Eric D. Vidoni

Impact of APOE on the Healthy Aging Brain: A Voxel-Based MRI and DTI Study

Neuroimaging studies of apolipoprotein E (ApoE4) have implicated its association with brain atrophy in Alzheimers disease. To date, few studies have used automated morphological analysis techniques to assess ApoE4-related brain structure change in both gray and white matter in nondemented older adults. Nondemented (CDR = 0, n = 53) subjects over 60 had MRI, diffusion tensor imaging, and neurocognitive assessments. We assessed differences in cognition and brain structure associated with ApoE4 genetic variation using voxel-based morphometry techniques, and tract-based spatial statistics of fractional anisotropy change. In nondemented older adults with the E4 allele, cognitive performance was reduced, and atrophy was present in the hippocampus and amygdala compared to ApoE4 negative participants. We also report that E4 carriers have decreased fractional anisotropy in the left parahippocampal gyrus white matter. In conclusion, the presence of an ApoE4 allele in nondemented older adults is associated with decreases in cognition and gray and white matter changes in the medial temporal cortex. Overall we provide further evidence of the effects of genetic variance related to imaging and cognitive measures of risk for Alzheimers disease.

Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease

Objective: A consistently identified risk factor for Alzheimer disease (AD) is family history of dementia, with maternal transmission significantly more frequent than paternal transmission. A history of maternal AD may be related to AD-like glucose consumption in cognitively healthy subjects. In this cross-sectional study, we tested whether cognitively healthy people with a family history of AD have less gray matter volume (GMV), an endophenotype for late-onset AD, than individuals with no family history, and whether decreases in GMV are different in subjects with a maternal family history. Methods: As part of the Kansas University Brain Aging Project, 67 cognitively intact individuals with a maternal history of late-onset AD (FHm, n = 16), a paternal history of AD (FHp, n = 8), or no parental history of AD (FH−, n = 43), similar in age, gender, education, and Mini-Mental State Examination score, were scanned at 3 T. We used voxel-based morphometry to examine GMV differences between groups, controlling for age, gender, and apoE4. Results: Cognitively healthy individuals with a family history of late-onset AD had significantly decreased GMV in the precuneus, middle frontal, inferior frontal, and superior frontal gyri compared with FH− individuals. FHm subjects had significantly smaller inferior frontal, middle frontal, precuneus, and lingual gyri compared with FH− and FHp subjects. Conclusions: Overall, maternal family history of Alzheimer disease (AD) in cognitively normal individuals is associated with lower gray matter volume in AD-vulnerable brain regions. These data complement and extend reports of cerebral metabolic differences in subjects with a maternal family history.

Motor sequence chunking is impaired by basal ganglia stroke

Our main aim was to determine whether individuals with stroke that affected the basal ganglia, organized movement sequences into chunks in the same fashion as neurologically intact individuals. To address this question, we compared motor response times during the performance of repeated sequences that were learned, and thus may be planned in advance, with random sequences where there is minimal if any advance preparation or organization of responses. The pattern of responses illustrated that, after basal ganglia stroke, individuals do not chunk elements of the repeated sequence into functional sub-sequences of movement to the same extent as neurologically intact age-matched people. Limited chunking of learned movements after stroke may explain past findings that show overall slower responses even when sequences of action are learned by this population. Further, our data in combination with other work, suggest that chunking may be a function of the basal ganglia.

Impaired glycemia increases disease progression in mild cognitive impairment

Insulin resistance and type 2 diabetes are associated with cognitive decline and increased risk for Alzheimers disease (AD). Relatively few studies have assessed the impact of metabolic dysfunction on conversion to AD in mild cognitive impairment (MCI), and it is unclear whether glycemic status is associated with clinically relevant measures of cognitive decline and brain structure in MCI. This study used the Alzheimers Disease Neuroimaging Initiative database to examine the relationship of baseline glycemia with conversion to AD and longitudinal clinical, cognitive, and imaging measures of decline. Subjects with MCI (n = 264) with baseline and 2-year Clinical Dementia Rating data available were classified according to American Diabetes Association criteria for fasting glucose at baseline. The groups were normoglycemic (fasting glucose, <100 mg/dL; n = 167) or impaired glycemia (fasting glucose, ≥ 100 mg/dL, n = 97). The impaired glycemia group included individuals with fasting glucose that either reached the American Diabetes Association cut point for impaired fasting glucose or individuals with diagnosed diabetes. Two-year change in Clinical Dementia Rating-Sum of Boxes, cognitive performance testing (global cognition), brain volume (whole-brain and hippocampal volume), fluorodeoxyglucose-positron emission tomography, and conversion to AD were assessed. Subjects with normoglycemia at baseline had less functional (Clinical Dementia Rating-Sum of Boxes) and global cognitive decline over 2 years than subjects with impaired glycemia. Subjects with normoglycemia also lost less whole-brain volume and exhibited lower conversion from MCI to AD. There was no difference in hippocampal volume change or fluorodeoxyglucose-positron emission tomography between groups. These results suggest that baseline glycemia is related to cognitive decline and progression to AD.

Is Alzheimer's disease a systemic disease?

Although Alzheimers disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease-modifying therapies.

Role of the primary somatosensory cortex in motor learning: An rTMS study

Somatosensation is thought to play an important role in skilled motor learning. The present study investigated how healthy adults learn a continuous implicit motor task when somatosensation is altered by 1 Hz repetitive transcranial magnetic stimulation (rTMS) delivered over the primary somatosensory cortex (S1). Twenty-seven right-handed participants enrolled in a two-part experiment. In Experiment 1, we verified that 20 min of 1 Hz rTMS over S1 disrupted cutaneous somatosensation (indexed by two-point discrimination) in the wrist/hand; the impact of 1 Hz rTMS on wrist proprioception (tested by limb-position matching) was variable. Sham rTMS had no effect on either measure. We exploited these effects in Experiment 2 by pairing either 1 Hz or sham rTMS with practice of a continuous tracking task over two separate sessions on different days. Implicit motor learning was indexed on a third, separate retention test day when no rTMS was delivered. Across practice in Experiment 2, both the 1 Hz and sham rTMS groups showed improved tracking performance; however, 1 Hz rTMS was associated with less accurate tracking and smaller improvements in performance. Importantly, at the no rTMS retention test the effects of altering sensation with stimulation over S1 were still evident in the persistently less accurate tracking behavior of the 1 Hz rTMS group. The current study shows that disruption of somatosensation during task practice impairs the magnitude of change associated with motor learning, perhaps through the development of an inaccurate internal model.

Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease.

Objective: Beyond age, having a family history is the most significant risk factor for Alzheimer disease (AD). This longitudinal brain imaging study examines whether there are differential patterns of regional gray matter atrophy in cognitively healthy elderly subjects with (FH+) and without (FH−) a family history of late-onset AD. Methods: As part of the KU Brain Aging Project, cognitively intact individuals with a maternal history (FHm, n = 11), paternal history (FHp, n = 10), or no parental history of AD (FH−, n = 32) similar in age, gender, education, and Mini-Mental State Examination (MMSE) score received MRI at baseline and 2-year follow-up. A custom voxel-based morphometry processing stream was used to examine regional differences in atrophy between FH groups, controlling for age, gender, and APOE ϵ4 (APOE4) status. We also analyzed APOE4-related atrophy. Results: Cognitively normal FH+ individuals had significantly increased whole-brain gray matter atrophy and CSF expansion compared to FH−. When FH+ groups were split, only FHm was associated with longitudinal measures of brain change. Moreover, our voxel-based analysis revealed that FHm subjects had significantly greater atrophy in the precuneus and parahippocampus/hippocampus regions compared to FH− and FHp subjects, independent of APOE4 status, gender, and age. Individuals with an ε4 allele had more regional atrophy in the frontal cortex compared to ε4 noncarriers. Conclusions: We conclude that FHm individuals without dementia have progressive gray matter volume reductions in select AD-vulnerable brain regions, specifically the precuneus and parahippocampal gyrus. These data complement and extend reports of regional cerebral metabolic differences and increases in amyloid-β burden in FHm subjects, which may be related to a higher risk for developing AD.

Alzheimer disease biomarkers are associated with body mass index

Objective: Both low and high body mass index (BMI) has been associated with cognitive impairment and dementia risk, including Alzheimer disease (AD). We examined the relationship of BMI with potential underlying biological substrates for cognitive impairment. Methods: We analyzed cross-sectional data from participants enrolled in the Alzheimers Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n = 101) or CSF analyses (n = 405) for β-amyloid peptide (Aβ) and total tau. We assessed the relationship of CSF biomarkers and global PiB uptake with BMI using linear regression controlling for age and sex. We also assessed BMI differences between those who were and were not considered biomarker positive. Finally, we assessed BMI change over 2 years in relationship to AD biomarkers. Results: No dementia, mild cognitive impairment (MCI), and AD groups were not different in age, education, or BMI. In the overall sample, CSF Aβ (β = 0.181, p < 0.001), tau (β = −0.179, p < 0.001), tau/Aβ ratio (β = −0.180, p < 0.001), and global PiB uptake (β = −0.272, p = 0.005) were associated with BMI, with markers of increased AD burden associated with lower BMI. Fewer overweight individuals had biomarker levels indicative of pathophysiology (p < 0.01). These relationships were strongest in the MCI and no dementia groups. Conclusions: The presence and burden of in vivo biomarkers of cerebral amyloid and tau are associated with lower BMI in cognitively normal and MCI individuals. This supports previous findings of systemic change in the earliest phases of the disease. Further, MCI in those who are overweight may be more likely to result from heterogeneous pathophysiology.

Motor learning after stroke: Is skill acquisition a prerequisite for contralesional neuroplastic change?

Limited data directly characterize the dynamic evolution of brain activity associated with motor learning after stroke. The current study considered whether sequence-specific motor skill learning or increasing non-specific use of the hemiparetic upper extremity drive functional reorganization of the contralesional motor cortex after stroke. Eighteen individuals with chronic middle cerebral artery stroke practiced one of two novel motor tasks; a retention test occurred on a separate fifth day. Using the hemiparetic arm, participants performed a serial targeting task during two functional MRI scans (day one and retention). Participants were randomized into either a task-specific group, who completed three additional sessions of serial targeting practice, or a general arm use group, who underwent three training sessions of increased but non-task specific use of the hemiparetic arm. Both groups performed a repeated sequence of responses that may be learned, and random sequences of movement, which cannot be learned. Change in reaction and movement time for the repeated sequence indexed motor learning; shifts in the laterality index (LI) within primary motor cortex (M1) for repeated and random sequences illustrated training effects on brain activity. Task-specific practice of the repeated sequence facilitated motor learning and shifted the LI for M1 as shown by a reduced volume of contralesional cortical activity. Random sequence performance did not stimulate motor learning or alter the LI within the task-specific training group. Further, between-group comparisons showed that increasing general arm use did not induce motor learning or alter brain activity for either random or repeated sequences. Motor skill learning of a repeated sequence altered cortical activation by inducing a more normal, contralateral pattern of brain activation. Our data suggest that task-specific motor learning may be an important stimulant for neuroplastic change and can remediate maladaptive patterns of brain activity after stroke.

Cardiorespiratory fitness is associated with atrophy in Alzheimer's and aging over 2 years.

We sought to describe change in cardiorespiratory (CR) fitness over 2 years in those with early-stage Alzheimers disease (AD) and nondemented aging and assess the relationship of CR fitness with cognitive decline, brain atrophy, and dementia progression. Individuals with early-stage AD (n = 37) and without dementia (n = 53) attended clinical evaluations, cognitive and exercise tests, and magnetic resonance imaging (MRI) at baseline and 2 years later. CR fitness was lower in those with AD over the study period. Lower baseline CR fitness was associated with progression of dementia severity in AD. Declining CR fitness over 2 years was associated with brain atrophy in AD, especially in the parahippocampus. In nondemented participants, there was a trend for lower baseline fitness to be related to cognitive decline. Both lower baseline CR fitness and declining CR fitness over 2 years were associated with regional brain atrophy. We conclude that CR fitness is chronically reduced in those with AD. Further, in those with AD, CR fitness is associated with progression of dementia severity and brain atrophy in AD, suggesting a link between progression of dementia severity and cardiorespiratory health.