Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Enhancing Innovation and Underlying Neural Mechanisms Via Cognitive Training in Healthy Older Adults

Non-invasive interventions, such as cognitive training (CT) and physical exercise, are gaining momentum as ways to augment both cognitive and brain function throughout life. One of the most fundamental yet little studied aspects of human cognition is innovative thinking, especially in older adults. In this study, we utilize a measure of innovative cognition that examines both the quantity and quality of abstracted interpretations. This randomized pilot trial in cognitively normal adults (56–75 years) compared the effect of cognitive reasoning training (SMART) on innovative cognition as measured by Multiple Interpretations Measure (MIM). We also examined brain changes in relation to MIM using two MRI-based measurement of arterial spin labeling (ASL) to measure cerebral blood flow (CBF) and functional connectivity MRI (fcMRI) to measure default mode and central executive network (CEN) synchrony at rest. Participants (N = 58) were randomized to the CT, physical exercise (physical training, PT) or control (CN) group where CT and PT groups received training for 3 h/week over 12 weeks. They were assessed at baseline-, mid- and post-training using innovative cognition and MRI measures. First, the CT group showed significant gains pre- to post-training on the innovation measure whereas the physical exercise and control groups failed to show significant gains. Next, the CT group showed increased CBF in medial orbitofrontal cortex (mOFC) and bilateral posterior cingulate cortex (PCC), two nodes within the Default Mode Network (DMN) compared to physical exercise and control groups. Last, significant correlations were found between innovation performance and connectivity of two major networks: CEN (positive correlation) and DMN (negative correlation). These results support the view that both the CEN and DMN are important for enhancement of innovative cognition. We propose that neural mechanisms in healthy older adults can be modified through reasoning training to better subserve enhanced innovative cognition

Modular Brain Network Organization Predicts Response to Cognitive Training in Older Adults.

Cognitive training interventions are a promising approach to mitigate cognitive deficits common in aging and, ultimately, to improve functioning in older adults. Baseline neural factors, such as properties of brain networks, may predict training outcomes and can be used to improve the effectiveness of interventions. Here, we investigated the relationship between baseline brain network modularity, a measure of the segregation of brain sub-networks, and training-related gains in cognition in older adults. We found that older adults with more segregated brain sub-networks (i.e., more modular networks) at baseline exhibited greater training improvements in the ability to synthesize complex information. Further, the relationship between modularity and training-related gains was more pronounced in sub-networks mediating "associative" functions compared with those involved in sensory-motor processing. These results suggest that assessments of brain networks can be used as a biomarker to guide the implementation of cognitive interventions and improve outcomes across individuals. More broadly, these findings also suggest that properties of brain networks may capture individual differences in learning and neuroplasticity. Trail Registration: ClinicalTrials.gov, NCT#00977418

Modular Brain Network Organization Predicts Response to Cognitive Training in Older Adults.

Cognitive training interventions are a promising approach to mitigate cognitive deficits common in aging and, ultimately, to improve functioning in older adults. Baseline neural factors, such as properties of brain networks, may predict training outcomes and can be used to improve the effectiveness of interventions. Here, we investigated the relationship between baseline brain network modularity, a measure of the segregation of brain sub-networks, and training-related gains in cognition in older adults. We found that older adults with more segregated brain sub-networks (i.e., more modular networks) at baseline exhibited greater training improvements in the ability to synthesize complex information. Further, the relationship between modularity and training-related gains was more pronounced in sub-networks mediating "associative" functions compared with those involved in sensory-motor processing. These results suggest that assessments of brain networks can be used as a biomarker to guide the implementation of cognitive interventions and improve outcomes across individuals. More broadly, these findings also suggest that properties of brain networks may capture individual differences in learning and neuroplasticity. Trail Registration: ClinicalTrials.gov, NCT#00977418

Distinct Brain and Behavioral Benefits from Cognitive vs. Physical Training: A Randomized Trial in Aging Adults.

Insidious declines in normal aging are well-established. Emerging evidence suggests that non-pharmacological interventions, specifically cognitive and physical training, may counter diminishing age-related cognitive and brain functions. This randomized trial compared effects of two training protocols: cognitive training (CT) vs. physical training (PT) on cognition and brain function in adults 56-75 years. Sedentary participants (N = 36) were randomized to either CT or PT group for 3 h/week over 12 weeks. They were assessed at baseline-, mid-, and post-training using neurocognitive, MRI, and physiological measures. The CT group improved on executive function whereas PT group's memory was enhanced. Uniquely deploying cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) MRI, the CT cohort showed increased CBF within the prefrontal and middle/posterior cingulate cortex (PCC) without change to CVR compared to PT group. Improvements in complex abstraction were positively associated with increased resting CBF in dorsal anterior cingulate cortex (dACC). Exercisers with higher CBF in hippocampi bilaterally showed better immediate memory. The preliminary evidence indicates that increased cognitive and physical activity improves brain health in distinct ways. Reasoning training enhanced frontal networks shown to be integral to top-down cognitive control and brain resilience. Evidence of increased resting CBF without changes to CVR implicates increased neural health rather than improved vascular response. Exercise did not improve cerebrovascular response, although CBF increased in hippocampi of those with memory gains. Distinct benefits incentivize testing effectiveness of combined protocols to strengthen brain health

Relationship between baseline modularity and cognitive changes after SMART.

<p>(A) Relationship between baseline whole-brain modularity and change in performance on the TOSL, calculated as the difference of post-training and pre-training (i.e., ‘baseline’), in Control (grey) and SMART (green) groups. Here, modularity values were calculated for each connection density threshold and averaged for each subject. (B) Relationship between baseline modularity and change in performance on the TOSL for each connection density threshold in each group.</p

Distinct Brain and Behavioral Benefits from Cognitive vs. Physical Training: A Randomized Trial in Aging Adults.

Insidious declines in normal aging are well-established. Emerging evidence suggests that non-pharmacological interventions, specifically cognitive and physical training, may counter diminishing age-related cognitive and brain functions. This randomized trial compared effects of two training protocols: cognitive training (CT) vs. physical training (PT) on cognition and brain function in adults 56-75 years. Sedentary participants (N = 36) were randomized to either CT or PT group for 3 h/week over 12 weeks. They were assessed at baseline-, mid-, and post-training using neurocognitive, MRI, and physiological measures. The CT group improved on executive function whereas PT group's memory was enhanced. Uniquely deploying cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) MRI, the CT cohort showed increased CBF within the prefrontal and middle/posterior cingulate cortex (PCC) without change to CVR compared to PT group. Improvements in complex abstraction were positively associated with increased resting CBF in dorsal anterior cingulate cortex (dACC). Exercisers with higher CBF in hippocampi bilaterally showed better immediate memory. The preliminary evidence indicates that increased cognitive and physical activity improves brain health in distinct ways. Reasoning training enhanced frontal networks shown to be integral to top-down cognitive control and brain resilience. Evidence of increased resting CBF without changes to CVR implicates increased neural health rather than improved vascular response. Exercise did not improve cerebrovascular response, although CBF increased in hippocampi of those with memory gains. Distinct benefits incentivize testing effectiveness of combined protocols to strengthen brain health

Relationship between module segregation and cognitive changes after SMART.

<p>(A) Module segregation for the Control and SMART groups. (B) Correlation between module segregation (all modules, sensory-motor modules, and association cortex modules) and change in performance on the TOSL. Correlations were performed using all network connections (left), only positive network connections (middle), and the absolute values of connections (right). SM, somatomotor; CO, cingulo-opercular; DMN, default mode network; DAN, dorsal attention network; FP, fronto-parietal, VAN, ventral attention network, Assoc., association cortex. ~P ≤ 0.10, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.</p

SMART-related cognitive changes.

<p>(A) Performance on the Test of Strategic Learning (TOSL) and (B) WAIS-III Similarities for Control and SMART groups pre- and post-training. Scores are presented as in Chapman et al. (2015), where the TOSL is presented as raw scores and Similarities is presented as standard scores. Data are presented as mean ± SEM. ~P ≤ 0.10, *P ≤ 0.05, ***P ≤ 0.001.</p