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 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).

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).

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.

Aging is associated with changes in cortical excitability which may affect motor learning and cognitive function via selective modulation of gamma aminobutyric acid (GABA). Previous studies using magnetic resonance spectroscopy (MRS) to measure GABA in older adults found that increased baseline GABA levels in the sensorimotor cortex (M1S1) were associated with better motor performance. GABA levels in M1S1 have tended to decrease during the execution of a repeated motor sequence. The dynamic change in GABA density in M1S1 in older adults is currently unknown and represents a critical gap in our understanding of how it could impact motor learning and cognitive performance. As such, the purpose of the current study is to quantify changes in cortical GABA during motor learning in the aging brain and examine those changes in relation to motor and cognitive performance. We hypothesize that older adults with greater dynamic range in M1S1 GABA levels will display more efficient motor learning and increased cognitive scores.

We report on a total of 18 healthy older adults aged 64 to 80 years (M = 70.44, SD = 4.99, 12 females). Using MRS at 3T, we measured changes in GABA concentration in M1S1 at rest, during an eight or 12 finger-movement motor entrainment task, and during a recall task. Gannett was used for GABA quantification relative to water. Change in GABA was calculated by subtracting Rest1 GABA from Recall1 GABA. In a separate session, participants completed a battery of cognitive assessments. We computed linear regressions to examine the relationship between dynamic GABA change, recall accuracy of the motor task and cognitive performance.

In relation to motor performance, we found that both greater baseline (Rest1) GABA levels and greater dynamic change in GABA significantly predicted better recall accuracy on the motor task. For cognitive performance, we found that greater dynamic change in GABA significantly predicted better performance on Word Reading in the Stroop Color and Word Test and Delayed Recall in the Hopkins Verbal Learning Test (HVLT). No additional significant relationships were found for the remaining cognitive assessments.

Older adults who were able to accurately perform the task had a greater dynamic change in GABA and increased baseline GABA levels. These adults with greater dynamic change also had better cognitive performance on HVLT Delay and Stroop Word Reading. This modulation of GABA associated with better performance could be related to changes in neuroplasticity. Although these results are in the preliminary stages, they point to a greater understanding of aging related changes in motor and cognitive performance. We’ll continue to explore the relationship between sensory motor performance and changes in GABA concentration as a potential predictor for cognitive performance and future rehabilitation.

Attention is the backbone of cognitive systems and is requisite for many cognitive processes vital to everyday functioning, including memory, problem solving, and the cognitive control of behavior. Attention is commonly impaired following traumatic brain injury and is a critical focus of rehabilitation efforts. The development of reliable methods to assess rehabilitation-related changes are paramount. The Attention Network Test (ANT) has been used previously to identify 3 independent, yet interactive attention networks—alerting, orienting, and executive control (EC). We examined the behavioral and neurophysiological robustness and temporal stability of these networks across multiple sessions to assess the ANT’s potential utility as an effective measure of change during attention rehabilitative interventions.

15 healthy young adults completed 4 sessions of the ANT (1 session/7-day period). ANT networks were assessed within the task by contrasting opposing stimulus conditions: cued vs. non-cued trials probed alerting, valid vs. invalid spatial cues probed orienting, and congruent vs. incongruent targets probed EC. Differences in median correct-trial reaction times (RTs) and error rates (ERs) between the condition pairs were assessed to determine attention network scores; robustness of networks effects, as determined by one-sample t-tests at each session, against a mean of 0, determining the presence of significant network effects at each session. Sixty-four-channel electroencephalography (EEG) data were acquired concurrently and processed using Matlab to create condition-related event-related potentials (ERPs)—particularly the cue- and probe-related P1, N1, and P3 deflection amplitudes, measured by using signed-area calculation in regions of interest (ROIs) determined by observation of spherical-spline voltages. This enabled us to examine the robustness of cue- and probe-attention-network ERPs.

All three attention networks showed robust effects. However, only the EC RT and ER network scores remained significantly robust [t(14)s>13.9,ps<.001] across all sessions, indicating that EC is robust in the face of repeated exposure. Session 1 showed the greatest EC-RT robustness effect which became smaller during the subsequent sessions per ANOVAs on Session x Congruency [F(3,42)=10.21,p<.0001], reflecting persistence despite practice effects. RT robustness of the other networks varied across sessions. Alerting and EC ERs were similarly robust across all 4 sessions, but were more variable for the orienting network. ERP results: The cue-locked P1-orienting (valid vs. invalid) was generally larger to valid- than invalid-cues, but the robustness across sessions was variable (significant in only sessions 1 and 4 [t(14)s>2.13,ps<.04], as reflected in a significant main effect of session [p=.0042]. Next, target-locked EC P3s were generally smaller to congruent than incongruent targets [F(1,14)=9.40,p=.0084], showing robust effects only in sessions 3 and 4 [ps<.005].

The EC network RT and ER scores were consistently robust across all sessions, suggesting that this network may be less vulnerable to practice effects across session than the other networks and may be the most reliable probe of attentional rehabilitation. ERP measures were more variable across attention networks with respect to robustness. Behavioral measures of EC-network may be most reliable for assessing progress related to attentional-rehabilitation efforts.

Numerous investigations have documented that age-related changes in the integrity of the corpus callosum are associated with age-related decline in the interhemispheric transfer of information. Conversely, there is accumulating evidence for more efficient white matter organization of the corpus callosum in individuals with extensive musical training. However, the relationship between making music and accuracy in interhemispheric transfer remains poorly explored.

To test the hypothesis that musicians show enhanced functional connectivity between the two hemispheres, 65 professional musicians (aged 56–90 years) and 65 age- and sex-matched non-musicians performed the fingertip cross-localization test. In this task, subjects must respond to a tactile stimulus presented to one hand using the ipsilateral (intra-hemispheric test) or contralateral (inter-hemispheric test) hand. Because the transfer of information from one hemisphere to another may imply a loss of accuracy, the value of the difference between the intrahemispheric and interhemispheric tests can be utilized as a reliable measure of the effectiveness of hemispheric interactions.

Older professional musicians show significantly greater accuracy in tactile interhemispheric transfer than non-musicians who suffer from age-related decline.

Musicians have more efficient interhemispheric communication than age-matched non-musicians. This finding is in keeping with studies showing that individuals with extensive musical training have a larger corpus callosum. The results are discussed in relation to relevant data suggesting that music positively influences aging brain plasticity.

Attention bias modification (ABM) training has been suggested to effectively reduce depressive symptoms, and may be useful in the prevention of the illness in individuals with subthreshold symptoms, yet little is known about the spontaneous brain activity changes associated with ABM training.

Resting-state functional MRI was used to explore the effects of ABM training on subthreshold depression (SubD) and corresponding spontaneous brain activity changes. Participants were 41 young women with SubD and 26 matched non-depressed controls. Participants with SubD were randomized to receive either ABM or placebo training during 28 sessions across 4 weeks. Non-depressed controls were assessed before training only. Attentional bias, depressive severity, and spontaneous brain activity before and after training were assessed in both training groups.

Findings revealed that compared to active control training, ABM training significantly decreased depression symptoms, and increased attention for positive stimuli. Resting-state data found that ABM training significantly reduced amplitude of low-frequency fluctuations (ALFF) of the right anterior insula (AI) and right middle frontal gyrus which showed greater ALFF than non-depressed controls before training; Functional connectivity strength between right AI and the right frontoinsular and right supramarginal gyrus were significantly decreased after training within the ABM group; moreover, the improvement of depression symptoms following ABM significantly correlated with the connectivity strength reductions between right AI and right frontoinsular and right supramarginal gyrus.

These results suggest that ABM has the potential to reshape the abnormal patterns of spontaneous brain activity in relevant neural circuits associated with depression.