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93 Impact of Cardiovascular Risk on Cognitive and Brain Aging in Autosomal Dominant Frontotemporal Dementia
- Anna M VandeBunte, Emily W Paolillo, Hyunwoo Lee, Ging-Yuek Robin Hsiung, Adam Staffaroni, Shannon Y Lee, Carmela Tartaglia, Hilary Heur, Joel H Kramer, Brad Boeve, Adam Boxer, Howie Rosen, Kaitlin B Casaletto
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 193-194
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Objective:
Poor cardiovascular health occurs with age and is associated with increased dementia risk, yet its impact on frontotemporal lobar degeneration (FTLD) and autosomal dominant neurodegenerative disease has not been well established. Examining cardiovascular risk in a population with high genetic vulnerability provides an opportunity to assess the impact of lifestyle factors on brain health outcomes. In the current study, we examined whether systemic vascular burden associates with accelerated cognitive and brain aging outcomes in genetic FTLD.
Participants and Methods:166 adults with autosomal dominant FTLD (C9orf72 n= 97; GRN n= 34; MAPT n= 35; 54% female; Mage = 47.9; Meducation = 15.6 years) enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Longitudinal FTD study (ALLFTD) were included. Participants completed neuroimaging and were screened for cardiovascular risk and functional impairment during a comprehensive neurobehavioral and medical interview. A vascular burden score (VBS) was created by summing vascular risk factors (VRS) [diabetes, hypertension, hyperlipidemia, and sleep apnea] and vascular diseases (VDS) [cerebrovascular disease (e.g., TIA, CVA), cardiac arrhythmia (e.g., atrial fibrillation, pacemaker, defibrillator), coronary artery disease (e.g., myocardial infarction, cardiac bypass, stent), and congestive heart failure] following a previously developed composite (range 0 to 8). We examined the interaction between each vascular health metric (VBS, VDS, VRS) and age (vascular health*age) on clinical severity (CDR plus NACC FTLD-SB), and white matter hyperintensity (WMH) volume outcomes, adjusting for age and sex. Vascular risk, disease, and overall burden scores were examined in separate models.
Results:There was a statistically significant interaction between total VBS and age on both clinical severity (ß=0.20, p=0.044) and WMH burden (ß=0.20, p=0.032). Mutation carriers with higher vascular burden evidenced worse clinical and WMH outcomes for their age. When breaking down the vascular burden score into (separate) vascular risk (VRS) and vascular disease (VDS) scores, the interaction between age and VRS remained significant only for WMH (ß=0.26, p=0.009), but not clinical severity (ß=0.04, p=0.685). On the other hand, the interaction between VDS and age remained significant only for clinical severity (ß=0.20, p=0.041) but not WMH (ß=0.17, p=0.066).
Conclusions:Our results demonstrate that systemic vascular burden is associated with an “accelerated aging” pattern on clinical and white matter outcomes in autosomal dominant FTLD. Specifically, mutation carriers with greater vascular burden show poorer neurobehavioral outcomes for their chronological age. When separating vascular risk from disease, risk was associated with higher age-related WMH burden, whereas disease was associated with poorer age-related clinical severity of mutation carriers. This pattern suggests preferential brain-related effects of vascular risk factors, while the functional impact of such factors may be more closely aligned with fulminant vascular disease. Our results suggest cardiovascular health may be an important, potentially modifiable risk factor to help mitigate the cognitive and behavioral disturbances associated with having a pathogenic variant of autosomal dominant FTLD. Future studies should continue to examine the neuropathological processes underlying the impact of cardiovascular risk in FTLD to inform more precise recommendations, particularly as it relates to lifestyle interventions.
5 Rejuvenating Blood Factor TIMP2 Relates to Physical Activity and Cognitive Functioning in Older Adults on The Alzheimer’s Disease Continuum
- Emily W Paolillo, Shannon Y Lee, Anna M Vandebunte, Rowan Saloner, Leslie S Gaynor, Joel H Kramer, Kaitlin B Casaletto
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 106-107
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Objective:
Tissue inhibitor of metalloproteinases 2 (TIMP2) is produced peripherally, crosses the blood-brain barrier, and improves synaptic plasticity and hippocampal-dependent cognition in aged mice; however, the role of TIMP2 in human cognitive aging is unclear. We examined associations of circulating TIMP2 levels in blood with a known plasticity-inducing behavior, physical activity, and cognitive functioning among older adults along the Alzheimer’s disease continuum.
Participants and Methods:Participants included 84 community-dwelling older adults (meanage = 78.8; 57% female; 82% cognitively normal; 14% MCI; 4% mild dementia; 35% PET Aß+) enrolled in the UC San Francisco Memory and Aging Center. All participants completed 30 days of observational FitbitTM monitoring to quantify physical activity (average daily steps), as well as a comprehensive in-person visit including blood draw (proteins assayed on SOMAscan platform), [18F]AV-45 positron emission tomography (PET) to quantify brain beta-amyloid (centiloids), and neuropsychological assessment. Composite cognitive z-scores were calculated for memory (California Verbal Learning Test-II [CVLT-II] and Benson Figure Recall), semantic processing (animal fluency and Boston Naming Test), and executive functioning (digits backwards span, Stroop inhibition, modified trail making test, lexical fluency, and design fluency). Multiple linear regression examined TIMP2 as a function of physical activity, covarying for age and PET centiloids. Additional regression models separately examined cognitive z-scores as a function of TIMP2, covarying for age, sex, education, PET centiloids, and body mass index (BMI).
Results:TIMP2 was not significantly correlated with age, sex, education, or PET centiloids (ps > 0.05); however, TIMP2 was negatively correlated with BMI (r = -0.23, p = 0.036). Greater average daily steps related to higher levels of TIMP2 (b = 0.30, 95%CI = 0.04-0.55, p = 0.022). TIMP2 also related to better semantic processing (b = 0.28, 95%CI = 0.04-0.51, p = 0.021) and executive functioning (b = 0.26, 95%CI = 0.03-0.49, p = 0.028). TIMP2 did not significantly relate to memory (p > 0.05).
Conclusions:Greater physical activity was associated with higher concentrations of blood factor TIMP2, which in turn related to better cognitive functioning independent of Alzheimer’s disease pathology burden. These results support previous mouse models by broadly replicating relationships between TIMP2 and cognition in humans, while also uniquely demonstrating an association between TIMP2 and physical activity, a modifiable protective factor in both typical and diseased cognitive aging. Our domain-specific results, however, suggest that benefits of TIMP2 in humans may involve a broader neuroanatomical network than the hippocampal-specific effects previously shown in mice. Although exact mechanisms of TIMP2 need further examination, TIMP2 is known to be enriched in human umbilical cord plasma, has been shown to be involved in cell-growth promoting activities, and may relate to increased neural plasticity in older age. Further examination of TIMP2 and other novel blood-based proteins as potential therapeutic targets for improved cognitive aging, including in the presence of Alzheimer’s disease, is warranted.
6 The Moderating Role of Physical Activity on Hippocampal Iron Deposition and Memory Outcomes in Typically Aging Older Adults
- Shannon Y Lee, Emily W Paolillo, Rowan Saloner, Torie Tsuei, Anna VandeBunte, Joel H Kramer, Kaitlin B Casaletto
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 794-795
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Objective:
Quantitative Susceptibility Mapping (QSM) is an MRI-based technique that sensitively measures in-vivo iron deposition via relaxation and magnetic susceptibility of brain tissue. Iron is essential for brain homeostasis, including oxidative metabolism, formation and maintenance of neural networks, and myelin synthesis. While increased levels of iron deposition occur during normal aging, high levels may have detrimental effects. Previous work has linked excessive brain iron accumulation to oxidative stress, beta-amyloid and tau toxicity, neurodegeneration, and cognitive dysfunction, particularly memory loss. Physical activity, on the other hand, correlates with higher synaptic integrity and memory performance, even in the presence of neuropathology. To date, it is unknown how physical activity may affect iron deposition-related cognition changes. We examined the moderating role of physical activity on the relationship between QSM hippocampal iron deposition and verbal memory in typically aging adults.
Participants and Methods:62 cognitively unimpaired older adults from the UCSF Memory and Aging Center (age mean(SD) = 78.34(7.28) years; 56% women; education mean(SD) = 17.94(1.72) years; 85% non-Hispanic White) completed neuropsychological testing and brain MRI during annual research visits, followed by Fitbit™ physical activity monitoring for 30 days. Average total daily steps were aggregated. Participants completed 3T Prisma neuroimaging with QSM, and regional iron deposition levels were quantified. All subjects also underwent diffusion tensor imaging (fractional anisotropy). Verbal memory was assessed via long delay free recall scores from the California Verbal Learning Test II (CVLT-II). Linear regression examined verbal memory as a function of hippocampal QSM (bilateral), physical activity, and their interaction. Models covaried for age, sex, and education. Additional models separately examined left and right hippocampal QSM, as well as subcortical QSM to determine lateralization and specificity of verbal memory effects to hippocampal iron deposition, respectively.
Results:Univariably, higher bilateral hippocampal QSM correlated with worse verbal memory (r= 0.35; p= 0.015). Adjusting for demographics, physical activity moderated the relationship between bilateral hippocampal QSM and verbal memory (ß= 0.41, p= 0.011), such that at higher levels of physical activity, the negative relationship between hippocampal QSM and verbal memory was significantly attenuated. Results persisted when adjusting for DTI integrity of the uncinate fasciculus and fornix white matter tracts. Lateralization models were both significant, suggesting that results were not dominantly driven by either left (ß= 0.34, p= 0.048), or right (ß=0.31, p= 0.035) hippocampal QSM. In contrast, subcortical QSM did not correlate with memory performance (r= 0.13, p > 0.05) or interact with physical activity on verbal memory outcomes (p > 0.05).
Conclusions:Physical activity significantly moderated the negative relationship between hippocampal QSM and verbal memory performance. Higher exercise engagement may buffer the adverse effect of hippocampal iron deposition on memory, potentially through its role in maintenance of myelin and synaptic integrity and/or protecting against other neurotoxic events (e.g., oxidative stress, neuronal cell death). Our results support that physical activity continues to be a modifiable risk factor that may offer a protective role in neurobiological pathways of memory and cognitive decline.