Robert M. Roth

Regional brain atrophy in cognitively intact adults with a single APOE ε4 allele

Objective: To determine whether cognitively intact adults with the APOE ε3/ε4 genotype show reduced gray matter density on voxel-based morphometry (VBM) vs those homozygous for the ε3 allele. Methods: Participants were healthy, cognitively intact, right-handed adults, age 19 to 80, who completed genotyping, neuropsychological testing, and MRI. Forty-nine participants had the ε3/ε3 genotype and 27 had the ε3/ε4 genotype. Gray matter data were analyzed using the general linear model as implemented in the Statistical Parametric Mapping package, adjusting for age and sex. Results: The ε3/ε4 participants showed lower gray matter density than the ε3/ε3 participants in right medial temporal and bilateral frontotemporal regions as well as other areas. There were no regions in which ε3/ε4 participants showed higher gray matter density than ε3/ε3 participants. Conclusions: Regionally reduced gray matter density is detectable in cognitively intact adults with a single copy of the APOE ε4 allele.

Verbal fluency performance in amnestic MCI and older adults with cognitive complaints

Verbal fluency tests are employed regularly during neuropsychological assessments of older adults, and deficits are a common finding in patients with Alzheimers disease (AD). Little extant research, however, has investigated verbal fluency ability and subtypes in preclinical stages of neurodegenerative disease. We examined verbal fluency performance in 107 older adults with amnestic mild cognitive impairment (MCI, n=37), cognitive complaints (CC, n=37) despite intact neuropsychological functioning, and demographically matched healthy controls (HC, n=33). Participants completed fluency tasks with letter, semantic category, and semantic switching constraints. Both phonemic and semantic fluency were statistically (but not clinically) reduced in amnestic MCI relative to cognitively intact older adults, indicating subtle changes in the quality of the semantic store and retrieval slowing. Investigation of the underlying constructs of verbal fluency yielded two factors: Switching (including switching and shifting tasks) and Production (including letter, category, and action naming tasks), and both factors discriminated MCI from HC albeit to different degrees. Correlational findings further suggested that all fluency tasks involved executive control to some degree, while those with an added executive component (i.e., switching and shifting) were less dependent on semantic knowledge. Overall, our findings highlight the importance of including multiple verbal fluency tests in assessment batteries targeting preclinical dementia populations and suggest that individual fluency tasks may tap specific cognitive processes.

Event-related functional magnetic resonance imaging of response inhibition in obsessive-compulsive disorder.

BACKGROUND Obsessive-compulsive disorder (OCD) has been hypothesized to involve inhibitory control dysfunction related to abnormal frontal-striatal-thalamic-cortical (FSTC) circuitry. METHODS We examined the neural substrates of response inhibition in adults with OCD using functional magnetic resonance imaging (fMRI) and a go/no-go task. Participants consisted of 12 adults with OCD and 14 healthy comparison subjects. RESULTS During response inhibition, healthy adults showed predominantly right-hemisphere activation including the right inferior frontal gyrus, whereas the patient group showed a more diffuse, bilateral pattern of activation. Furthermore, the OCD group demonstrated less activation than the comparison group in several right-hemisphere regions during response inhibition, including inferior and medial frontal gyri. Symptom severity was inversely correlated with activation in right orbitofrontal and anterior cingulate gyri and positively correlated with thalamic and posterior cortical activations. Neither depressed mood nor medication status could account for the results. CONCLUSIONS These findings indicate that adults with OCD demonstrate underactivation of FSTC circuitry during response inhibition. Results suggest that the thalamus and related circuitry may play a role in the expression or intensity of OCD symptoms, whereas right frontal subregions may be involved in the suppression of symptoms.

Executive dysfunction in attention-deficit/hyperactivity disorder: cognitive and neuroimaging findings ☆

Attention-deficit/hyperactivity disorder has been associated with a prominent disturbance of executive functions. There is no pathognomic neuropsychological profile for the disorder, however. Nonetheless, results of neuropsychological testing, in concert with other clinical information,provide a more comprehensive and detailed picture of the individual patients cognitive and emotional strengths and weaknesses than a psychiatric diagnostic interview alone. This approach to the evaluation of ADHD therefore can provide a strong objective basis from which to make patient-specific recommendations for compensatory strategies and treatment. It should be noted, however, that although executive dysfunction in the form of impaired response inhibition remains the most prominent cognitive theory of ADHD, other theories have been put forth that also deserve further investigation. These include a disturbance in delay aversion (referring to intolerance for waiting) and impaired temporal processing, among others [79]. The neural substrates of executive dysfunction in ADHD have begun to be revealed by a growing body of structural and functional neuroimaging research. Although still in its infancy, neuroimaging of ADHD is pointing toward disruption of FSTC circuitry and the cerebellum as being central to the cognitive and motor abnormalities seen in the disorder. Further research using cognitive tasks assessing executive functions in combination with functional imaging techniques will provide further insight into the etiology of the disorder. It is expected that advances in structural and functional neuroimaging will yield valuable information that will facilitate the differential diagnosis of ADHD. Evidence cited suggests that psychostimulant medication can improve executive functions and their underlying FSTC circuitry. Furthermore, a recent study of adults with ADHD found significant improvements in organization skills and other symptoms of ADHD following cognitive remediation targeting several executive and emotional aspects of the disorder [80]. Additional studies investigating the effects of treatment on executive dysfunction and brain integrity in ADHD will be necessary to determine the degree to which the structural and functional brain abnormalities observed are mutable. Finally, because the myriad cognitive, behavioral and emotional symptoms in ADHD likely reflect the interplay of multiple cognitive and psychosocial factors, development of treatments for ADHD likely will require a multi-modal approach.

Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports

Background: Deep brain stimulation (DBS) offers a non-ablative alternative to thalamotomy for the surgical treatment of medically refractory tremor in multiple sclerosis. However, relatively few outcomes have been reported. Objective: To provide a systematic review of the published cases of DBS use in multiple sclerosis and to present four additional patients. Methods: Quantitative and qualitative review of the published reports and description of a case series from one centre. Results: In the majority of reported cases (n=75), the surgical target for DBS implantation was the ventrointeromedial nucleus of the thalamus. Tremor reduction and improvement in daily functioning were achieved in most patients, with 87.7% experiencing at least some sustained improvement in tremor control postsurgery. Effects on daily functioning were less consistently assessed across studies; in papers reporting relevant data, 76.0% of patients experienced improvement in daily functioning. Adverse effects were similar to those reported for DBS in other patient populations. Conclusions: Few of the studies reviewed used highly standardised quantitative outcome measures, and follow up periods were generally one year or less. Nonetheless, the data suggest that chronic DBS often produces improved tremor control in multiple sclerosis. Complete cessation of tremor is not necessarily achieved, there are cases in which tremor control decreases over time, and frequent reprogramming appears to be necessary.

Contribution of Rating Scales to the Assessment of Executive Functions

Abstract Executive functions play a vital role in the everyday functioning of healthy individuals across the lifespan and have been implicated in a wide variety of clinical conditions. Historically, the assessment of executive functions in clinical and research settings relied on performance-based measures. A number of authors have argued, however, that such measures have limited ecological validity. In response to this limitation of performance-based measures, several rating scales have been developed that seek to gauge a persons or their knowledgeable informants (e.g., parent or teacher) subjective view of executive functioning in everyday life. In this article we review evidence supporting the use of rating scales of executive function including profiles in clinical populations, biological correlates, relationships to relevant outcome measures such as academic performance, and correlations with performance-based measures. We conclude that performance-based and rating scale measures provide complementary information with respect to a childs executive functions, offering a more comprehension view than either approach alone.

COMT Val158met genotype and individual differences in executive function in healthy adults

The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene may be related to individual differences in cognition, likely via modulation of prefrontal dopamine catabolism. However, the available studies have yielded mixed results, possibly in part because they do not consistently account for other genes that affect cognition. We hypothesized that COMT Met allele homozygosity, which is associated with higher levels of prefrontal dopamine, would predict better executive function as measured using standard neuropsychological testing, and that other candidate genes might interact with COMT to modulate this effect. Participants were 95 healthy, right-handed adults who underwent genotyping and cognitive testing. COMT genotype predicted executive ability as measured by the Trail-Making Test, even after covarying for demographics and Apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), and ankyrin repeat and kinase domain containing 1 (ANKK1) genotype. There was a COMT-ANKK1 interaction in which individuals having both the COMT Val allele and the ANKK1 T allele showed the poorest performance. This study suggests the heterogeneity in COMT effects reported in the literature may be due in part to gene-gene interactions that influence central dopaminergic systems.

Cognitive effects of pharmacotherapy for major depressive disorder: a systematic review.

OBJECTIVE Cognitive impairment frequently accompanies major depressive disorder (MDD) and can persist during remission. This review examined pharmacotherapy effects on cognitive function in MDD. DATA SOURCES PubMed and EMBASE searches were conducted on July 30, 2013, for English language reports of cognitive assessments following pharmacologic monotherapy or augmentation therapy in MDD. STUDY SELECTION A total of 43 research reports were identified (31 monotherapy [8 placebo-controlled, 11 active-comparator, 12 open-label], 12 augmentation therapy [7 placebo-controlled, 5 open-label]). DATA EXTRACTION Results reported in each publication were examined for open-label and placebo- or active comparator-controlled studies. RESULTS Studies varied widely in terms of size (median, 50 participants; interquartile range, 21-143 participants), populations examined, duration (median, 8 weeks; interquartile range, 6-12 weeks), and neurocognitive assessments used. Most individual studies reported some benefit to cognition with pharmacotherapy, but there was no pattern of response in specific domains and only 12% of individually analyzed changes favored active treatment over placebo or untreated healthy controls. Sample weighted mean effect sizes revealed that verbal memory improved with monotherapy, while the largest treatment effect with augmentation therapy was for visual memory. CONCLUSIONS Pharmacotherapy may have benefit in reducing cognitive impairment in MDD, with augmentation therapy being a potential approach for addressing cognitive deficits that persist after monotherapy has brought about clinical response or remission. However, given the wide variability in study design and treatment duration across studies, these findings should be interpreted cautiously. More definitive research is required before firm conclusions can be reached.

Confirmatory Factor Analysis of the Behavior Rating Inventory of Executive Function-Adult Version in Healthy Adults and Application to Attention-Deficit/Hyperactivity Disorder

The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) is a questionnaire measure designed to assess executive functioning in everyday life. Analysis of data from the BRIEF-A standardization sample yielded a two-factor solution (labeled Behavioral Regulation and Metacognition). The present investigation employed confirmatory factor analysis (CFA) to evaluate four alternative models of the factor structure of the BRIEF-A self-report form in a sample of 524 healthy young adults. Results indicated that a three-factor model best fits the data: a Metacognition factor, a Behavioral Regulation factor consisting of the Inhibit and Self-Monitor scales, and an Emotional Regulation factor composed of the Emotional Control and Shift scales. The three factors contributed 14%, 19%, and 24% of unique variance to the model, respectively, and a second-order general factor accounted for 41% of variance overall. This three-factor solution is consistent with recent CFAs of the Parent report form of the BRIEF. Furthermore, although the Behavioral Regulation factor score in the two-factor model did not differ between adults with attention-deficit/hyperactivity disorder and a matched healthy comparison group, greater impairment on the Behavioral Regulation factor but not the Emotional Regulation factor was found using the three-factor model. Together, these findings support the multidimensional nature of executive function and the clinical relevance of a three-factor model of the BRIEF-A.

Fever in the wake of a stroke

We performed a prospective study of the frequency and cause of fever, defined as a rectal temperature of ≥ 101 °F detected within the first 5 days, in 104 consecutive adults admitted to a community/teaching hospital because of a nontraumatic stroke. Fever was documented in 23 patients. A source for the fever was identified in 19 patients and was attributed to a pulmonary insult, either aspiration chemical pneumonitis or an infectious pneumonia, in 13 of these patients. Patients who experienced lacunar infarcts did not develop fever. Fever occurring in the wake of a stroke should not be attributed to the vascular process, but should direct attention to inflammatory disorders of the lungs.