81 MCI and 60 control participants were examined with the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. For each fiber bundle, the mean fractional anisotropy (FA), and mean, radial and axial diffusivities were calculated. Individuals with AD had increased diffusivities in both left and right cingulum-angular bundles compared to control participants (p<0.001). Individuals with MCI also had increased axial and mean diffusivities and increased FA in both cingulum-angular bundles compared to control participants (p<0.05) and decreased radial diffusivity compared to individuals with AD (p<0.05). We additionally examined how white matter deterioration relates to hippocampal volume, a traditional imaging measure of AD pathology, and found the strongest negative correlations in AD patients between hippocampal volume and the diffusivities of the cingulum-angular and cingulum-cingulate gyrus bundles and of the corticospinal tracts (p<0.05). However, statistically controlling for hippocampal volume did not remove all group differences in white matter measures, suggesting a unique contribution of white matter damage to AD unexplained by this disease biomarker. These results suggest that (1) AD-associated deterioration of white matter fibers is greatest in tracts known to be connected to areas of pathology in AD and (2) lower white matter tract integrity is more diffusely associated with lower hippocampal volume indicating that the pathology in the white matter follows to some degree the neurodegenerative staging and progression of this condition.

Imaging small vessel-associated white matter changes in aging.

Alterations in cerebrovascular structure and function may underlie the most common age-associated cognitive, psychiatric, and neurological conditions presented by older adults. Although much remains to understand, existing research suggests several age-associated detrimental conditions may be mediated through sometimes subtle small vessel-induced damage to the cerebral white matter. Here we review a selected portion of the vast work that demonstrates links between changes in vascular and neural health as a function of advancing age, and how even changes in low-to-moderate risk individuals, potentially beginning early in the adult age-span, may have an important impact on functional status in late life.

Correlations between MRI white matter lesion location and executive function and episodic memory.

OBJECTIVES: MRI white matter hyperintensity (WMH) volume is associated with cognitive impairment. We hypothesized that specific loci of WMH would correlate with cognition even after accounting for total WMH volume. METHODS: Subjects were identified from a prospective community-based study: 40 had normal cognition, 94 had mild impairment (defined here as a Clinical Dementia Rating [CDR] score of 0.5 without dementia), and 11 had mild Alzheimer's dementia. Factor analysis of a 22-item neuropsychological battery yielded 4 factors (episodic memory, executive function, spatial skills, and general knowledge). MRI WMH segmentation and analysis was performed using FreeSurfer software. RESULTS: Higher WMH volume was independently associated with lower executive function and episodic memory factor scores. Voxel-based general linear models showed loci where WMH was strongly inversely associated with specific cognitive factor scores (p < 0.001), controlling for age, education, sex, APOE genotype, and total WMH volume. For episodic memory, clusters were observed in bilateral temporal-occipital and right parietal periventricular white matter, and the left anterior limb of the internal capsule. For executive function, clusters were observed in bilateral inferior frontal white matter, bilateral temporal-occipital and right parietal periventricular white matter, and the anterior limb of the internal capsule bilaterally. CONCLUSIONS: Specific WMH loci are closely associated with executive function and episodic memory, independent of total WMH volume. The anatomic locations suggest that WMH may cause cognitive impairment by affecting connections between cortex and subcortical structures, including the thalamus and striatum, or connections between the occipital lobe and frontal or parietal lobes.

Hippocampal degeneration is associated with temporal and limbic gray matter/white matter tissue contrast in Alzheimer's disease.

Recent studies have demonstrated alterations in cortical gray to white matter tissue contrast with nondemented aging and in individuals with Alzheimer's disease (AD). However, little information exists about the clinical relevance of such changes. It is possible that changes in MRI tissue contrast occur via independent mechanisms from those traditionally used in the assessment of AD associated degeneration such as hippocampal degeneration measured by more traditional volumetric magnetic resonance imaging (MRI). We created cortical surface models of 95 cognitively healthy individuals and 98 individuals with AD to characterize changes in regional gray and white matter T1-weighted signal intensities in dementia and to evaluate how such measures related to classically described hippocampal and cortical atrophy. We found a reduction in gray matter to white matter tissue contrast throughout portions of medial and lateral temporal cortical regions as well as in anatomically associated regions including the posterior cingulate, precuneus, and medial frontal cortex. Decreases in tissue contrast were associated with hippocampal volume, however, the regional patterns of these associations differed for demented and nondemented individuals. In nondemented controls, lower hippocampal volume was associated with decreased gray/white matter tissue contrast globally across the cortical mantle. In contrast, in individuals with AD, selective associations were found between hippocampal volume and tissue contrast in temporal and limbic tissue. These results demonstrate that there are strong regional changes in neural tissue properties in AD which follow a spatial pattern including regions known to be affected from pathology studies. Such changes are associated with traditional imaging metrics of degeneration and may provide a unique biomarker of the tissue loss that occurs as a result of AD.

Tapping linked to function and structure in premanifest and symptomatic Huntington disease.

OBJECTIVE: Motor signs are functionally disabling features of Huntington disease. Characteristic motor signs define disease manifestation. Their severity and onset are assessed by the Total Motor Score of the Unified Huntington's Disease Rating Scale, a categorical scale limited by interrater variability and insensitivity in premanifest subjects. More objective, reliable, and precise measures are needed which permit clinical trials in premanifest populations. We hypothesized that motor deficits can be objectively quantified by force-transducer-based tapping and correlate with disease burden and brain atrophy. METHODS: A total of 123 controls, 120 premanifest, and 123 early symptomatic gene carriers performed a speeded and a metronome tapping task in the multicenter study TRACK-HD. Total Motor Score, CAG repeat length, and MRIs were obtained. The premanifest group was subdivided into A and B, based on the proximity to estimated disease onset, the manifest group into stages 1 and 2, according to their Total Functional Capacity scores. Analyses were performed centrally and blinded. RESULTS: Tapping variability distinguished between all groups and subgroups in both tasks and correlated with 1) disease burden, 2) clinical motor phenotype, 3) gray and white matter atrophy, and 4) cortical thinning. Speeded tapping was more sensitive to the detection of early changes. CONCLUSION: Tapping deficits are evident throughout manifest and premanifest stages. Deficits are more pronounced in later stages and correlate with clinical scores as well as regional brain atrophy, which implies a link between structure and function. The ability to track motor phenotype progression with force-transducer-based tapping measures will be tested prospectively in the TRACK-HD study.

White matter pathology isolates the hippocampal formation in Alzheimer's disease.

Prior work has demonstrated that the memory dysfunction of Alzheimer's disease (AD) is accompanied by marked cortical pathology in medial temporal lobe (MTL) gray matter. In contrast, changes in white matter (WM) of pathways associated with the MTL have rarely been studied. We used diffusion tensor imaging (DTI) to examine regional patterns of WM tissue changes in individuals with AD. Alterations of diffusion properties with AD were found in several regions including parahippocampal WM, and in regions with direct and secondary connections to the MTL. A portion of the changes measured, including effects in the parahippocampal WM, were independent of gray matter degeneration as measured by hippocampal volume. Examination of regional changes in unique diffusion parameters including anisotropy and axial and radial diffusivity demonstrated distinct zones of alterations, potentially stemming from differences in underlying pathology, with a potential myelin specific pathology in the parahippocampal WM. These results demonstrate that deterioration of neocortical connections to the hippocampal formation results in part from the degeneration of critical MTL and associated fiber pathways.

Age-associated alterations in cortical gray and white matter signal intensity and gray to white matter contrast.

Prior studies have focused on patterns of brain atrophy with aging and age-associated cognitive decline. It is possible that changes in neural tissue properties could provide an important marker of more subtle changes compared to gross morphometry. However, little is known about how MRI tissue parameters are altered in aging. We created cortical surface models of 148 individuals and mapped regional gray and white matter T1-weighted signal intensities from 3D MPRAGE images to examine patterns of age-associated signal alterations. Gray matter intensity was decreased with aging with strongest effects in medial frontal, anterior cingulate, and inferior temporal regions. White matter signal intensity decreased with aging in superior and medial frontal, cingulum, and medial and lateral temporal regions. The gray/white ratio (GWR) was altered throughout a large portion of the cortical mantle, with strong changes in superior and inferior frontal, lateral parietal, and superior temporal and precuneus regions demonstrating decreased overall contrast. Statistical effects of contrast changes were stronger than those of cortical thinning. These results demonstrate that there are strong regional changes in neural tissue properties with aging and tissue intensity measures may serve as an important biomarker of degeneration.

Detection of cortical thickness correlates of cognitive performance: Reliability across MRI scan sessions, scanners, and field strengths.

In normal humans, relationships between cognitive test performance and cortical structure have received little study, in part, because of the paucity of tools for measuring cortical structure. Computational morphometric methods have recently been developed that enable the measurement of cortical thickness from MRI data, but little data exist on their reliability. We undertook this study to evaluate the reliability of an automated cortical thickness measurement method to detect correlates of interest between thickness and cognitive task performance. Fifteen healthy older participants were scanned four times at 2-week intervals on three different scanner platforms. The four MRI data sets were initially treated independently to investigate the reliability of the spatial localization of findings from exploratory whole-cortex analyses of cortical thickness-cognitive performance correlates. Next, the first data set was used to define cortical ROIs based on the exploratory results that were then applied to the remaining three data sets to determine whether the relationships between cognitive performance and regional cortical thickness were comparable across different scanner platforms and field strengths. Verbal memory performance was associated with medial temporal cortical thickness, while visuomotor speed/set shifting was associated with lateral parietal cortical thickness. These effects were highly reliable - in terms of both spatial localization and magnitude of absolute cortical thickness measurements - across the four scan sessions. Brain-behavior relationships between regional cortical thickness and cognitive task performance can be reliably identified using an automated data analysis system, suggesting that these measures may be useful as imaging biomarkers of disease or performance ability in multicenter studies in which MRI data are pooled.

Neuroimaging H.M.: a 10-year follow-up examination.

In 1997, Corkin et al. described the anatomical boundaries of the amnesic patient H.M.'s surgical resection, based on a comprehensive analysis of magnetic resonance imaging (MRI) scans collected in 1992 and 1993 (Corkin et al. (1997) J Neurosci 17:3964-3979). We subsequently scanned H.M. on several occasions, employing more advanced data acquisition and analysis methods, and now describe additional details about his brain anatomy and pathology. This account combines results from high-resolution T1-weighted scans, which provide measures of cortical and subcortical morphometry, diffusion tensor images, which provide quantitative information about white matter microstructure and the anatomy of major fasciculi, and T2-weighted images, which highlight damage to deep white matter. We applied new MRI analysis techniques to these scans to assess the integrity of areas throughout H.M.'s brain. We documented a number of new changes, including cortical thinning, atrophy of deep gray matter structures, and a large volume of abnormal white matter and deep gray matter signal. Most of these alterations were not apparent in his prior scans, suggesting that they are of recent origin. Advanced age and hypertension likely contributed to these new findings.

Regional cortical thinning in preclinical Huntington disease and its relationship to cognition.

The authors studied presymptomatic individuals with the Huntington disease (HD) mutation to determine whether cortical thinning was present. They found thinning that was regionally selective, semi-independent of striatal volume loss, and correlated with cognitive performance. Early, extensive cortical involvement occurs during the preclinical stages of HD.

Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD.

OBJECTIVE: To use fMRI to investigate whether hippocampal and entorhinal activation during learning is altered in the earliest phase of mild cognitive impairment (MCI). METHODS: Three groups of older individuals were studied: 10 cognitively intact controls, 9 individuals at the mild end of the spectrum of MCI, and 10 patients with probable Alzheimer disease (AD). Subjects performed a face-name associative encoding task during fMRI scanning, and were tested for recognition of stimuli afterward. Data were analyzed using a functional-anatomic method in which medial temporal lobe (MTL) regions of interest were identified from each individual's structural MRI, and fMRI activation was quantified within each region. RESULTS: Significantly greater hippocampal activation was present in the MCI group compared to controls; there were no differences between these two groups in hippocampal or entorhinal volumes. In contrast, the AD group showed hippocampal and entorhinal hypoactivation and atrophy in comparison to controls. The subjects with MCI performed similarly to controls on the fMRI recognition memory task; patients with AD exhibited poorer performance. Across all 29 subjects, greater mean entorhinal activation was found in the subgroup of 13 carriers of the APOE epsilon4 allele than in the 16 noncarriers. CONCLUSIONS: The authors hypothesize that there is a phase of increased medial temporal lobe activation early in the course of prodromal Alzheimer disease followed by a subsequent decrease as the disease progresses.

Age-related alterations in white matter microstructure measured by diffusion tensor imaging.

Cerebral white matter (WM) undergoes various degenerative changes with normal aging, including decreases in myelin density and alterations in myelin structure. We acquired whole-head, high-resolution diffusion tensor images (DTI) in 38 participants across the adult age span. Maps of fractional anisotropy (FA), a measure of WM microstructure, were calculated for each participant to determine whether particular fiber systems of the brain are preferentially vulnerable to WM degeneration. Regional FA measures were estimated from nine regions of interest in each hemisphere and from the genu and splenium of the corpus callosum (CC). The results showed significant age-related decline in FA in frontal WM, the posterior limb of the internal capsule (PLIC), and the genu of the CC. In contrast, temporal and posterior WM was relatively preserved. These findings suggest that WM alterations are variable throughout the brain and that particular fiber populations within prefrontal region and PLIC are most vulnerable to age-related degeneration.

Age-related changes in prefrontal white matter measured by diffusion tensor imaging.

Age-related degeneration of brain white matter (WM) has received a great deal of attention, with recent studies demonstrating that such changes are correlated with cognitive decline and increased risk for the development of age-related neurodegenerative disease. Past studies have used magnetic resonance imaging (MRI) to measure the volume of normal and abnormal tissue signal as an index of tissue pathology. More recently, diffusion tensor MRI (DTI) has been employed to obtain regional measures of tissue microstructure, such as fractional anisotropy (FA), providing better spatial resolution and potentially more sensitive metrics of tissue damage than traditional volumetric measures. We used DTI to examine the regional basis of age-related alterations in prefrontal WM. As expected from prior volumetric and DTI studies, prefrontal FA was reduced in older adults (OA) compared to young adults (YA). Although WM volume has been reported to be relatively preserved until late aging, FA was significantly reduced by middle age. Much of prefrontal WM showed reduced FA with increasing age. Ventromedial and deep prefrontal regions showed a somewhat greater reduction compared to other prefrontal areas. Prefrontal WM anisotropy correlated with prefrontal WM volume, but the correlation was significant only when the analysis was limited to participants over age 40. This evidence of widespread and regionally accelerated alterations in prefrontal WM with aging illustrates FA's potential as a microstructural index of volumetric measures.

Regional and progressive thinning of the cortical ribbon in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a fatal and progressive neurodegenerative disease that is accompanied by involuntary movements, cognitive dysfunction, and psychiatric symptoms. Although progressive striatal degeneration is known to occur, little is known about how the disease affects the cortex, including which cortical regions are affected, how degeneration proceeds, and the relationship of the cortical degeneration to clinical symptoms. The cortex has been difficult to study in neurodegenerative diseases primarily because of its complex folding patterns and regional variability; however, an understanding of how the cortex is affected by the disease may provide important new insights into it. METHODS: Novel automated surface reconstruction and high-resolution MR images of 11 patients with HD and 13 age-matched subjects were used to obtain cortical thickness measurements. The same analyses were performed on two postmortem brains to validate these methods. RESULTS: Regionally specific heterogeneous thinning of the cortical ribbon was found in subjects with HD. Thinning occurred early, differed among patients in different clinical stages of disease, and appeared to proceed from posterior to anterior cortical regions with disease progression. The sensorimotor region was statistically most affected. Measurements performed on MR images of autopsy brains analyzed similarly were within 0.25 mm of those obtained using traditional neuropathologic methods and were statistically indistinguishable. CONCLUSIONS: The authors propose that the cortex degenerates early in disease and that regionally selective cortical degeneration may explain the heterogeneity of clinical expression in HD. These measures might provide a sensitive prospective surrogate marker for clinical trials of neuroprotective medications.

Selective preservation and degeneration within the prefrontal cortex in aging and Alzheimer disease.

BACKGROUND: The prefrontal cortex (PFC) is a heterogeneous cortical structure that supports higher cognitive functions, including working memory and verbal abilities. The PFC is vulnerable to neurodegeneration with healthy aging and Alzheimer disease (AD). OBJECTIVE: We used volumetric magnetic resonance imaging to determine whether any region within the PFC is more vulnerable to deterioration with late aging or AD. METHODS: Volumetric analysis of PFC regions was performed on younger healthy elderly subjects (n = 26; 14 men and 12 women [mean age, 71.7 years] for aging analysis; 12 men and 14 women [mean age, 71.4 years] for AD analysis), oldest healthy elderly (OHE) subjects (n = 22 [11 men and 11 women]; mean age, 88.9 years), and patients with AD (n = 22 [12 men and 10 women]; mean age, 69.8 years). RESULTS: The OHE subjects had less PFC white matter than did young healthy elderly subjects. The orbital region was selectively preserved relative to other PFC regions in the OHE subjects. Subjects with AD had less total PFC gray matter than did age-matched healthy subjects and significantly less volume in the inferior PFC region only. CONCLUSIONS: Orbital PFC is selectively preserved in OHE subjects. In contrast, degeneration within the PFC with AD is most prominent in the inferior PFC region. Thus, degeneration within the PFC has a regionally distinct pattern in healthy aging and AD.

Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease.

OBJECTIVES: To quantify the contribution of gray and white matter volumes to total prefrontal volume in healthy aging. To determine if prefrontal tissue volumes distinguish healthy aging from Alzheimer disease (AD). DESIGN: Volumes of total prefrontal cortex, prefrontal gray matter, and prefrontal white matter were compared among young healthy elderly (YHE) (n = 14; mean age, 70 years), old healthy elderly (OHE) (n = 14; mean age, 90 years), and subjects with AD (n = 14; mean age, 70 years) by analysis of variance. Additionally, Pearson correlations were performed between volumes and age. RESULTS: Old healthy elderly and subjects with AD had significantly less total prefrontal volume (approximately 15% less in both groups) and prefrontal white matter volume (approximately 30% less and 20% less in the OHE and AD groups, respectively) than YHE, but there were no differences between the OHE and AD groups. There was a significant difference in gray-white matter volume ratio with OHE having a higher ratio than YHE. Subjects with AD did not differ from YHE or OHE in this ratio. There were significant negative correlations between age and total prefrontal volume and age and prefrontal white matter volume in the healthy subjects. CONCLUSIONS: In the very old, the decline of white matter volume is disproportionately greater than the decline of gray matter volume. In subjects with AD both gray and white matter loss contribute to the decline of prefrontal volume. This is demonstrated by the gray-white matter ratio that does not differ between YHE and subjects with AD. Thus, it is likely that AD is different from accelerated aging.

Sex differences in prefrontal volume with aging and Alzheimer's disease.

We used volumetric magnetic resonance imaging to examine sex differences in prefrontal tissue volumes of healthy aged and patients with Alzheimer's disease (AD). Healthy subjects had greater total prefrontal volume than AD, and men had greater total prefrontal volume than women (ps < or = 0.02). This was true for both gray and white matter volumes. There were no interactions between group and sex for total prefrontal volume. An exploratory analysis of each group suggested that sex differences in both gray and white matter in healthy aging are not sustained in AD.