Angela Luedke

Use of Physical and Intellectual Activities and Socialization in the Management of Cognitive Decline of Aging and in Dementia: A Review

Lifestyle nonpharmacological interventions can have a deep effect on cognitive aging. We have reviewed the available literature on the effectiveness of physical activity, intellectual stimulation, and socialization on the incidence of dementia and on the course of dementia itself. Even though physical activity appears to be beneficial in both delaying dementia onset and in the course of the disease, more research is needed before intellectual stimulation and socialization can be considered as treatments and prevention of the disease. Through our paper, we found that all three nonpharmacological treatments provide benefits to cognition and overall well-being in patients with age-related cognitive impairments. These interventions may be beneficial in the management of dementia.

Effects of reaction time variability and age on brain activity during Stroop task performance

Variability in reaction time during task performance may reflect fluctuations in attention and cause reduced performance in goal-directed tasks, yet it is unclear whether the mechanisms behind this phenomenon change with age. Using fMRI, we tested young and cognitively healthy older adults with the Stroop task to determine whether aging affects the neural mechanisms underlying intra-individual reaction time variability. We found significant between-group differences in BOLD activity modulated by reaction time. In older adults, longer reaction times were associated with greater activity in frontoparietal attentional areas, while in younger adults longer reaction times were associated with greater activity in default mode network areas. Our results suggest that the neural correlates of reaction time variability change with healthy aging, reinforcing the concept of functional plasticity to maintain high cognitive function throughout the lifespan.

Cognitive Function and 3-Tesla Magnetic Resonance Imaging Tractography of White Matter Hyperintensities in Elderly Persons

Background/Aims: This study used 3-Tesla magnetic resonance imaging (MRI) tractography to determine if there was an association between tracts crossing white matter hyperintensities (WMH) and cognitive function in elderly persons. Methods: Brain T2-weighted fluid-attenuated inversion recovery (FLAIR) and diffusion tensor MRI scans were acquired in participants above the age of 60 years. Twenty-six persons had WMH identified on T2 FLAIR scans. They completed a battery of neuropsychological tests and were classified as normal controls (n = 15) or with Alzheimers dementia (n = 11). Tractography was generated by the Fiber Assignment by Continuous Tracking method. All tracts that crossed WMH were segmented. The average fractional anisotropy and average mean diffusivity of these tracts were quantified. We studied the association between cognitive test scores with the average mean diffusivity and average fractional anisotropy of tracts while controlling for age, total WMH volume and diagnosis. Results: An increased mean diffusivity of tracts crossing WMH was associated with worse performance on the Wechsler Memory Scale-III Longest Span Forward (p = 0.02). There was no association between the fractional anisotropy of tracts and performance on cognitive testing. Conclusion: The mean diffusivity of tracts crossing WMH measured by tractography is a novel correlate of performance on the Wechsler Memory Scale-III Longest Span Forward in elderly persons.

Super-Resolution Structure of DNA Significantly Differs in Buccal Cells of Controls and Alzheimer's Patients†

The advent of super‐resolution microscopy allowed for new insights into cellular and physiological processes of normal and diseased cells. In this study, we report for the first time on the super‐resolved DNA structure of buccal cells from patients with Alzheimers disease (AD) versus age‐ and gender‐matched healthy, non‐caregiver controls. In this super‐resolution study cohort of 74 participants, buccal cells were collected and their spatial DNA organization in the nucleus examined by 3D Structured Illumination Microscopy (3D‐SIM). Quantitation of the super‐resolution DNA structure revealed that the nuclear super‐resolution DNA structure of individuals with AD significantly differs from that of their controls (p < 0.05) with an overall increase in the measured DNA‐free/poor spaces. This represents a significant increase in the interchromatin compartment. We also find that the DNA structure of AD significantly differs in mild, moderate, and severe disease with respect to the DNA‐containing and DNA‐free/poor spaces. We conclude that whole genome remodeling is a feature of buccal cells in AD.

Quantitative 3D Telomeric Imaging of Buccal Cells Reveals Alzheimer’s Disease-Specific Signatures

This study validates and expands on our previous work that assessed three-dimensional (3D) nuclear telomere profiling in buccal cells of Alzheimer’s disease (AD) patients and non-AD controls (Mathur et al., J Alzheimers Dis 39, 35–48, 2014). While the previous study used age- and gender-matched caregiver controls, the current study consented a new cohort of 44 age- and gender-matched healthy non-caregiver controls and 44 AD study participants. 3D telomeric profiles of buccal cells of AD patients and their non-AD controls were examined with participant information blinded to the analysis. In agreement with our previous study, we demonstrate that 3D telomeric profiles allow for the distinction between AD and non-AD individuals. This validation cohort provides an indication that the total number of 3D telomeric signals and their telomere lengths may be a suitable biomarker to differentiate between AD and non-AD and between mild, moderate, and severe AD. Further studies with larger sample sizes are required to move this technology further toward the clinic.

Altered Superficial White Matter on Tractography MRI in Alzheimer's Disease.

Background/Aims: Superficial white matter provides extensive cortico-cortical connections. This tractography study aimed to assess the diffusion characteristics of superficial white matter tracts in Alzheimers disease. Methods: Diffusion tensor 3T magnetic resonance imaging scans were acquired in 24 controls and 16 participants with Alzheimers disease. Neuropsychological test scores were available in some participants. Tractography was performed by the Fiber Assignment by Continuous Tracking (FACT) method. The superficial white matter was manually segmented and divided into frontal, parietal, temporal and occipital lobes. The mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AxD) and fractional anisotropy (FA) of these tracts were compared between controls and participants with Alzheimers disease and correlated with available cognitive tests while adjusting for age and white matter hyperintensity volume. Results: Alzheimers disease was associated with increased MD (p = 0.0011), increased RD (p = 0.0019) and increased AxD (p = 0.0017) in temporal superficial white matter. In controls, superficial white matter was associated with the performance on the Montreal Cognitive Assessment, Stroop and Trail Making Test B tests, whereas in Alzheimers disease patients, it was not associated with the performance on cognitive tests. Conclusion: Temporal lobe superficial white matter appears to be disrupted in Alzheimers disease.

Tractography at 3T MRI of Corpus Callosum Tracts Crossing White Matter Hyperintensities

BACKGROUND AND PURPOSE: The impact of white matter hyperintensities on the diffusion characteristics of crossing tracts is unclear. This study used quantitative tractography at 3T MR imaging to compare, in the same individuals, the diffusion characteristics of corpus callosum tracts that crossed white matter hyperintensities with the diffusion characteristics of corpus callosum tracts that did not pass through white matter hyperintensities. MATERIALS AND METHODS: Brain T2 fluid-attenuated inversion recovery–weighted and diffusion tensor 3T MR imaging scans were acquired in 24 individuals with white matter hyperintensities. Tractography data were generated by the Fiber Assignment by Continuous Tracking method. White matter hyperintensities and corpus callosum tracts were manually segmented. In the corpus callosum, the fractional anisotropy, radial diffusivity, and mean diffusivity of tracts crossing white matter hyperintensities were compared with the fractional anisotropy, radial diffusivity, and mean diffusivity of tracts that did not cross white matter hyperintensities. The cingulum, long association fibers, corticospinal/bulbar tracts, and thalamic projection fibers were included for comparison. RESULTS: Within the corpus callosum, tracts that crossed white matter hyperintensities had decreased fractional anisotropy compared with tracts that did not pass through white matter hyperintensities (P = .002). Within the cingulum, tracts that crossed white matter hyperintensities had increased radial diffusivity compared with tracts that did not pass through white matter hyperintensities (P = .001). CONCLUSIONS: In the corpus callosum and cingulum, tracts had worse diffusion characteristics when they crossed white matter hyperintensities. These results support a role for white matter hyperintensities in the disruption of crossing tracts.

ASSOCIATIONS BETWEEN QUANTITATIVE TRACTOGRAPHY AT 3T MRI AND COGNITIVE FUNCTION IN ALZHEIMER’S DISEASE

was apparent as a single focal spot in all but 2 MCI and 2 AD patients who displayed two or more spots bilaterally. No enhancement was detected on pre-contrast FLAIR images. Leptomeningeal enhancement was associated with (non-lacunar) cerebral and/or cerebellar ischaemic stroke presence (p1⁄40.029), and marginally with white matter hyperintensity score (p1⁄40.083). The stroke location did not correspond to the site of BBB leakage. No associations between leptomeningeal enhancement and other markers of cerebrovascular damage were found. Conclusions: Post-contrast leptomeningeal enhancement on FLAIR images is prevalent in MCI and AD and may serve as a new marker for subtle BBB leakage. This type of BBB damage may be associated with ischaemic and/or inflammatory processes and possibly relates to cortical atrophy and cognitive decline. Future longitudinal MRI studies in larger samples and with post-mortem histology are needed to reveal its role in the onset and progression of dementia.

COGNITIVE FUNCTION AND TRACTOGRAPHY OF WHITE MATTER TRACTS CROSSING HYPERINTENSITIES IN ELDERLY PERSONS

ipsilateral hippocampus, frontal and temporal cortices (Figure 1) . Conclusions: WM connectivity in dementia patients was regionally reduced in comparison to MCI patients. Such structural connectivity declines possibly reflects a higher magnitude of microstructural WM abnormalities in dementia patients. WM tract alterations might be associated with language, attention, and working memory performance and relate to key clinical features of AD-related cognitive decline.

Quantitative tractography of fibers crossing white matter hyperintensities

Background: Angiotensin II type 2 (AT 2) receptor activation has been reported to play a role in the cognitive function, although its detailed mechanisms are not fully understood. Compound 21 (C21) has become available to use as a direct AT 2 receptor agonist. Therefore, we examined the possibility that direct AT 2 receptor stimulation by C21 could prevent cognitive decline associated with hypo-perfusion in the brain. Methods:We employed bilateral common carotid artery stenosis model (BCAS) in mice by micro coil technique as model of vascular dementia. The Morris water maze task was performed 6 weeks after BCAS operation. C21 (10 m g/kg/day) was administrated daily by intraperitoneal injection 1 week before BCAS until Morris water maze task.C erebral blood flow (CBF) was analyzed by laser speckle flowmetry and i nflammatory cytokine levels were assessed by quantitative RT-PCR. Total protein was prepared from hippocampus and cortex, and phosphorylation of NMDA receptor (Ty 1472) was determined by immunoblot analysis. Results: The mice showed a significant impairment of spatial learning activity after BCAS and this impairment was significantly attenuated by C21 treatment without influencing blood pressure. Spatial learning ability was severely impaired in AT 2 receptor deficient mice and preventive effect of C21 on cognitive decline was not observed in this mouse strain. CBF in BCAS-treated group was significantly decreased and this decrease was blunted by the treatment with C21. TNFa and MCP-1 mRNA expressions were significantly increased after BCAS, but attenuated by treatment with C21. To further examine the role of direct stimulation of AT2 receptor in cognitive function, we focused on NMDA receptor, which would be influenced by AT 2 receptor activation. After BCAS, phosphorylation of NMDA receptor with water maze task was impaired and the administration of C21 attenuated the decrease in NMDA receptor phosphorylation in BCAS-treated mice. Conclusions: These findings indicate that direct AT 2 stimulation by C21 prevents ischemic vascular dementia induced by hypoperfusion at least in part due to increase in CBF, reduction of inflammation and activation of NMDA receptor. This study principally could offer the possibility to use direct AT 2 receptor stimulation by C21 as a therapeutic tool.