Objectives: The apolipoprotein E (APOE) ε4 allele is an established risk factor for dementia, yet this genetic variant is associated with a mixed cognitive profile across the lifespan. This study undertakes both a systematic and meta-analytic review of research investigating APOE-related differences in cognition in mid-adulthood, when detrimental effects of the allele may first be detectable. Methods: Thirty-six papers investigating the behavioral effects of APOE ε4 in mid-adulthood (defined as a mean sample age between 35 and 60 years) were reviewed. In addition, the effect of carrying an ε4 allele on individual cognitive domains was assessed in separate meta-analyses. Results: The average effect size of APOE ε4 status was non-significant across cognitive domains. Further consideration of genotype effects indicates preclinical effects of APOE ε4 may be observable in memory and executive functioning. Conclusions: The cognitive profile of APOE ε4 carriers at mid-age remains elusive. Although there is support for comparable performance by ε4 and non-e4 carriers in the 5th decade, studies administering sensitive cognitive paradigms indicate a more nuanced profile of cognitive differences. Methodological issues in this field preclude strong conclusions, which future research must address, as well as considering the influence of further vulnerability factors on genotype effects. (JINS, 2016, 23, 239–253)

Objectives: Mild cognitive impairments (MCI) is a transitional state in aging associated with increased risk of incident dementia. The current study investigated whether MCI status moderated the effect of time on word generation during verbal fluency tasks. Specifically, the objective was to determine whether MCI status had differential effects on initial automatic or latter more effortful retrieval processes of fluency tasks. Methods: Participants were community residing older adults enrolled in a longitudinal cohort study. Of the 408 participants, 353 were normal (age=76.06±6.61; %female=57.8) and 55 were diagnosed with MCI (age=78.62±7.00; %female=52.7). Phonemic and category fluency were each administered for 60 s, but performance was recorded at three consecutive 20-s intervals (0–20 s [T1], 21–40 s [T2], 41–60 s [T3]. Separate linear mixed effects models for each fluency task were used to determine the effects of group, time, and their interaction on word generation. Results: In both fluency tasks, word generation declined as a function of time. Individuals with MCI generated fewer words compared to controls during the first 20 s of phonemic (beta=−1.56; p<.001; d=0.28) and category fluency (beta=−1.85; p<.001; d=0.37). Group by time interactions revealed that individuals with MCI demonstrated attenuated declines in word generation from the first to the second and third time intervals of both phonemic ([T1 vs. T2] beta=2.17, p=.001; d=0.41; [T1 vs. T3]beta=2.28, p=.001; d=0.45) and category ([T1 vs. T2] beta= 2.22, p=.002; d=0.50; [T1 vs. T3]beta=3.16, p<.001; d=0.71) fluency. Conclusions: Early automatic retrieval processes in verbal fluency tasks are compromised in MCI. (JINS, 2017, 23, 44–55)

Objectives: Little is known about the very long-term cognitive outcome in patients with childhood-onset epilepsy. The aim of this unique prospective population-based cohort study was to examine cognitive outcomes in aging participants with childhood-onset epilepsy (mean onset age=5.3 years) five decades later (mean age at follow-up=56.5 years).Methods: The sample consisted of 48 participants with childhood-onset epilepsy and 48 age-matched healthy controls aged 48–63 years. Thirty-six epilepsy participants were in remission and 12 continued to have seizures. Cognitive function was examined with 11 neuropsychological tests measuring language and semantic function, episodic memory, and learning, visuomotor function, executive function, and working memory. Results: The risk of cognitive impairment was very high in participants with continuing seizures; odds ratio (OR)=11.7 (95% confidence interval [CI] (2.8, 49.6), p=.0008). They exhibited worse performances across measures of language and semantic function, and visuomotor function compared to participants with remitted epilepsy and healthy controls. In the participants with remitted epilepsy, the risk of cognitive impairment was somewhat elevated, but not statistically significant; OR=2.6 (95% CI [0.9, 7.5], p=.08).Conclusions: Our results showed that the distinction of continued versus discontinued seizures was critical for determining long-term cognitive outcome in childhood-onset epilepsy. Few participants in remission exhibited marked cognitive impairment compared to age-matched peers. However, a subgroup of participants with decades long active epilepsy, continuous seizure activity and anti-epileptic drug (AED) medication, showed clinically significant cognitive impairment and are thus in a more precarious position when entering older age. (JINS, 2017, 23, 332–340)

Studies of language disorders have shaped our understanding of brain–language relationships over the last two centuries. This article provides a review of this research and how our thinking has changed over the years regarding how the brain processes language. In the 19th century, a series of famous case studies linked distinct speech and language functions to specific portions of the left hemisphere of the brain, regions that later came to be known as Broca’s and Wernicke’s areas. One hundred years later, the emergence of new brain imaging tools allowed for the visualization of brain injuries in vivo that ushered in a new era of brain-behavior research and greatly expanded our understanding of the neural processes of language. Toward the end of the 20th century, sophisticated neuroimaging approaches allowed for the visualization of both structural and functional brain activity associated with language processing in both healthy individuals and in those with language disturbance. More recently, language is thought to be mediated by a much broader expanse of neural networks that covers a large number of cortical and subcortical regions and their interconnecting fiber pathways. Injury to both grey and white matter has been seen to affect the complexities of language in unique ways that have altered how we think about brain–language relationships. The findings that support this paradigm shift are described here along with the methodologies that helped to discover them, with some final thoughts on future directions, techniques, and treatment interventions for those with communication impairments. (JINS, 2017, 23, 741–754)

Objectives: Social cognitive deficits have been discussed to be endophenotypes for schizophrenia and other serious mental illnesses. The current study aimed to assess emotional intelligence (EI) in unaffected siblings of schizophrenia patients to investigate its potential role as endophenotype for schizophrenia. Methods: EI was measured in 56 schizophrenia patients, 57 unaffected siblings, and 127 healthy control subjects by using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). In addition, non-social cognition was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Linear mixed models with compound symmetric correlation structure were used for of the three groups with respect to EI and non-social cognition. Results: Schizophrenia patients showed significantly lower overall EI and performed significantly worse in three out of four MSCEIT branches compared to unaffected siblings and control subjects, whereas the two latter groups had comparable EI levels. Similar performance patterns (patients<unaffected siblings=control subjects) were found with respect to non-social cognition. Solely in the “Tower of London” test, siblings achieved significantly lower task scores compared to control subjects. Conclusions: Based on our results, EI as measured with the MSCEIT does not seem to represent a marker of risk for schizophrenia. Further investigations should concentrate on other EI measures to reassess this finding. (JINS, 2017, 23, 577–583)

Objectives: In unpredictable situations, individuals often show tradeoffs between response initiation and inhibition speeds. We tested the hypothesis that Parkinson’s disease (PD) motor subtypes differentially impact tradeoffs between these two action-oriented processes. We predicted that, compared to tremor dominant (TD) patients, predominant postural instability and gait dysfunction (PIGD) patients would show exacerbated tradeoffs between response initiation and inhibition in situations requiring the sudden potential need to interrupt an action. Methods: Fifty-one PD patients (subdivided into PIGD [n=27] and TD [n=24]) and 21 healthy controls (HCs) completed a choice reaction task to establish baseline response initiation speed between groups. Subsequently, participants completed a stop-signal task which introduced an occasional, unpredictable stop stimulus. We measured changes in initiation speed in preparation of an unpredictable stop (i.e., proactive slowing) and inhibition latency (i.e., stop-signal reaction time). Results: Compared to HCs, PD patients showed slower response initiation speeds in the choice reaction task. All groups showed proactive slowing in the stop-signal task but the magnitude was considerably larger in PIGD patients, almost twice as large as TD patients. PD patients, irrespective of motor subtype, showed longer inhibition latencies than HCs. Conclusions: PIGD and TD subtypes both showed exacerbated response inhibition deficits. However, PIGD patients showed much more pronounced proactive slowing in situations with an expected yet unpredictable need to stop action abruptly. This suggests that PIGD is accompanied by exaggerated tradeoffs between response initiation and inhibition processes to meet situational action demands. We discuss putative neural mechanisms and clinical implications of these findings. (JINS, 2017, 23, 665–674)

Objectives: In complex real life situations, memories for temporal and spatial information are naturally linked since sequential events coincide in time and space. Whether this connection is inseparable or instead whether these processes are functionally dissociable was investigated in this patient study. Methods: Spatial object-location and temporal order memory tasks were administered to 36 stroke patients and 44 healthy control participants. Results: On group level, patients with a stroke in the left hemisphere performed worse on temporal order memory, compared to the control participants. On individual level, using a multiple case-study approach, a clear pattern of dissociations was found between memory for temporal and for spatial features. Conclusions: These findings indicate that location and temporal order memory contain functionally separable processes. This adds to our understanding of how context information is processed in human memory. (JINS, 2017, 23, 421–430)

Objectives: The cardinal motor deficits seen in ideomotor limb apraxia are thought to arise from damage to internal representations for actions developed through learning and experience. However, whether apraxic patients learn to develop new representations with training is not well understood. We studied the capacity of apraxic patients for motor adaptation, a process associated with the development of a new internal representation of the relationship between movements and their sensory effects. Methods: Thirteen healthy adults and 23 patients with left hemisphere stroke (12 apraxic, 11 nonapraxic) adapted to a 30-degree visuomotor rotation. Results: While healthy and nonapraxic participants successfully adapted, apraxics did not. Rather, they showed a rapid decrease in error early but no further improvement thereafter, suggesting a deficit in the slow, but not the fast component of a dual-process model of adaptation. The magnitude of this late learning deficit was predicted by the degree of apraxia, and was correlated with the volume of damage in parietal cortex. Apraxics also demonstrated an initial after-effect similar to the other groups likely reflecting the early learning, but this after-effect was not sustained and performance returned to baseline levels more rapidly, consistent with a disrupted slow learning process. Conclusions: These findings suggest that the early phase of learning may be intact in apraxia, but this leads to the development of a fragile representation that is rapidly forgotten. The association between this deficit and left parietal damage points to a key role for this region in learning to form stable internal representations. (JINS, 2017, 23, 139–149)

Objectives: Longitudinal research indicates that cognitive load dual-task gait assessment is predictive of cognitive decline and thus might provide a sensitive measure to screen for mild cognitive impairment (MCI). However, research among older adults being clinically evaluated for cognitive concerns, a defining feature of MCI, is lacking. The present study investigated the effect of performing a cognitive task on normal walking speed in patients presenting to a memory clinic with cognitive complaints. Methods: Sixty-one patients with a mean age of 68 years underwent comprehensive neuropsychological testing, clinical interview, and gait speed (simple- and dual-task conditions) assessments. Thirty-four of the 61 patients met criteria for MCI. Results: Repeated measure analyses of covariance revealed that greater age and MCI both significantly associated with slower gait speed, ps<.05. Follow-up analysis indicated that the MCI group had significantly slower dual-task gait speed but did not differ in simple-gait speed. Multivariate linear regression across groups found that executive attention performance accounted for 27.4% of the variance in dual-task gait speed beyond relevant demographic and health risk factors. Conclusions: The present study increases the external validity of dual-task gait assessment of MCI. Differences in dual-task gait speed appears to be largely attributable to executive attention processes. These findings have clinical implications as they demonstrate expected patterns of gait-brain behavior relationships in response to a cognitive dual task within a clinically representative population. Cognitive load dual-task gait assessment may provide a cost efficient and sensitive measure to detect older adults at high risk of a dementia disorder. (JINS, 2017, 23, 493–501)

Objectives: The effect of sleep disordered breathing (SDB) on driving performance in older adults has not been extensively investigated, especially in those with mild cognitive impairment (MCI). The aim of this study was to examine the relationship between severity measures of SDB and a simulated driving task in older adults with and without MCI. Methods: Nineteen older adults (age ≥50) meeting criteria for MCI and 23 age-matched cognitively intact controls underwent neuropsychological assessment and a driving simulator task in the evening before a diagnostic sleep study. Results: There were no differences in driving simulator performance or SDB severity between the two groups. In patients with MCI, a higher oxygen desaturation index (ODI) was associated with an increased number of crashes on the simulator task, as well as other driving parameters such as steering and speed deviation. Poorer driving performance was also associated with poorer executive functioning (set-shifting) but the relationship between ODI and crashes was independent of executive ability. Conclusions: While driving ability did not differ between older adults with and without MCI, oxygen saturation dips in MCI were related to worse driving performance. These results suggest that decreased brain integrity may render those with SDB particularly vulnerable to driving accidents. In older adults, both cognition and SDB need to be considered concurrently in relation to driving ability. (JINS, 2017, 23, 502–510)

Objectives: Executive dysfunction is a common feature in Parkinson’s disease (PD). However, there is a lack of brief validated instruments for executive dysfunction in PD. Methods: The aim of the present study was to assess the relation of Frontal Assessment Battery (FAB) scores to age and education, to verify the utility of FAB in the evaluation of executive dysfunction in PD and to differentiate between controls (n=41), PD patients with normal cognition (PD-NC; n=41; Hoehn and Yahr stages 2–3) and PD with mild cognitive impairment (PD-MCI; n=32; Hoehn and Yahr stages 2–3). In addition, we studied the relation between voxel-based morphometric (VBM) data and FAB results in PD. Results: We found that FAB scores are significantly related to age and education. The FAB has shown discriminative validity for the differentiation of PD-MCI from PD-NC and controls (area under the curve >.80). Also, the VBM analysis revealed lower FAB scores are specifically related to lower gray matter density in the right ventromedial prefrontal areas and precuneus. Conclusions: The FAB can be recommended as a valid instrument for PD-MCI Level I screening. FAB is sensitive to frontal lobe involvement in PD as reflected by lower gray matter density in prefrontal areas. (JINS, 2017, 23, 675–684)

Our knowledge of the functions of the prefrontal cortex, often called executive, supervisory, or control, has been transformed over the past 50 years. After operationally defining terms for clarification, we review the impact of advances in functional, structural, and theoretical levels of understanding upon neuropsychological assessment practice as a means of identifying 11 principles/challenges relating to assessment of executive function. Three of these were already known 50 years ago, and 8 have been confirmed or emerged since. Key themes over this period have been the emergence of the use of naturalistic tests to address issues of “ecological validity”; discovery of the complexity of the frontal lobe control system; invention of new tests for clinical use; development of key theoretical frameworks that address the issue of the role of prefrontal cortex systems in the organization of human cognition; the move toward considering brain systems rather than brain regions; the advent of functional neuroimaging, and its emerging integration into clinical practice. Despite these huge advances, however, practicing neuropsychologists are still desperately in need of new ways of measuring executive function. We discuss pathways by which this might happen, including decoupling the two levels of explanation (information processing; brain structure) and integrating very recent technological advances into the neuropsychologist’s toolbox. (JINS, 2017, 23, 755–767)

Objectives: Accurate detection of executive dysfunction in neuropsychological assessments is complicated by the fact that executive functioning (EF) is vulnerable to temporary disruption (i.e., lapses), with more frequent lapses in older adulthood. Effortful regulation of affect (i.e., expressive suppression) is a well-known source of executive lapses in younger adults, but the generalizability of this depleting effect to older adults is unknown. The purpose of this study was to (1) determine whether EF is subject to depletion via expressive suppression and (2) to examine whether this effect is unique to EF, or whether it also applies to lower-order component processes in older adults. Methods: Ninety-seven non-demented, community-dwelling older adults were randomly assigned to either an expressive suppression group or control group. We compared performance of the groups on a battery of tests measuring EF and component processes both before and after exposure to emotionally evocative stimuli. Results: Consistent with the hypothesized depletion effect, suppressing participants showed an attenuated practice effect on post-manipulation EF relative to controls, while performance on lower-order component processes was unaffected by suppression. Conclusions: These results suggest that depletion contributes to executive lapses in older adulthood. (JINS, 2017, 23, 341–351)

Objectives: Prospective memory (PM) impairments are common following acquired brain injury (ABI). PM is the ability to keep a goal in mind for future action and interventions have the potential to increase independence. This review aimed to evaluate studies examining PM rehabilitation approaches in adults and children with ABI. Methods:Relevant literature was identified using PsycARTICLES (1894 to present), PsycINFO (1880 to present), the Cochrane Library (1972 to present), MEDLINE PubMed, reference lists from relevant journal articles, and searches of key journals. Literature searches were conducted using variants of the terms brain injury, stroke, encephalitis, meningitis, and tumor, combined with variants of the terms rehabilitation and prospective memory.Results: Of the 435 papers identified, 11 were included in the review. Findings demonstrated a variety of interventions to alleviate PM deficits, including compensatory strategies (e.g., external memory aids) that provide either content-specific or content-free cueing, and remediation strategies (e.g., meta-cognitive training programs) aimed at improving the self-monitoring of personal goals. Risk of bias for individual studies was considered and the strengths and limitations of each of the included studies and the review itself were discussed. Conclusions: Interventions used with adults can be effective; PM abilities can be improved by using simple reminder systems and performance can be generalized to facilitate everyday PM functioning. There is, however, a lack of research of PM interventions conducted with children with ABI, and pediatric interventions need to consider on-going cognitive maturation. (JINS, 2017, 23, 254–265)

Objectives: The worldwide spread of Parkinson’s disease (PD) calls for sensitive and specific measures enabling its early (or, ideally, preclinical) detection. Here, we use language measures revealing deficits in PD to explore whether similar disturbances are present in asymptomatic individuals at risk for the disease. Methods: We administered executive, semantic, verb-production, and syntactic tasks to sporadic PD patients, genetic PD patients with PARK2 (parkin) or LRRK2 (dardarin) mutation, asymptomatic first-degree relatives of the latter with similar mutations, and socio-demographically matched controls. Moreover, to detect sui generis language disturbances, we ran analysis of covariance tests using executive functions as covariate. Results: The two clinical groups showed impairments in all measures, most of which survived covariation with executive functions. However, the key finding concerned asymptomatic mutation carriers. While these subjects showed intact executive, semantic, and action-verb production skills, they evinced deficits in a syntactic test with minimal working memory load. Conclusions: We propose that this sui generis disturbance may constitute a prodromal sign anticipating eventual development of PD. Moreover, our results suggest that mutations on specific genes (PARK2 and LRRK2) compromising basal ganglia functioning may be subtly related to language-processing mechanisms. (JINS, 2017, 23, 150–158)

Objectives: Intraindividual variability (IIV) in reaction time refers to the trial-to-trial fluctuations in responding across a given cognitive task. Cross-sectional research suggests that IIV increases with normal and neuropathological ageing and it may serve as a marker of neurobiological integrity. This raises the possibility that IIV may also predict future cognitive decline and, indeed, neuropathology. Therefore, we conducted a systematic review to address these issues. Methods: A search of electronic databases Embase, Medline, PsycINFO, and Web of Science was completed on May 17, 2016 that identified longitudinal investigations of IIV in middle-aged or older adults. Results: A total of 688 studies were initially identified of which 22 met the inclusion criteria. Nine included longitudinal IIV measures and 17 predicted subsequent outcome (cognitive decline or impairment, dementia, mortality) from baseline IIV. The results suggested IIV increased over time, particularly in participants aged over 75 years. Greater baseline IIV was consistently associated with increased risk of adverse outcomes including cognitive decline or impairment, and mortality. Conclusions: Increased IIV over time is associated with normal ageing. However, further increases in IIV over and above those found in normal ageing may be a risk factor for future cognitive impairment or mortality. Measures of IIV may, therefore, have considerable potential as a supplement to existing clinical assessment to aid identification of individuals at risk of adverse outcomes such as dementia or death. (JINS, 2017, 23, 431–445)

Objectives: Cognitive dysfunction is a key feature of major depressive (MDD) and bipolar (BD) disorders. However, rather than a single cognitive profile corresponding to each diagnostic categories, recent studies have identified significant intra- and cross-diagnostic variability in patterns of cognitive impairment. The goal of this study was to contribute to the literature on cognitive heterogeneity in mood disorders by identifying cognitive subprofiles in a population of patients with MDD, BD type I, BD type II, and healthy adults. Methods: Participants completed a neuropsychological battery; scores were converted into Z-scores using normative data and submitted to hierarchical cluster analysis. Results: Three distinct neuropsychological clusters were identified: (1) a large cluster containing mostly control participants, as well as some patients with BD and MDD, who performed at above-average levels on all neuropsychological domains; (2) a cluster containing some patients from all diagnostic groups, as well as healthy controls, who performed worse than cluster 1 on most tasks, and showed impairments in motor inhibition and verbal fluency; (3) a cluster containing mostly patients with mood disorders with severe impairments in verbal inhibition and cognitive flexibility. Conclusions: These findings revealed multiple cognitive profiles within diagnostic categories, as well as significant cross-diagnostic overlap, highlighting the importance of developing more specific treatment approaches which consider patients’ demographic and cognitive profiles in addition to their diagnosis. (JINS, 2017, 23, 584–593)

Objectives: The aim of this study was to characterize the neuropsychological profile of lifetime traumatic brain injury (TBI) in older Veterans. Methods: Participants were 169 older Veterans [mean age=79.1 years (range, 51–97 years), 89% male, 92% Caucasian], 88 with lifetime TBI and 81 without TBI, living in Veterans’ retirement homes in independent residence. TBI history was ascertained with the Ohio State TBI Identification Method structured interview. Cognition was assessed with neuropsychological tests: Raw scores were converted to Z-scores compared to age-corrected normative data and combined into five domain composite Z-scores (attention/working memory, learning/memory, language, processing speed, executive functioning). We investigated the association between TBI and performance in each cognitive domain in linear mixed effects models, with and without adjustment for demographics, medical comorbidities, and psychiatric variables. Results: Compared to those without TBI, older Veterans with TBI had greater deficits in processing speed (estimate=−.52; p=.01; f2=.08 in fully adjusted model) and executive functioning (estimate=−.41; p=.02; f2=.06 in fully adjusted model) but performed similarly in the attention/working memory, learning/memory, and language domains (all p>.05). TBI-associated deficits were most prominent among individuals with multiple mild TBIs and those with any moderate-to-severe TBI, but were not clearly present among those with single mild TBI. Conclusions: The neuropsychological profile of lifetime TBI in older Veterans is characterized by slowed processing speed and executive dysfunction, especially among those with greater injury burden. This pattern may reflect long-standing deficits or a TBI-associated cognitive decline process distinct from Alzheimer’s disease. (JINS, 2017, 23, 56–64)

Objectives: Two theories of tool use, namely the gesture engram and the technical reasoning theories, make distinct predictions about the involvement of the left inferior parietal lobe (IPL) in manipulation judgement tasks. The objective here is to test these alternative predictions based on previous studies on manipulation judgment tasks using transcranial magnetic stimulations (TMS) targeting the left supramarginal gyrus (SMG). Methods: We review recent TMS studies on manipulation judgement tasks and confront these data with predictions made by both tool use theories. Results: The left SMG is a highly intertwined region, organized following several functionally distinct areas and TMS may have disrupted a cortical network involved in the ability to use tools rather than only one functional area supporting manipulation knowledge. Moreover, manipulation judgement tasks may be impaired following virtual lesions outside the IPL. Conclusions: These data are more in line with the technical reasoning hypothesis, which assumes that the left IPL does not store manipulation knowledge per se. (JINS, 2017, 23, 685–691)

Objectives: Mild cognitive impairment is common in non-demented Parkinson disease patients (PD-MCI) and is considered as a risk factor for dementia. Executive dysfunction has been widely described in PD and the Verbal Fluency Tests (VFT) are often used for executive function assessment in this pathology. The Movement Disorder Society (MDS) published guidelines for PD-MCI diagnosis in 2012. However, no investigation has focused on the qualitative analysis of VFT in PD-MCI. The aim of this work was to study the clustering and switching strategies in VFT in PD-MCI patients. Moreover, these variables are considered as predictors for PD-MCI diagnosis. Methods: Forty-three PD patients and twenty normal controls were evaluated with a neuropsychological protocol and the MDS criteria for PD-MCI were applied. Clustering and switching analysis were conducted for VFT. Results: The percentage of patients diagnosed with PD-MCI was 37.2%. The Mann-Whitney U test analysis showed that PD-MCI performed poorly in different cognitive measures (digit span, Wisconsin Card Sorting Test, judgment of line orientation, and comprehension test), compared to PD patients without mild cognitive impairment (PD-nMCI). Phonemic fluency analyses showed that PD-MCI patients produced fewer words and switched significantly less, compared to controls and PD-nMCI. Concerning semantic fluency, the PD-MCI group differed significantly, compared to controls and PD-nMCI, in switches. Discriminant function analyses and logistic regression analyses revealed that switches predicted PD-MCI. Conclusions: PD-MCI patients showed poor performance in VFT related to the deficient use of production strategies. The number of switches is a useful predictor for incident PD-MCI. (JINS, 2017, 23, 511–520)