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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.
73 Sex Differences in Verbal Memory and Alzheimer’s Disease Biomarkers in Clinically Normal Older Adults: Role of SNAP-25 Genetics
- Rowan Saloner, Emily W Paolillo, Kevin J Wojta, Corrina Fonseca, Eva Q Gontrum, Argentina Lario-Lago, Gil D Rabinovici, Jennifer S Yokoyama, Jessica E Rexach, 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. 377-378
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Objective:
Females outperform males on verbal memory tests across the lifespan. Females also exhibit greater Alzheimer’s disease (AD) pathology at preclinical stages and faster atrophy and memory decline during disease progression. Synaptic factors influence the accumulation of AD proteins and may underpin cognitive resilience against AD, though their role in sex-related cognitive and brain aging is unknown. We tested interactive effects of sex and genetic variation in SNAP-25, which encodes a presynaptic protein that is dysregulated in AD, on cognition and AD-related biomarkers in cognitively unimpaired older adults.
Participants and Methods:Participants included a discovery cohort of 311 cognitively unimpaired older adults (age mean [range]=70 [44-100]; 56% female; education mean=17.3 years; 24% APOE-e4+), and an independent, demographically-comparable replication cohort of 82 cognitively unimpaired older adults. All participants completed neurological examination, informant interview (CDR=0), neuropsychological testing, and blood draw. Participants were genotyped for the SNAP-25 rs105132 (T→C) single-nucleotide polymorphism via Sequenom (discovery cohort) or Omni 2.5M (replication cohort). In vitro models show the C-allele is associated with increased SNAP-25 expression compared to T/T genotype. A subset of the discovery cohort completed structural MRI (n=237) and florbetapir Aβ-PET (n=97). Regression analyses across cohorts examined the interaction of sex and SNAP-25 genotype (T/T homozygotes [53% prevalence] vs. C-carriers [47% prevalence]) on cognitive z-scores (verbal memory, visual memory, executive function, language), adjusting for age, education, APOE-e4, and APOE-e4 x sex. Discovery cohort models also examined sex-dependent effects of SNAP-25 on temporal lobe volumes and Aβ-PET positivity.
Results:SNAP-25 T/T vs. C-carriers did not differ on demographics or APOE-e4 status across cohorts or within sexes. Sex interacted with SNAP-25 to predict verbal memory (p=.024) and language (p=.008) in the discovery cohort, with similar verbal memory differences observed in the replication cohort. In sex-stratified analyses, C-carriers exhibited better verbal memory than T/T carriers among females (d range: 0.41 to 0.64, p range: .008 to .046), but not males (d range: 0.03 to 0.12, p range: .499 to .924). In SNAP-25-stratified analyses, female verbal memory advantages were larger among C-carriers (d range: 0.74 to 0.89, p range: <.001 to .034) than T/T (d range: 0.13 to 0.36, p range: .022 to .682). Sex also interacted with SNAP-25 to predict Aβ-PET positivity (p=.046) such that female C-carriers exhibited the lowest prevalence of Aβ-PET positivity (13%) compared to other groups (23% to 35%). C-carriers exhibited larger temporal lobe volumes across sex, yet this effect only reached statistical significance among females (females: d=0.41, p=.018; males: d=0.26, p=.179). In post-hoc analyses, larger temporal lobe volumes were selectively associated with better verbal memory in female C-carriers (β=0.36, p=.026; other groups: |βs|<0.10, ps>.538).
Conclusions:Among clinically normal older adults, we demonstrate female-specific advantages of carrying the SNAP-25 rs105132 C-allele across cognitive, neural, and molecular markers of AD. The rs105132 C-allele putatively reflects higher endogenous levels of SNAP-25. Our findings suggest a female-specific pathway of cognitive and neural resistance, whereby higher genetically-driven expression of SNAP-25 may reduce likelihood of amyloid plaque formation and support verbal memory, possibly through fortification of temporal lobe structure.
A numerical investigation of the Stokes boundary layer in the turbulent regime
- S. Salon, V. Armenio, A. Crise
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- Journal:
- Journal of Fluid Mechanics / Volume 570 / 10 January 2007
- Published online by Cambridge University Press:
- 14 October 2021, pp. 253-296
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The Stokes boundary layer in the turbulent regime is investigated by using large-eddy simulations (LES). The Reynolds number, based on the thickness of the Stokes boundary layer, is set equal to Reδ = 1790, which corresponds to test 8 of the experimental study of Jensen et al. (J. Fluid Mech. vol. 206, 1989, p. 265).
Our results corroborate and extend the findings of relevant experimental studies: the alternating phases of acceleration and deceleration are correctly reproduced, as is the sharp transition to turbulence, observable at a phase angle between 30° and 45°, and its maximum between 90° and 105°. Overall, a very good agreement was found between our LES first- and second-order turbulent statistics and those of Jensen et al. (1989). Some discrepancies were observed when comparing turbulent intensities in the phases of the cycle characterized by a low level of turbulent activity.
In the central part of the cycle, namely from the mid acceleration to the late deceleration phases, fully developed equilibrium turbulence is present in the flow field, and the boundary layer resembles that of a canonical, steady, wall-bounded flow. In those phases characterized by low turbulent activity, two separate regions can be detected in the flow field: a near-wall one, where the vertical turbulent kinetic energy varies much more rapidly than the other two components, thus giving rise to the formation of horizontal, pancake-like turbulence; and an outer region where both vertical and spanwise velocity fluctuations vary much faster than the streamwise ones, hence producing cigar-like turbulence.
As a side result, the range of application of the plane-averaged dynamic mixed model was assessed based on the qualitative behaviour over the cycle of a significant parameter representing the ratio between a turbulent time scale and a free-stream time scale associated with the oscillatory motion.
P01.157 Dream as an index of psychic modifications
- A. Salone, G. Ruggeri, M. Sarchiapone, S. De Risio
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- European Psychiatry / Volume 15 / Issue S2 / October 2000
- Published online by Cambridge University Press:
- 16 April 2020, p. 362s
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A numerical investigation of the turbulent Stokes–Ekman bottom boundary layer
- S. Salon, V. Armenio
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- Journal:
- Journal of Fluid Mechanics / Volume 684 / 10 October 2011
- Published online by Cambridge University Press:
- 06 September 2011, pp. 316-352
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In the present paper turbulent mixing in the Stokes–Ekman bottom boundary layer is investigated analytically and by wall-resolving large-eddy simulations (LES). The analytical solution shows that when the Rossby number oscillation and rotation interact with each other, this gives rise to a thickening of the boundary layer compared with the purely oscillating or the purely rotating case. The solution also shows the presence of elliptical patterns developing on the horizontal planes that shrink when approaching the low latitudes. In the turbulent regime, a LES was applied for an east–west tidal current, considered at three different latitudes in the Northern Hemisphere, namely, the polar case, the mid-latitude case () and the quasi-equatorial case (). The Reynolds number of the simulation, based on the viscous penetration depth and the frequency of the purely oscillatory flow, was set equal to . The analysis suggests that rotation has two main effects on the flow field: in the polar case, rotation tends to delay the cyclic re-transition to turbulence and to narrow the turbulent phases of the cycle. Also, rotation suppresses vertical fluctuations of velocity and redistributes energy from the streamwise direction to the spanwise direction. It is noteworthy that the high-latitude effect makes the turbulent field substantially different from the reference Stokes boundary layer case, whereas the low-latitude effects appear to be of secondary importance, owing to the weakness of the rotation rate. Consequently, the study shows that the Stokes boundary layer may be representative of the oceanic bottom boundary layer in the low-latitude cases ( cases in our simulations). Conversely, it cannot be considered as archetypal of the oceanic boundary layer at high latitudes ( case of our study), where the vertical background vorticity profoundly modifies the turbulent field.