Training Cognitive Control in Older Adults with the Space Fortress Game: The Role of Training Instructions and Basic Motor Ability

This study examined if and how cognitively healthy older adults can learn to play a complex computer-based action game called the Space Fortress (SF) as a function of training instructions [Standard vs. Emphasis Change (EC); e.g., Gopher et al., 1989] and basic motor ability. A total of 35 cognitively healthy older adults completed a 3-month SF training program with three SF sessions weekly. Twelve 3-min games were played during each session. Basic motor ability was assessed with an aiming task, which required rapidly rotating a spaceship to shoot targets. Older adults showed improved performance on the SF task over time, but did not perform at the same level as younger adults. Unlike studies of younger adults, overall SF performance in older adults was greater following standard instructions than following EC instructions. However, this advantage was primarily due to collecting more bonus points and not – the primary goal of the game – shooting and destroying the fortress, which in contrast benefited from EC instructions. Basic motor ability was low and influenced many different aspects of SF game learning, often interacted with learning rate, and influenced overall SF performance. These findings show that older adults can be trained to deal with the complexity of the SF task but that overall SF performance, and the ability to capitalize on EC instructions, differs when a basic ability such as motor control is low. Hence, the development of this training program as a cognitive intervention that can potentially compensate for age-related cognitive decline should consider that basic motor ability can interact with the efficiency of training instructions that promote the use of cognitive control (e.g., EC instructions) – and the confluence between such basic abilities and higher-level cognitive control abilities should be further examined

Distinct Pools of β-Amyloid in Alzheimer Disease-Affected Brain: A Clinicopathologic Study

Objective: To determine whether β-amyloid (Aβ) peptides segregated into distinct biochemical compartments would differentially correlate with clinical severity of Alzheimer disease (AD). Design: Clinicopathologic correlation study. Participants: Twenty-seven patients from a longitudinal study of AD and 13 age- and sex-matched controls without a known history of cognitive impairment or dementia were included in this study. Interventions: Temporal and cingulate neocortex were processed using a 4-step extraction, yielding biochemical fractions that are hypothesized to be enriched with proteins from distinct anatomical compartments: TRIS (extracellular soluble), Triton (intracellular soluble), sodium dodecyl sulfate (SDS) (membrane associated), and formic acid (extracellular insoluble). Levels of Aβ₄₀ and Aβ₄₂ were quantified in each biochemical compartment by enzyme-linked immunosorbent assay. Results: The Aβ₄₂ level in all biochemical compartments was significantly elevated in patients with AD vs controls (P < .01). The Aβ₄₀ levels in the TRIS and formic acid fractions were elevated in patients with AD (temporal, P < .01; cingulate, P = .03); however, Triton and SDS Aβ₄₀ levels were similar in patients with AD and in controls. Functional impairment proximal to death correlated with Triton Aβ₄₂ (r = 0.48, P = .02) and SDS Aβ₄₂ (r = 0.41, P = .04) in the temporal cortex. Faster cognitive decline was associated with elevated temporal SDS Aβ₄₂ levels (P < .001), whereas slower decline was associated with elevated cingulate formic acid Aβ₄₂ and SDS Aβ₄₂ levels (P = .02 and P = .01, respectively). Conclusion: Intracellular and membrane-associated Aβ, especially Aβ₄₂ in the temporal neocortex, may be more closely related to AD symptoms than other measured Aβ species

Validating the use of brain volume cutoffs to identify clinically relevant atrophy in RRMS

Background: Baseline brain volume (BV) is predictive at a group level but is difficult to interpret at the single patient level. Objective: To validate BV cutoffs able to identify clinically relevant atrophy in relapsing–remitting multiple sclerosis (RRMS) patients. Methods: The expected normalized brain volume (NBV) for each patient was calculated using RRMS patients from two phase III clinical trials, applying a linear formula developed on the baseline variable of an independent data set. The difference between these expected NBV values and those actually observed was calculated and used to categorize the patients in the low-NBV, medium-NBV, and high-NBV groups. Results: The 2-year probability of 3-month confirmed disability worsening was significantly associated with the NBV categorization (p = 0.006), after adjusting for treatment effect. Taking the high-NBV group as a reference, the hazard ratios for the medium-NBV and low-NBV groups were 1.22 (95% confidence interval (CI): 0.85–1.76, p = 0.27) and 1.69 (95% CI: 1.11–2.57, p = 0.01), respectively. Conclusion: This study validates the use of BV cutoffs to identify clinically relevant atrophy in RRMS study by showing that the three groups classified according to the baseline NBV adjusted for the other prognostic variables have a significant prognostic impact on the risk of disability progression

Validating the use of brain volume cutoffs to identify clinically relevant atrophy in RRMS

Baseline brain volume (BV) is predictive at a group level but is difficult to interpret at the single patient level

Distinct Pools of ␤-Amyloid in Alzheimer Disease–Affected Brain

Objective: To determine whether β-amyloid (Aβ) peptides segregated into distinct biochemical compartments would differentially correlate with clinical severity of Alzheimer disease (AD). Design: Clinicopathologic correlation study. Participants: Twenty-seven patients from a longitudinal study of AD and 13 age- and sex-matched controls without a known history of cognitive impairment or dementia were included in this study. Interventions: Temporal and cingulate neocortex were processed using a 4-step extraction, yielding biochemical fractions that are hypothesized to be enriched with proteins from distinct anatomical compartments: TRIS (extracellular soluble), Triton (intracellular soluble), sodium dodecyl sulfate (SDS) (membrane associated), and formic acid (extracellular insoluble). Levels of Aβ40 and Aβ42 were quantified in each biochemical compartment by enzyme-linked immunosorbent assay. Results: The Aβ42 level in all biochemical compartments was significantly elevated in patients with AD vs controls (P < .01). The Aβ40 levels in the TRIS and formic acid fractions were elevated in patients with AD (temporal, P < .01; cingulate, P = .03); however, Triton and SDS Aβ40 levels were similar in patients with AD and in controls. Functional impairment proximal to death correlated with Triton Aβ42 (r = 0.48, P = .02) and SDS Aβ42 (r = 0.41, P = .04) in the temporal cortex. Faster cognitive decline was associated with elevated temporal SDS Aβ42 levels (P < .001), whereas slower decline was associated with elevated cingulate formic acid Aβ42 and SDS Aβ42 levels (P = .02 and P = .01, respectively). Conclusion: Intracellular and membrane-associated Aβ, especially Aβ42 in the temporal neocortex, may be more closely related to AD symptoms than other measured Aβ species. A critical role of the β-amyloid (Aβ) peptide in the pathogenesis of Alzheimer disease (AD) has been supported by human, animal, and in vitro studies.1 Most measures of Aβ are markedly elevated in the AD-affected brain, yet the extent of total Aβ accumulation tends to correlate poorly with ADseverity.2-4 Because there is evidence that specific biochemical forms of Aβ (eg, Aβ42, soluble Aβ, and oligomeric Aβ) selectively lead to neuronal dysfunction and neurodegeneration5-7 and can be more reliable correlates of clinical status,8,9 identification and reliable measurement of these toxic Aβ species should enhance their utility as biological markers of disease. Clarifying the dynamics of Aβ production and compartmentalization is also necessary to explain AD pathogenesis. Specific Aβ species may preferentially exert toxic effects as a function of their cellular location. Although established histologic techniques identify primarily insoluble extracellular and vascular amyloid deposits, novel methods can enhance detection of intraneuronal Aβ, distinguish Aβ pools, and measure changes in Aβ concentration and location over time.10-14 The Aβ in the brain can be segregated into distinct biochemical compartments defined by sequential extraction procedures. In this study of brain autopsy samples from a well-characterized longitudinal cohort of patients with AD and matched controls, we quantified Aβ40 and Aβ42 in biochemical compartments defined by their solubility in 4 solutions. Proteins in these biochemical pools are predicted to derive from distinct anatomical compartments within the cerebral cortex: extracellular soluble, intracellular, membrane associated, and extracellular insoluble.7 We hypothesized that these measures would differentially correlate with disease diagnosis, progression, and severity

A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis.

OBJECTIVE: To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS). METHODS: In the randomized, double-blind, placebo-controlled, phase 2 study, ARPEGGIO (A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations in MRI and Clinical Outcomes), eligible patients with PPMS were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016, due to findings of cardiovascular events. RESULTS: A total of 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg vs placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio 0.4; 95% confidence interval, 0.26-0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) vs laquinimod 1.5 mg (66%) and placebo (78%). CONCLUSIONS: Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48. CLINICALTRIALSGOV IDENTIFIER: NCT02284568. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, although well tolerated, laquinimod 0.6 mg did not demonstrate a significant treatment effect on PBVC in patients with PPMS