Impact of age and apolipoprotein E ε4 status on regional white matter hyperintensity volume and cognition in healthy aging.

OBJECTIVE: White matter hyperintensity (WMH) volume is a neuroimaging marker of lesion load related to small vessel disease that has been associated with cognitive aging and Alzheimer's disease (AD) risk. METHOD: The present study sought to examine whether regional WMH volume mediates the relationship between APOE ε4 status, a strong genetic risk factor for AD, and cognition and if this association is moderated by age group differences within a sample of 187 healthy older adults (APOE ε4 status [carrier/non-carrier] = 56/131). RESULTS: After we controlled for sex, education, and vascular risk factors, ANCOVA analyses revealed significant age group by APOE ε4 status interactions for right parietal and left temporal WMH volumes. Within the young-old group (50-69 years), ε4 carriers had greater right parietal and left temporal WMH volumes than non-carriers. However, in the old-old group (70-89 years), right parietal and left temporal WMH volumes were comparable across APOE ε4 groups. Further, within ε4 non-carriers, old-old adults had greater right parietal and left temporal WMH volumes than young-old adults, but there were no significant differences across age groups in ε4 carriers. Follow-up moderated mediation analyses revealed that, in the young-old, but not the old-old group, there were significant indirect effects of ε4 status on memory and executive functions through left temporal WMH volume. CONCLUSIONS: These findings suggest that, among healthy young-old adults, increased left temporal WMH volume, in the context of the ε4 allele, may represent an early marker of cognitive aging with the potential to lead to greater risk for AD.

Validity of the NIH toolbox cognitive battery in a healthy oldest-old 85+ sample.

OBJECTIVE: To evaluate the construct validity of the NIH Toolbox Cognitive Battery (NIH TB-CB) in the healthy oldest-old (85+ years old). METHOD: Our sample from the McKnight Brain Aging Registry consists of 179 individuals, 85 to 99 years of age, screened for memory, neurological, and psychiatric disorders. Using previous research methods on a sample of 85 + y/o adults, we conducted confirmatory factor analyses on models of NIH TB-CB and same domain standard neuropsychological measures. We hypothesized the five-factor model (Reading, Vocabulary, Memory, Working Memory, and Executive/Speed) would have the best fit, consistent with younger populations. We assessed confirmatory and discriminant validity. We also evaluated demographic and computer use predictors of NIH TB-CB composite scores. RESULTS: Findings suggest the six-factor model (Vocabulary, Reading, Memory, Working Memory, Executive, and Speed) had a better fit than alternative models. NIH TB-CB tests had good convergent and discriminant validity, though tests in the executive functioning domain had high inter-correlations with other cognitive domains. Computer use was strongly associated with higher NIH TB-CB overall and fluid cognition composite scores. CONCLUSION: The NIH TB-CB is a valid assessment for the oldest-old samples, with relatively weak validity in the domain of executive functioning. Computer use's impact on composite scores could be due to the executive demands of learning to use a tablet. Strong relationships of executive function with other cognitive domains could be due to cognitive dedifferentiation. Overall, the NIH TB-CB could be useful for testing cognition in the oldest-old and the impact of aging on cognition in older populations.

Phospholipid headgroups govern area per lipid and emergent elastic properties of bilayers.

Phospholipid bilayers are liquid-crystalline materials whose intermolecular interactions at mesoscopic length scales have key roles in the emergence of membrane physical properties. Here we investigated the combined effects of phospholipid polar headgroups and acyl chains on biophysical functions of membranes with solid-state 2H NMR spectroscopy. We compared the structural and dynamic properties of phosphatidylethanolamine and phosphatidylcholine with perdeuterated acyl chains in the solid-ordered (so) and liquid-disordered (ld) phases. Our analysis of spectral lineshapes of 1,2-diperdeuteriopalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE-d62) and 1,2-diperdeuteriopalmitoyl-sn-glycero-3-phosphocholine (DPPC-d62) in the so (gel) phase indicated an all-trans rotating chain structure for both lipids. Greater segmental order parameters (SCD) were observed in the ld (liquid-crystalline) phase for DPPE-d62 than for DPPC-d62 membranes, while their mixtures had intermediate values irrespective of the deuterated lipid type. Our results suggest the SCD profiles of the acyl chains are governed by methylation of the headgroups and are averaged over the entire system. Variations in the acyl chain molecular dynamics were further investigated by spin-lattice (R1Z) and quadrupolar-order relaxation (R1Q) measurements. The two acyl-perdeuterated lipids showed distinct differences in relaxation behavior as a function of the order parameter. The R1Z rates had a square-law dependence on SCD, implying collective mesoscopic dynamics, with a higher bending rigidity for DPPE-d62 than for DPPC-d62 lipids. Remodeling of lipid average and dynamic properties by methylation of the headgroups thus provides a mechanism to control the actions of peptides and proteins in biomembranes.

Auditory and Visual System White Matter Is Differentially Impacted by Normative Aging in Macaques.

Deficits in auditory and visual processing are commonly encountered by older individuals. In addition to the relatively well described age-associated pathologies that reduce sensory processing at the level of the cochlea and eye, multiple changes occur along the ascending auditory and visual pathways that further reduce sensory function in each domain. One fundamental question that remains to be directly addressed is whether the structure and function of the central auditory and visual systems follow similar trajectories across the lifespan or sustain the impacts of brain aging independently. The present study used diffusion magnetic resonance imaging and electrophysiological assessments of auditory and visual system function in adult and aged macaques to better understand how age-related changes in white matter connectivity at multiple levels of each sensory system might impact auditory and visual function. In particular, the fractional anisotropy (FA) of auditory and visual system thalamocortical and interhemispheric corticocortical connections was estimated using probabilistic tractography analyses. Sensory processing and sensory system FA were both reduced in older animals compared with younger adults. Corticocortical FA was significantly reduced only in white matter of the auditory system of aged monkeys, while thalamocortical FA was lower only in visual system white matter of the same animals. Importantly, these structural alterations were significantly associated with sensory function within each domain. Together, these results indicate that age-associated deficits in auditory and visual processing emerge in part from microstructural alterations to specific sensory white matter tracts, and not from general differences in white matter condition across the aging brain.SIGNIFICANCE STATEMENT Age-associated deficits in sensory processing arise from structural and functional alterations to both peripheral sensory organs and central brain regions. It remains unclear whether different sensory systems undergo similar or distinct trajectories in function across the lifespan. To provide novel insights into this question, this study combines electrophysiological assessments of auditory and visual function with diffusion MRI in aged macaques. The results suggest that age-related sensory processing deficits in part result from factors that impact the condition of specific white matter tracts, and not from general decreases in connectivity between sensory brain regions. Such anatomic specificity argues for a framework aimed at understanding vulnerabilities with relatively local influence and brain region specificity.

Influence of regional white matter hyperintensity volume and apolipoprotein E ε4 status on hippocampal volume in healthy older adults.

While total white matter hyperintensity (WMH) volume on magnetic resonance imaging (MRI) has been associated with hippocampal atrophy, less is known about how the regional distribution of WMH volume may differentially affect the hippocampus in healthy aging. Additionally, apolipoprotein E (APOE) ε4 carriers may be at an increased risk for greater WMH volumes and hippocampal atrophy in aging. The present study sought to investigate whether regional WMH volume mediates the relationship between age and hippocampal volume and if this association is moderated by APOE ε4 status in a group of 190 cognitively healthy adults (APOE ε4 status [carrier/non-carrier] = 59/131), ages 50-89. Analyses revealed that temporal lobe WMH volume significantly mediated the relationship between age and average bilateral hippocampal volume, and this effect was moderated by APOE ε4 status (-0.020 (SE = 0.009), 95% CI, [-0.039, -0.003]). APOE ε4 carriers, but not non-carriers, showed negative indirect effects of age on hippocampal volume through temporal lobe WMH volume (APOE ε4 carriers: -0.016 (SE = 0.007), 95% CI, [-0.030, -0.003]; APOE ε4 non-carriers: .005 (SE = 0.006), 95% CI, [-0.006, 0.017]). These findings remained significant after additionally adjusting for sex, years of education, hypertension status and duration, cholesterol status, diabetes status, Body Mass Index, history of smoking, and the Wechsler Adult Intelligence Scale-IV Full Scale IQ. There were no significant moderated mediation effects for frontal, parietal, and occipital lobe WMH volumes, with or without covariates. Our findings indicate that in cognitively healthy older adults, elevated WMH volume regionally localized to the temporal lobes in APOE ε4 carriers is associated with reduced hippocampal volume, suggesting greater vulnerability to brain aging and the risk for Alzheimer's disease.

Auditory Processing Deficits Are Selectively Associated with Medial Temporal Lobe Mnemonic Function and White Matter Integrity in Aging Macaques.

Deficits in auditory function and cognition are hallmarks of normative aging. Recent evidence suggests that hearing-impaired individuals have greater risks of developing cognitive impairment and dementia compared to people with intact auditory function, although the neurobiological bases underlying these associations are poorly understood. Here, a colony of aging macaques completed a battery of behavioral tests designed to probe frontal and temporal lobe-dependent cognition. Auditory brainstem responses (ABRs) and visual evoked potentials were measured to assess auditory and visual system function. Structural and diffusion magnetic resonance imaging were then performed to evaluate the microstructural condition of multiple white matter tracts associated with cognition. Animals showing higher cognitive function had significantly better auditory processing capacities, and these associations were selectively observed with tasks that primarily depend on temporal lobe brain structures. Tractography analyses revealed that the fractional anisotropy (FA) of the fimbria-fornix and hippocampal commissure were associated with temporal lobe-dependent visual discrimination performance and auditory sensory function. Conversely, FA of frontal cortex-associated white matter was not associated with auditory processing. Visual sensory function was not associated with frontal or temporal lobe FA, nor with behavior. This study demonstrates significant and selective relationships between ABRs, white matter connectivity, and higher-order cognitive ability.

Bootstrap analysis of diffusion tensor and mean apparent propagator parameters derived from multiband diffusion MRI.

PURPOSE: To directly compare diffusion metrics derived from multiband (MB) imaging sequences to those derived using a single-band acquisition. METHODS: In this work, diffusion metrics from DTI and mean apparent propagator MRI derived from a commercial MB sequence with an acceleration factor of 3 are compared with those derived from a conventional diffusion MRI sequence using a novel bootstrapping analysis scheme on oversampled diffusion MRI data. The average parameter values for fractional anisotropy and mean diffusivity derived from DTI, as well as propagator anisotropy and return to origin probability derived from mean apparent propagator MRI, are compared. RESULTS: Fractional anisotropy and propagator anisotropy are very similar when computed from data collected with and without MB, but show minor differences at low and high values of fractional anisotropy/propagator anisotropy. Mean diffusivity values are generally lower in the MB-derived maps, and return to origin probability is generally higher. The coefficient of variation of each parameter is shown to be slightly higher on average from the maps derived from MB versus single band when the TR is short, and slightly lower when the TR of the MB and single-band experiments is equal. CONCLUSION: These results demonstrate that the MB sequence tested in this work provides very similar results to a conventional diffusion MRI sequence. The MB sequence is affected minimally by the slight decrease in SNR associated with the parallel reconstruction and reduced TR, and there are relaxation effects associated with the reduced TR.

Volumetric MRI of the lungs during forced expiration.

PURPOSE: Lung function is typically characterized by spirometer measurements, which do not offer spatially specific information. Imaging during exhalation provides spatial information but is challenging due to large movement over a short time. The purpose of this work is to provide a solution to lung imaging during forced expiration using accelerated magnetic resonance imaging. The method uses radial golden angle stack-of-stars gradient echo acquisition and compressed sensing reconstruction. METHODS: A technique for dynamic three-dimensional imaging of the lungs from highly undersampled data is developed and tested on six subjects. This method takes advantage of image sparsity, both spatially and temporally, including the use of reference frames called bookends. Sparsity, with respect to total variation, and residual from the bookends, enables reconstruction from an extremely limited amount of data. RESULTS: Dynamic three-dimensional images can be captured at sub-150 ms temporal resolution, using only three (or less) acquired radial lines per slice per timepoint. The images have a spatial resolution of 4.6×4.6×10 mm. Lung volume calculations based on image segmentation are compared to those from simultaneously acquired spirometer measurements. CONCLUSION: Dynamic lung imaging during forced expiration is made possible by compressed sensing accelerated dynamic three-dimensional radial magnetic resonance imaging. Magn Reson Med 75:2295-2302, 2016. © 2015 Wiley Periodicals, Inc.

Orbitofrontal cortex volume in area 11/13 predicts reward devaluation, but not reversal learning performance, in young and aged monkeys.

The orbitofrontal cortex (OFC) and amygdala are both necessary for decisions based on expected outcomes. Although behavioral and imaging data suggest that these brain regions are affected by advanced age, the extent to which aging alters appetitive processes coordinated by the OFC and the amygdala is unknown. In the current experiment, young and aged bonnet macaques were trained on OFC- and amygdala-dependent tasks that test the degree to which response selection is guided by reward value and can be adapted when expected outcomes change. To assess whether the structural integrity of these regions varies with levels of performance on reward devaluation and object reversal tasks, volumes of areas 11/13 and 14 of the OFC, central/medial (CM), and basolateral (BL) nuclei of the amygdala were determined from high-resolution anatomical MRIs. With age, there were significant reductions in OFC, but not CM and BL, volume. Moreover, the aged monkeys showed impairments in the ability to associate an object with a higher value reward, and to reverse a previously learned association. Interestingly, greater OFC volume of area 11/13, but not 14, was significantly correlated with an animal's ability to anticipate the reward outcome associated with an object, and smaller BL volume was predictive of an animal's tendency to choose a higher value reward, but volume of neither region correlated with reversal learning. Together, these data indicate that OFC volume has an impact on monkeys' ability to guide choice behavior based on reward value but does not impact ability to reverse a previously learned association.

White matter ischemic changes in hyperacute ischemic stroke: voxel-based analysis using diffusion tensor imaging and MR perfusion.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate changes in fractional anisotropy (FA), as measured by diffusion tensor imaging, of white matter (WM) infarction and hypoperfusion in patients with acute ischemic stroke using a quantitative voxel-based analysis. METHODS: In this prospective study, diffusion tensor imaging and dynamic susceptibility contrast perfusion sequences were acquired in 21 patients with acute ischemic stroke who presented within 6 hours of symptom onset. The coregistered FA, apparent diffusion coefficient, and dynamic susceptibility contrast time to maximum (Tmax) maps were used for voxel-based quantification using a region of interest approach in the ipsilateral affected side and in the homologous contralateral WM. The regions of WM infarction versus hypoperfusion were segmented using a threshold method. Data were analyzed by regression and ANOVA. RESULTS: There was an overall significant mean difference (P<0.001) for the apparent diffusion coefficient, Tmax, and FA values between the normal, hypoperfused, and infarcted WM. The mean±SD of FA was significantly higher (P<0.001) in hypoperfused WM (0.397±0.019) and lower (P<0.001) in infarcted WM (0.313±0.037) when compared with normal WM (0.360±0.020). Regression tree analysis of hypoperfused WM showed the largest mean FA difference at Tmax above versus below 5.4 s with a mean difference of 0.033 (P=0.0096). CONCLUSIONS: Diffusion tensor imaging-FA was decreased in regions of WM infarction and increased in hypoperfused WM in patients with hyperacute acute ischemic stroke. The significantly increased FA values in the hypoperfused WM with Tmax≥5.4 s are suggestive of early ischemic microstructural changes.

A novel mouse model of Niemann-Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations.

We have identified a point mutation in Npc1 that creates a novel mouse model (Npc1(nmf164)) of Niemann-Pick type C1 (NPC) disease: a single nucleotide change (A to G at cDNA bp 3163) that results in an aspartate to glycine change at position 1005 (D1005G). This change is in the cysteine-rich luminal loop of the NPC1 protein and is highly similar to commonly occurring human mutations. Genetic and molecular biological analyses, including sequencing the Npc1(spm) allele and identifying a truncating mutation, confirm that the mutation in Npc1(nmf164) mice is distinct from those in other existing mouse models of NPC disease (Npc1(nih), Npc1(spm)). Analyses of lifespan, body and spleen weight, gait and other motor activities, as well as acoustic startle responses all reveal a more slowly developing phenotype in Npc1(nmf164) mutant mice than in mice with the null mutations (Npc1(nih), Npc1(spm)). Although Npc1 mRNA levels appear relatively normal, Npc1(nmf164) brain and liver display dramatic reductions in Npc1 protein, as well as abnormal cholesterol metabolism and altered glycolipid expression. Furthermore, histological analyses of liver, spleen, hippocampus, cortex and cerebellum reveal abnormal cholesterol accumulation, glial activation and Purkinje cell loss at a slower rate than in the Npc1(nih) mouse model. Magnetic resonance imaging studies also reveal significantly less demyelination/dysmyelination than in the null alleles. Thus, although prior mouse models may correspond to the severe infantile onset forms of NPC disease, Npc1(nmf164) mice offer many advantages as a model for the late-onset, more slowly progressing forms of NPC disease that comprise the large majority of human cases.

Design, manufacture, and analysis of customized phantoms for enhanced quality control in small animal MRI systems.

PURPOSE: Magnetic resonance imaging (MRI) is widely used in human brain research to evaluate the effects of healthy aging and development, as well as neurological disorders. Although standardized methods for quality assurance of human MRI instruments have been established, such approaches have typically not been translated to small animal imaging. We present a method for the generation and analysis of customized phantoms for small animal MRI systems that allows rapid and accurate system stability monitoring. METHODS: Computer-aided design software was used to produce a customized phantom using a rapid prototyping printer. Automated registration algorithms were used on three-dimensional images of the phantom to allow system stability to be easily monitored over time. RESULTS: The design of the custom phantom allowed reliable placement relative to the imaging coil. Automated registration showed superior ability to detect gradient changes reflected in the images than with manual measurements. Registering images acquired over time allowed monitoring of gradient drifts of less than one percent. CONCLUSION: A low cost, MRI compatible phantom was successfully designed using computer-aided design software and a three-dimensional printer. Registering phantom images acquired over time allows monitoring of gradient stability of the MRI system.

Frontal-temporal regional differences in brain energy metabolism and mitochondrial function using 31P MRS in older adults.

Aging is a major risk for cognitive decline and transition to dementia. One well-known age-related change involves decreased brain efficiency and energy production, mediated in part by changes in mitochondrial function. Damaged or dysfunctional mitochondria have been implicated in the pathogenesis of age-related neurodegenerative conditions like Alzheimer's disease (AD). The aim of the current study was to investigate mitochondrial function over frontal and temporal regions in a sample of 70 cognitively normal older adults with subjective memory complaints and a first-degree family history of AD. We hypothesized cerebral mitochondrial function and energy metabolism would be greater in temporal as compared to frontal regions based on the high energy consumption in the temporal lobes (i.e., hippocampus). To test this hypothesis, we used phosphorous (31P) magnetic resonance spectroscopy (MRS) which is a non-invasive and powerful method for investigating in vivo mitochondrial function via high energy phosphates and phospholipid metabolism ratios. We used a single voxel method (left temporal and bilateral prefrontal) to achieve optimal sensitivity. Results of separate repeated measures analyses of variance showed 31P MRS ratios of static energy, energy reserve, energy consumption, energy demand, and phospholipid membrane metabolism were greater in the left temporal than bilateral prefrontal voxels. Our findings that all 31P MRS ratios were greater in temporal than bifrontal regions support our hypothesis. Future studies are needed to determine whether findings are related to cognition in older adults.

Regional covariance of white matter hyperintensity volume patterns associated with hippocampal volume in healthy aging.

Hippocampal volume is particularly sensitive to the accumulation of total brain white matter hyperintensity volume (WMH) in aging, but how the regional distribution of WMH volume differentially impacts the hippocampus has been less studied. In a cohort of 194 healthy older adults ages 50-89, we used a multivariate statistical method, the Scaled Subprofile Model (SSM), to (1) identify patterns of regional WMH differences related to left and right hippocampal volumes, (2) examine associations between the multimodal neuroimaging covariance patterns and demographic characteristics, and (3) investigate the relation of the patterns to subjective and objective memory in healthy aging. We established network covariance patterns of regional WMH volume differences associated with greater left and right hippocampal volumes, which were characterized by reductions in left temporal and right parietal WMH volumes and relative increases in bilateral occipital WMH volumes. Additionally, we observed lower expression of these hippocampal-related regional WMH patterns were significantly associated with increasing age and greater subjective memory complaints, but not objective memory performance in this healthy older adult cohort. Our findings indicate that, in cognitively healthy older adults, left and right hippocampal volume reductions were associated with differences in the regional distribution of WMH volumes, which were exacerbated by advancing age and related to greater subjective memory complaints. Multivariate network analyses, like SSM, may help elucidate important early effects of regional WMH volume on brain and cognitive aging in healthy older adults.

Chronic consequences of ischemic stroke: Profiling brain injury and inflammation in a mouse model with reperfusion.

Stroke is a pervasive and debilitating global health concern, necessitating innovative therapeutic strategies, especially during recovery. While existing literature often focuses on acute interventions, our study addresses the uniqueness of brain tissue during wound healing, emphasizing the chronic phase following the commonly used middle cerebral artery (MCA) occlusion model. Using clinically relevant endpoints in male and female mice such as magnetic resonance imaging (MRI) and plasma neurofilament light (NFL) measurement, along with immunohistochemistry, we describe injury evolution. Our findings document significant alterations in edema, tissue remodeling, and gadolinium leakage through MRI. Plasma NFL concentration remained elevated at 30 days poststroke. Microglia responses are confined to the region adjacent to the injury, rather than continued widespread activation, and boron-dipyrromethene (BODIPY) staining demonstrated the persistent presence of foam cells within the infarct. Additional immunohistochemistry highlighted sustained B and T lymphocyte presence in the poststroke brain. These observations underscore potentially pivotal roles played by chronic inflammation brought on by the lipid-rich brain environment, and chronic blood-brain barrier dysfunction, in the development of secondary neurodegeneration. This study sheds light on the enduring consequences of ischemic stroke in the most used rodent stroke model and provides valuable insights for future research, clinical strategies, and therapeutic development.

Npc1 haploinsufficiency promotes weight gain and metabolic features associated with insulin resistance.

A recent population-based genome-wide association study has revealed that the Niemann-Pick C1 (NPC1) gene is associated with early-onset and morbid adult obesity. Concurrently, our candidate gene-based mouse growth study performed using the BALB/cJ NPC1 mouse model (Npc1) with decreased Npc1 gene dosage independently supported these results by suggesting an Npc1 gene-diet interaction in relation to early-onset weight gain. To further investigate the Npc1 gene in relation to weight gain and metabolic features associated with insulin resistance, we interbred BALB/cJ Npc1(+/-) mice with wild-type C57BL/6J mice, the latter mouse strain commonly used to study aspects of diet-induced obesity and insulin resistance. This breeding produced a hybrid (BALB/cJ-C57BL/6J) Npc1(+/-) mouse model with increased susceptibility to weight gain and insulin resistance. The results from our study indicated that these Npc1(+/-) mice were susceptible to increased weight gain characterized by increased whole body and abdominal adiposity, adipocyte hypertrophy and hepatic steatosis in the absence of hyperphagia. Moreover, these Npc1(+/-) mice developed abnormal metabolic features characterized by impaired fasting glucose, glucose intolerance, hyperinsulinemia, hyperleptinemia and dyslipidemia marked by an increased concentration of cholesterol and triacylglycerol associated with low-density lipoprotein and high-density lipoprotein. The overall results are consistent with a unique Npc1 gene-diet interaction that promotes both weight gain and metabolic features associated with insulin resistance. Therefore, the NPC1 gene now represents a previously unrecognized gene involved in maintaining energy and metabolic homeostasis that will contribute to our understanding concerning the current global epidemic of obesity and type 2 diabetes mellitus.

(1) H magnetic resonance spectroscopy of neurodegeneration in a mouse model of niemann-pick type C1 disease.

PURPOSE: To evaluate brain metabolite levels as in vivo indicators of disease progression in a widely studied mouse model of Niemann-Pick type C1 (NPC1) disease with quantitative (1) H magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: Single voxel MRS experiments were carried out in vivo in a mouse model of NPC1 disease and in control mice in two brain regions (central and posterior) at two timepoints (presymptomatic and endstage) to examine changes in metabolite levels in NPC1 disease. Concentrations of nine metabolites were quantified by fitting a simulated basis set of metabolite signals to the acquired spectra. RESULTS: The only differences found in brain metabolite levels between NPC1 disease model and control mice were increased myo-inositol and decreased taurine in the posterior region of the brain at the endstage of the disease. Metabolite changes reported in past clinical MRS studies of NPC disease were not found in the current study of the mouse model. CONCLUSIONS: The (1) H spectra obtained from NPC1 mice and control mice were very similar, even at endstages of the disease. Although differences in two metabolites associated with neurodegenerative diseases were found and could inform future studies of the disease model, it appears that MRS in this mouse model of NPC1 disease does not have the sensitivity desired for a biomarker.

Association of homocysteine-related subcortical brain atrophy with white matter lesion volume and cognition in healthy aging.

Homocysteine (Hcy) is a vascular risk factor associated with cognitive impairment and cerebrovascular disease but has also been implicated in Alzheimer's disease (AD). Using multivariate Scaled Subprofile Model (SSM) analysis, we sought to identify a network pattern in structural neuroimaging reflecting the regionally distributed association of plasma Hcy with subcortical gray matter (SGM) volumes and its relation to other health risk factors and cognition in 160 healthy older adults, ages 50-89. We identified an SSM Hcy-SGM pattern that was characterized by bilateral hippocampal and nucleus accumbens volume reductions with relative volume increases in bilateral caudate, pallidum, and putamen. Greater Hcy-SGM pattern expression was associated with greater white matter hyperintensity (WMH) volume, older age, and male sex, but not with other vascular and AD-related risk factors. Mediation analyses revealed that age predicted WMH volume, which predicted Hcy-SGM pattern expression, which, in turn, predicted cognitive processing speed performance. These findings suggest that the multivariate SSM Hcy-SGM pattern may be indicative of cognitive aging, reflecting a potential link between vascular health and cognitive dysfunction in healthy older adults.

In vivo assessment of neurodegeneration in Niemann-Pick type C mice by quantitative T2 mapping and diffusion tensor imaging.

PURPOSE: To quantitatively and noninvasively assess neurological disease progression in a mouse model of Niemann-Pick type C (NPC) disease by measuring white matter status with magnetic resonance imaging (MRI) techniques of T2 mapping and diffusion tensor imaging (DTI). MATERIALS AND METHODS: Quantitative T2 and DTI experiments were performed in vivo in NPC disease model and control mice at three timepoints to quantify differences and changes in white matter with measurements of T2 relaxation and DTI parameters. Histological staining for myelin content was also performed at two timepoints to compare with the MRI findings. RESULTS: The results of the T2 and DTI measurements show significant differences in white matter areas of the brain in the NPC disease model compared to control mice at several timepoints, and were seen to change over time in both groups. CONCLUSION: The findings of this study suggest that quantitative MRI measurements may be suitable in vivo biomarkers of disease status for future studies of NPC disease models. The changes in white matter measurements between timepoints in both control and NPC disease groups suggest that white matter structures continue to change and develop over time in the NPC model and can be tracked with MRI techniques.

Changes in intracellular water diffusion and energetic metabolism in response to ischemia in perfused C6 rat glioma cells.

This work reports results of experiments in hollow-fiber bioreactor C6 glioma cell cultures where the apparent diffusion coefficient (ADC) of intracellular water (iADC) was measured at diffusion times between 0.83 and 40 ms. The experiments were carried out before and after the onset of permanent ischemia. The changes in iADC following ischemia were dependent on the diffusion time employed in the experiment. An ischemia-induced decrease in the iADC was measured at short diffusion times, while at long diffusion times the iADC increased. Decreases in the iADC measured at short diffusion times are interpreted to be a result of a decrease in the intrinsic diffusivity of intracellular water due to energy failure. Increases in iADC measured at long diffusion times, are interpreted to result from cell swelling.