Neurocognitive correlates of cerebral mitochondrial function and energy metabolism using phosphorus magnetic resonance spectroscopy in older adults.

The goal of the current study was to learn about the role of cerebral mitochondrial function on cognition. Based on established cognitive neuroscience, clinical neuropsychology, and cognitive aging literature, we hypothesized mitochondrial function within a focal brain region would map onto cognitive behaviors linked to that brain region. To test this hypothesis, we used phosphorous (31P) magnetic resonance spectroscopy (MRS) to derive indirect markers of mitochondrial function and energy metabolism across two regions of the brain (bifrontal, left temporal). We administered cognitive tasks sensitive to frontal-executive or temporal-hippocampal systems to a sample of 70 cognitively unimpaired older adults with subjective memory complaints and a first-degree family history of Alzheimer's disease and predicted better executive function and recent memory performance would be related to greater frontal and temporal 31P MRS indirect markers, respectively. Results of separate hierarchical linear regressions indicated better recent memory scores were related to 31P MRS indirect markers of lower static energy and higher energy reserve within the left temporal voxel; these findings were associated with moderate effect sizes. Contrary to predictions, executive function performance was unrelated to 31P MRS indirect markers within the bilateral frontal voxel, which may reflect a combination of theoretical and/or methodological issues. Findings represent a snapshot of the relationship between cognition and 31P MRS indirect markers of mitochondrial function, providing potential avenues for future work investigating mitochondrial underpinnings of cognition. 31P MRS may provide a sensitive neuroimaging marker for differences in aspects of memory among persons at-risk for mild cognitive impairment or dementia.

Cortical lobar volume reductions associated with homocysteine-related subcortical brain atrophy and poorer cognition in healthy aging.

Homocysteine (Hcy) is a cardiovascular risk factor implicated in cognitive impairment and cerebrovascular disease but has also been associated with Alzheimer's disease. In 160 healthy older adults (mean age = 69.66 ± 9.95 years), we sought to investigate the association of cortical brain volume with white matter hyperintensity (WMH) burden and a previously identified Hcy-related multivariate network pattern showing reductions in subcortical gray matter (SGM) volumes of hippocampus and nucleus accumbens with relative preservation of basal ganglia. We additionally evaluated the potential role of these brain imaging markers as a series of mediators in a vascular brain pathway leading to age-related cognitive dysfunction in healthy aging. We found reductions in parietal lobar gray matter associated with the Hcy-SGM pattern, which was further associated with WMH burden. Mediation analyses revealed that slowed processing speed related to aging, but not executive functioning or memory, was mediated sequentially through increased WMH lesion volume, greater Hcy-SGM pattern expression, and then smaller parietal lobe volume. Together, these findings suggest that volume reductions in parietal gray matter associated with a pattern of Hcy-related SGM volume differences may be indicative of slowed processing speed in cognitive aging, potentially linking cardiovascular risk to an important aspect of cognitive dysfunction in healthy aging.

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.

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.

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.

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.

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.

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.

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.

Interaction of Age and Self-reported Physical Sports Activity on White Matter Hyperintensity Volume in Healthy Older Adults.

Cerebral white matter (WM) lesion load, as measured by white matter hyperintensity (WMH) volume with magnetic resonance imaging (MRI), has been associated with increasing age and cardiovascular risk factors, like hypertension. Physical sports activity (PSA) may play an important role in maintaining WM in the context of healthy aging. In 196 healthy older adults, we investigated whether participants reporting high levels of PSA (n = 36) had reduced total and regional WMH volumes compared to those reporting low levels of PSA (n = 160). Age group [young-old (YO) = 50-69 years; old-old (OO) = 70-89 years], PSA group, and age by PSA group interaction effects were tested, with sex, hypertension, and body mass index (BMI) as covariates. We found significant main effects for age group and age by PSA group interactions for total, frontal, temporal, and parietal WMH volumes. There were no main effects of PSA group on WMH volumes. The OO group with low PSA had greater total, frontal, temporal, and parietal WMH volumes than the YO with low PSA and OO with high PSA groups. WMH volumes for the YO and OO groups with high PSA were comparable. These findings indicate an age group difference in those with low PSA, with greater WMH volumes in older adults, which was not observed in those with high PSA. The results suggest that engaging in high levels of PSA may be an important lifestyle factor that can help to diminish WMH lesion load in old age, potentially reducing the impact of brain aging.

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.

Age-Related Regional Network Covariance of Magnetic Resonance Imaging Gray Matter in the Rat.

Healthy human aging has been associated with brain atrophy in prefrontal and selective temporal regions, but reductions in other brain areas have been observed. We previously found regional covariance patterns of gray matter with magnetic resonance imaging (MRI) in healthy humans and rhesus macaques, using multivariate network Scaled Subprofile Model (SSM) analysis and voxel-based morphometry (VBM), supporting aging effects including in prefrontal and temporal cortices. This approach has yet to be applied to neuroimaging in rodent models of aging. We investigated 7.0T MRI gray matter covariance in 10 young and 10 aged adult male Fischer 344 rats to identify, using SSM VBM, the age-related regional network gray matter covariance pattern in the rodent. SSM VBM identified a regional pattern that distinguished young from aged rats, characterized by reductions in prefrontal, temporal association/perirhinal, and cerebellar areas with relative increases in somatosensory, thalamic, midbrain, and hippocampal regions. Greater expression of the age-related MRI gray matter pattern was associated with poorer spatial learning in the age groups combined. Aging in the rat is characterized by a regional network pattern of gray matter reductions corresponding to aging effects previously observed in humans and non-human primates. SSM MRI network analyses can advance translational aging neuroscience research, extending from human to small animal models, with potential for evaluating mechanisms and interventions for cognitive aging.

Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin.

The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.

Right hippocampal volume mediation of subjective memory complaints differs by hypertension status in healthy aging.

Subjective memory complaints (SMCs) may be an important early indicator of cognitive aging and preclinical Alzheimer's disease risk. This study investigated whether age-related differences in right or left hippocampal volume underlie SMCs, if these relationships differ by hypertension status, and how they are related to objective memory performance in a group of 190 healthy older adults, 50-89 years of age. Analyses revealed a significant mediation of the relationship between age and mild SMCs by right hippocampal volume that was moderated by hypertension status. This moderated mediation effect was not observed with left hippocampal volume. Additionally, a moderated serial mediation model showed that age predicted right hippocampal volume, which predicted SMCs, and in turn predicted objective memory performance on several measures of verbal selective reminding in individuals with hypertension, but not in non-hypertensives. Together, these findings suggest that even mild SMCs, in the context of hypertension, provide an early indicator of cognitive aging, reflecting a potential link among vascular risk, SMCs, and the preclinical risk for Alzheimer's disease.

Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice.

Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.

Distribution and Diffusion of Macromolecule Delivery to the Brain via Focused Ultrasound using Magnetic Resonance and Multispectral Fluorescence Imaging.

Focused ultrasound (FUS), in combination with microbubble contrast agents, can be used to transiently open the blood-brain barrier (BBB) to allow intravascular agents to cross into the brain. Often, FUS is carried out in conjunction with magnetic resonance imaging (MRI) to evaluate BBB opening to gadolinium-based MRI contrast agents. Although MRI allows direct visualization of the distribution of gadolinium-based contrast agents in the brain parenchyma, it does not allow measurements of the distribution of other molecules crossing the BBB. Therapeutic molecules (e.g., monoclonal antibodies) are much different in size than MRI contrast agents and have been found to have different distributions in the brain after FUS-mediated BBB opening. In the work described here, we combined in vivo MRI and ex vivo multispectral fluorescence imaging to compare the distributions of MRI contrast and dextran molecules of different molecular weights (3, 70 and 500 kDa) after FUS-mediated BBB opening through a range of ultrasound pressures (0.18-0.46 MPa) in laboratory mice. The volume of brain exposed was calculated from the MRI and fluorescence images and was significantly dependent on both molecular weight and ultrasound pressure. Diffusion coefficients of the different-molecular-weight dextran molecules in the brain parenchyma were also calculated from the fluorescence images and were negatively correlated with the molecular weight of the dextran molecules. The results of this work build on a body of knowledge that is critically important for the FUS technique to be used in clinical delivery of therapeutics to the brain.

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.

Gradual hypertension induction in middle-aged Cyp1a1-Ren2 transgenic rats produces significant impairments in spatial learning.

Hypertension is a major health concern in the developed world, and its prevalence increases with advancing age. The impact of hypertension on the function of the renal and cardiovascular systems is well studied; however, its influence on the brain regions important for cognition has garnered less attention. We utilized the Cyp1a1-Ren2 xenobiotic-inducible transgenic rat model to mimic both the age of onset and rate of induction of hypertension observed in humans. Male, 15-month-old transgenic rats were fed 0.15% indole-3-carbinol (I3C) chow to slowly induce renin-dependent hypertension over a 6-week period. Systolic blood pressure significantly increased, eventually reaching 200 mmHg by the end of the study period. In contrast, transgenic rats fed a control diet without I3C did not show significant changes in blood pressure (145 mmHg at the end of study). Hypertension was associated with cardiac, aortic, and renal hypertrophy as well as increased collagen deposition in the left ventricle and kidney of the I3C-treated rats. Additionally, rats with hypertension showed reduced savings from prior spatial memory training when tested on the hippocampus-dependent Morris swim task. Motor and sensory functions were found to be unaffected by induction of hypertension. Taken together, these data indicate a profound effect of hypertension not only on the cardiovascular-renal axis but also on brain systems critically important for learning and memory. Future use of this model and approach may empower a more accurate investigation of the influence of aging on the systems responsible for cardiovascular, renal, and neurological health.