High cortical iron is associated with the disruption of white matter tracts supporting cognitive function in healthy older adults.

Aging is associated with brain iron accumulation, which has been linked to cognitive decline. However, how brain iron affects the structure and function of cognitive brain networks remains unclear. Here, we explored the possibility that iron load in gray matter is associated with disruption of white matter (WM) microstructure within a network supporting cognitive function, in a cohort of 95 cognitively normal older adults (age range: 60-86). Functional magnetic resonance imaging was used to localize a set of brain regions involved in working memory and diffusion tensor imaging based probabilistic tractography was used to identify a network of WM tracts connecting the functionally defined regions. Brain iron concentration within these regions was evaluated using quantitative susceptibility mapping and microstructural properties were assessed within the identified tracts using neurite orientation dispersion and density imaging. Results indicated that high brain iron concentration was associated with low neurite density (ND) within the task-relevant WM network. Further, regional associations were observed such that brain iron in cortical regions was linked with lower ND in neighboring but not distant WM tracts. Our results provide novel evidence suggesting that age-related increases in brain iron concentration are associated with the disruption of WM tracts supporting cognitive function in normal aging.

Amyloid-PET Levels in the Precuneus and Posterior Cingulate Cortices Are Associated with Executive Function Scores in Preclinical Alzheimer's Disease Prior to Overt Global Amyloid Positivity.

BACKGROUND: Global amyloid-ß (Aß) deposition in the brain can be quantified by Aß-PET scans to support or refute a diagnosis of preclinical Alzheimer's disease (pAD). Yet, Aß-PET scans enable quantitative evaluation of regional Aß elevations in pAD, potentially allowing even earlier detection of pAD, long before global positivity is achieved. It remains unclear as to whether such regional changes are clinically meaningful. OBJECTIVE: Test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in pAD. METHODS: Global and regional standardized uptake value ratios (SUVr) from 18F-florbetapir PET/CT scanning were determined using the Siemens Syngo.via® Neurology software package across a sample of 99 clinically normal participants with Montreal Cognitive Assessment (MoCA) scores≥23. Relationships between regional SUVr and cognitive test scores were analyzed using linear regression models adjusted for age, sex, and education. Participants were divided into two groups based on SUVr in the posterior cingulate and precuneus gyri (SUVR≥1.17). Between group differences in cognitive test scores were analyzed using ANCOVA models. RESULTS: Executive function performance was associated with increased regional SUVr in the precuneus and posterior cingulate regions only (p < 0.05). There were no significant associations between memory and Aß-PET SUVr in any regions of the brain. CONCLUSION: These data demonstrate that increased Aß deposition in the precuneus and posterior cingulate (the earliest brain regions affected with Aß pathology) is associated with changes in executive function that may precede memory decline in pAD.

White Matter Hyperintensity Volume and Location: Associations With WM Microstructure, Brain Iron, and Cerebral Perfusion.

Cerebral white matter hyperintensities (WMHs) represent macrostructural brain damage associated with various etiologies. However, the relative contributions of various etiologies to WMH volume, as assessed via different neuroimaging measures, is not well-understood. Here, we explored associations between three potential early markers of white matter hyperintensity volume. Specifically, the unique variance in total and regional WMH volumes accounted for by white matter microstructure, brain iron concentration and cerebral blood flow (CBF) was assessed. Regional volumes explored were periventricular and deep regions. Eighty healthy older adults (ages 60-86) were scanned at 3 Tesla MRI using fluid-attenuated inversion recovery, diffusion tensor imaging (DTI), multi-echo gradient-recalled echo and pseudo-continuous arterial spin labeling sequences. In a stepwise regression model, DTI-based radial diffusivity accounted for significant variance in total WMH volume (adjusted R 2 change = 0.136). In contrast, iron concentration (adjusted R 2 change = 0.043) and CBF (adjusted R 2 change = 0.027) made more modest improvements to the variance accounted for in total WMH volume. However, there was an interaction between iron concentration and location on WMH volume such that iron concentration predicted deep (p = 0.034) but not periventricular (p = 0.414) WMH volume. Our results suggest that WM microstructure may be a better predictor of WMH volume than either brain iron or CBF but also draws attention to the possibility that some early WMH markers may be location-specific.

Healthy dietary intake moderates the effects of age on brain iron concentration and working memory performance.

Age-related brain iron accumulation is linked with oxidative stress, neurodegeneration and cognitive decline. Certain nutrients can reduce brain iron concentration in animal models, however, this association is not well established in humans. Moreover, it remains unknown if nutrition can moderate the effects of age on brain iron concentration and/or cognition. Here, we explored these issues in a sample of 73 healthy older adults (61-86 years old), while controlling for several factors such as age, gender, years of education, physical fitness and alcohol-intake. Quantitative susceptibility mapping was used for assessment of brain iron concentration and participants performed an N-Back paradigm to evaluate working memory performance. Nutritional-intake was assessed via a validated questionnaire. Nutrients were grouped into nutrition factors based on previous literature and factor analysis. One factor, comprised of vitamin E, lysine, DHA omega-3 and LA omega-6 PUFA, representing food groups such as nuts, healthy oils and fish, moderated the effects of age on both brain iron concentration and working memory performance, suggesting that these nutrients may slow the rate of brain iron accumulation and working memory declines in aging.

Cortical iron disrupts functional connectivity networks supporting working memory performance in older adults.

Excessive brain iron negatively affects working memory and related processes but the impact of cortical iron on task-relevant, cortical brain networks is unknown. We hypothesized that high cortical iron concentration may disrupt functional circuitry within cortical networks supporting working memory performance. Fifty-five healthy older adults completed an N-Back working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Participants also underwent quantitative susceptibility mapping (QSM) imaging for assessment of non-heme brain iron concentration. Additionally, pseudo continuous arterial spin labeling scans were obtained to control for potential contributions of cerebral blood volume and structural brain images were used to control for contributions of brain volume. Task performance was positively correlated with strength of task-based functional connectivity (tFC) between brain regions of the frontoparietal working memory network. However, higher cortical iron concentration was associated with lower tFC within this frontoparietal network and with poorer working memory performance after controlling for both cerebral blood flow and brain volume. Our results suggest that high cortical iron concentration disrupts communication within frontoparietal networks supporting working memory and is associated with reduced working memory performance in older adults.

An n→π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole.

Aspartic proteases regulate many biological processes and are prominent targets for therapeutic intervention. Structural studies have captured intermediates along the reaction pathway, including the Michaelis complex and tetrahedral intermediate. Using a Ramachandran analysis of these structures, we discovered that residues occupying the P1 and P1' positions (which flank the scissile peptide bond) adopt the dihedral angle of an inverse γ-turn and polyproline type-II helix, respectively. Computational analyses reveal that the polyproline type-II helix engenders an n→π* interaction in which the oxygen of the scissile peptide bond is the donor. This interaction stabilizes the negative charge that develops in the tetrahedral intermediate, much like the oxyanion hole of serine proteases. The inverse γ-turn serves to twist the scissile peptide bond, vacating the carbonyl π* orbital and facilitating its hydration. These previously unappreciated interactions entail a form of substrate-assisted catalysis and offer opportunities for drug design.

A Mild Traumatic Brain Injury in Mice Produces Lasting Deficits in Brain Metabolism.

Metabolic uncoupling has been well-characterized during the first minutes-to-days after a traumatic brain injury (TBI), yet mitochondrial bioenergetics during the weeks-to-months after a brain injury is poorly defined, particularly after a mild TBI. We hypothesized that a closed head injury (CHI) would be associated with deficits in mitochondrial bioenergetics at one month after the injury. A significant decrease in state-III (adenosine triphosphate production) and state-V (complex-I) driven mitochondrial respiration was found at one month post-injury in adult C57Bl/6J mice. Isolation of synaptic mitochondria demonstrated that the deficit in state-III and state-V was primarily neuronal. Injured mice had a temporally consistent deficit in memory recall at one month post-injury. Using proton magnetic resonance spectroscopy (1H MRS) at 7-Tesla, we found significant decreases in phosphocreatine, N-Acetylaspartic acid, and total choline. We also found regional variations in cerebral blood flow, including both hypo- and hyperperfusion, as measured by a pseudocontinuous arterial spin labeling MR sequence. Our results highlight a chronic deficit in mitochondrial bioenergetics associated with a CHI that may lead toward a novel approach for neurorestoration after a mild TBI. MRS provides a potential biomarker for assessing the efficacy of candidate treatments targeted at improving mitochondrial bioenergetics.

A case report comparing clinical, imaging and neuropsychological assessment findings in twins discordant for the VCP p.R155C mutation.

Inclusion body myopathy, Paget disease of bone and/or frontotemporal dementia is an autosomal dominant disease caused by mutations in the Valosin Containing Protein (VCP) gene. We compared clinical findings including MRI images and neuropsychological assessment data in affected and unaffected twin brothers aged 56 years from a family with the p.R155C VCP gene mutation. The affected twin presented with a 10 year history of progressive proximal muscle weakness, difficulty swallowing, gastroesophageal reflux, fecal incontinence, and peripheral neuropathy. Comprehensive neuropsychological testing revealed rapid cognitive decline in the absence of any behavioral changes in a span of 1 year. This case illustrates that frontotemporal dementia related cognitive impairment may precede behavioral changes in VCP disease as compared with predominance of behavioral impairment reported in previous studies. Our findings suggest that there is a need to establish VCP disease specific tools and normative rates of decline to detect pre-clinical cognitive impairment among affected individuals.

Reversible cognitive, motor, and driving impairments in severe hypothyroidism.

BACKGROUND: Hypothyroidism has been associated with cognitive and motor impairments that are likely to constitute hazards in the operation of motor vehicles and a public safety risk. However, there is a paucity of data that would provide an evidence basis for recommendations to hypothyroid patients. The purpose of this study was to determine the specific neurological and psychological deficits consequent to hypothyroidism and whether they are of sufficient magnitude to impede the safe operation of motor vehicles. METHODS: Repeated measurements were obtained in euthyroid, hypothyroid, and euthyroid hormone replaced states of thyroid cancer outpatients, at an academic medical center, who underwent thyroid hormone withdrawal preparation for radioiodine scanning. Study design used a within-subjects longitudinal "A-B-A" with each subject tested at three visits in the same sequence: euthyroid, hypothyroid, and euthyroid for a total of 32 subjects. Data on clinical status and cognitive performance were collected using standard instruments, including ThyDQoL and ThySRQ measures, National Adult Reading Test, Boston Naming Test, Mini-Mental State Exam, Wechsler Adult Intelligence Test-Revised, Letter Fluency FAS, and Beck Depression Inventory. Fine-motor function was measured with an automated assessment panel, and driving performance on a commercial driving simulator. RESULTS: In severe hypothyroidism (median thyrotropin 83.2 mIU/L), fine-motor performance of hands and reaction times in emergency braking tests were slowed, as well as subjective slowing reported on structured clinical scales. Depression was present, typified by vegetative and mood alterations, but lacking reported guilt and lowered self-esteem seen in other types of depression. Cognitive impairment was characterized by declines on speeded executive tests. In contrast, episodic memory performance improved over time regardless of thyroid hormone status. Braking times increased in hypothyroidism by 8.5%, equivalent to reports of effects from a blood alcohol level of 0.082 g/100 mL (above the U.S. legal driving limit). CONCLUSIONS: Transient profound hypothyroidism is characterized by reversible depression, decreased fine-motor performance, slowed reaction times, and decreased processing speed. These data represent new empirical evidence that support the recommendation that complex activities requiring rapid responses, such as operating motor vehicles, should be avoided during hypothyroidism. This has broader implications regarding functional impairments and risk to public health.

Learning to imitate novel motion sequences.

Many imitative behaviors entail complex sequences of component actions that must be recalled and performed in the proper order. It is well known that imitation of complex actions tends to improve with repeated opportunities to observe and execute the target behavior. But what actually makes this practice-based improvement possible? To address this question, we had subjects view and then reproduce sequences of connected, randomly directed motions of a disc. Even a single repetition of a motion sequence substantially reduced errors in reproduction. Improvement seemed to follow a power law, with accuracy in reproducing each motion segment improving by an amount proportional to the current error for that segment. Analysis of the pauses separating a reproduction's segments suggests that with learning, multiple segments in memory are grouped into more compact representations. To test overt performance's contribution to repetition-based improvement, we compared subjects' performance when they reproduced the stimulus trajectory after each repetition to when they did so only once, after the final repetition. Performance was similar following the final repetition in both conditions, indicating that seeing the model, without actual imitation, was sufficient for learning--even in the absence of an explicit error signal. In another experiment, subjects viewed three presentations of each model, with the second presentation given in forward (start to end) or backward (end to start) order. Performance was significantly better when all three presentations were in the same, consistent order, suggesting that repetition reinforced some temporal aspects of a trajectory as it was being learned, and not merely a better representation of the static shape traced by the motion of the disc. These results provide a first look into explicit learning of sequential, nonverbal material, which is central to many tasks of daily life.