Declines in inflammation predict greater white matter microstructure in older adults.

Protracted systemic inflammation has been associated with adverse effects on cognition and brain structure and may accelerate neurodegenerative disease processes; however, it is less clear whether changes in inflammation are associated with brain structure. We studied 276 black and white older adults (mean age = 83 years at time of imaging) enrolled in a prospective study of aging. Inflammation (measured with c-reactive protein, CRP) was assessed repeatedly over 6 years (i.e., year 2, 4, 6, and 8). Brain magnetic resonance imaging (MRIs) were obtained at years 10-11 with diffusion tensor imaging; regions of interest included late-myelinating areas vulnerable to aging, including frontal-parietal (superior longitudinal fasciculus [SLF]-dorsal) and temporal (SLF-temporal; uncinate) white matter tracts. Mean CRP values significantly declined (t = -5.54, p < 0.0001) over 6 years, and subject-specific slopes (best linear unbiased predictors of slopes) all showed a decline (mean = -0.57, standard deviation = 0.53) for our participant sample. More than 50% of study participants were still in the moderate to high cardiovascular risk range based on CRP values at year 8. After controlling for demographics, vascular risk factors and MRI white matter hyperintensities, larger decreases in CRP values over time were significantly associated with higher fractional anisotropy in the SLF-dorsal (beta = -0.0052, standard error [SE] = 0.003; 95% confidence interval [CI] = -0.0103 to -0.0025, p = 0.04), SLF-temporal (beta = -0.0109, SE = 0.004; 95% CI = -0.0189 to -0.0029, p = 0.008), and uncinate (beta = -0.0067, SE = 0.003; 95% CI = -0.0132 to -0.0001, p = 0.05) fasciculi. Results suggest that in a prospective cohort of older individuals, faster declines in inflammation over time are related to indicators of white matter health, even after accounting for vascular risk factors.

Memory consolidation in aging and MCI after 1 week.

OBJECTIVE: To assess consolidation in amnestic mild cognitive impairment (aMCI), controlling for differences in initial learning and using a protracted delay period for recall. METHOD: 15 individuals with aMCI were compared with 15 healthy older adult controls on a story learning task. Subjects were trained to criteria to equalize initial learning across subjects. Recall was tested at both the 30-min typically used delay and a 1-week delay used to target consolidation. RESULTS: Using repeated measures ANOVAs adjusted for age, we found group × time point interactions across the entire task between the final trial and 30-min delay, and again between the 30-min and 1-week delay periods, with aMCI having greater declines in recall as compared with controls. Significant group main effects were also found, with aMCI recalling less than controls. CONCLUSION: Consolidation was impaired in aMCI as compared with controls. Our findings indicate that aMCI-related performance typically measured at 30 min underestimates aMCI-associated memory deficits. This is the first study to isolate consolidation by controlling for initial learning differences and using a protracted delay period to target consolidation in an aMCI sample.

Body mass and white matter integrity: the influence of vascular and inflammatory markers.

High adiposity is deleteriously associated with brain health, and may disproportionately affect white matter integrity; however, limited information exists regarding the mechanisms underlying the association between body mass (BMI) and white matter integrity. The present study evaluated whether vascular and inflammatory markers influence the relationship between BMI and white matter in healthy aging. We conducted a cross-sectional evaluation of white matter integrity, BMI, and vascular/inflammatory factors in a cohort of 138 healthy older adults (mean age: 71.3 years). Participants underwent diffusion tensor imaging, provided blood samples, and participated in a health evaluation. Vascular risk factors and vascular/inflammatory blood markers were assessed. The primary outcome measure was fractional anisotropy (FA) of the genu, body, and splenium (corpus callosum); exploratory measures included additional white matter regions, based on significant associations with BMI. Regression analyses indicated that higher BMI was associated with lower FA in the corpus callosum, cingulate, and fornix (p<.001). Vascular and inflammatory factors influenced the association between BMI and FA. Specifically, BMI was independently associated with the genu [ß=-.21; B=-.0024; 95% CI, -.0048 to -.0000; p=.05] and cingulate fibers [ß=-.39; B=-.0035; 95% CI,-.0056 to -.0015; p<.001], even after controlling for vascular/inflammatory risk factors and blood markers. In contrast, BMI was no longer significantly associated with the fornix and middle/posterior regions of the corpus callosum after controlling for these markers. Results partially support a vascular/inflammatory hypothesis, but also suggest a more complex relationship between BMI and white matter characterized by potentially different neuroanatomic vulnerability.

Inflammation and clinical presentation in neurodegenerative disease: a volatile relationship.

A proposed immune mechanism that potentially modifies or exacerbates neurodegenerative disease presentation in older adults has received considerable attention in the past decade, with recent studies demonstrating a strong link between pro-inflammatory markers and neurodegeneration. The overarching aim of the following review is to synthesize recent research that supports a possible relationship between inflammation and clinical features of neurodegenerative diseases, including risk of development, cognitive and clinical correlates, and progression of the specified diseases. Specific emphasis is placed on providing a temporal context for the association between inflammation and neurodegeneration.

C-reactive protein is related to memory and medial temporal brain volume in older adults.

Recent research suggests a central role for inflammatory mechanisms in cognitive decline that may occur prior to evidence of neurodegeneration. Limited information exists, however, regarding the relationship between low-grade inflammation and cognitive function in healthy older adults. This study examined the relation between inflammation, verbal memory consolidation, and medial temporal lobe volumes in a cohort of older community-dwelling subjects. Subjects included 141 functionally intact, community-dwelling older adults with detectable (n=76) and undetectable (n=65) levels of C-reactive protein. A verbal episodic memory measure was administered to all subjects, and measures of delayed recall and recognition memory were assessed. A semiautomated parcellation program was used to analyze structural MRI scans. On the episodic memory task, analysis of covariance revealed a significant CRP group by memory recall interaction, such that participants with detectable levels of CRP evidenced worse performance after a delay compared to those with undetectable levels of CRP. Individuals with detectable CRP also demonstrated lower performance on a measure of recognition memory. Imaging data demonstrated smaller left medial temporal lobe volumes in the detectable CRP group as compared with the undetectable CRP group. These findings underscore a potential role for inflammation in cognitive aging as a modifiable risk factor.

To err is human, to monitor divine: environmental adaptations reduce everyday errors but do not improve monitoring.

The current study aimed to address error monitoring impairments in dementia using an intervention for execution deficits. Thirty-eight participants completed the Naturalistic Action Test (NAT) under two conditions: Standard and User-Centered. The Standard NAT followed the manual procedures; in the User-Centered NAT, objects were arranged sequentially, and distractor items were separated from target objects. While participants committed fewer errors in the User-Centered condition, there was no difference in the proportion of errors detected. However, the neuropsychological processes associated with monitoring differed across conditions. The results have implications for a neuropsychological model of error monitoring in dementia.

Improving everyday error detection, one picture at a time: a performance-based study of everyday task training.

OBJECTIVE: Research suggests that dementia patients detect fewer action errors than age-matched controls; however, little is known about the derivation of their error-monitoring difficulties. The aims of the study are to evaluate a novel, task-training action intervention (TT-NAT) designed to increase error monitoring in dementia patients and to pinpoint the relation between error monitoring and neuropsychological processes. METHOD: Participants (n = 45) with dementia were administered the Standard NAT, a performance-based test requiring completion of three everyday tasks. A second group (n = 42) was administered the TT-NAT, which includes a brief training session prior to the commencement of each task. All participants were compared on the following variables: total errors, proportion of errors detected, and proportion of errors corrected. Correlations between error-monitoring variables and neuropsychological tests of executive functioning and language were performed. RESULTS: TT-NAT participants produced fewer total errors and detected significantly more errors than Standard NAT participants (z = 3.0; t = 3.36; p < .05). Error detection was strongly related to only the language composite index (r = .57, p = .00) in the TT-NAT, whereas it was moderately related to both the language (r = .31, p = .04) and executive composite (r = .36, p = .02) indices in the Standard NAT condition. CONCLUSION: Review of task steps and objects before task performance may be a promising intervention for error-monitoring deficits in dementia patients; this finding has implications for neuropsychological rehabilitation of functional deficits in this population.

Target-related distractors disrupt object selection in everyday action: evidence from participants with dementia.

This study evaluated the impact of distractor objects and their similarity to target objects on everyday task performance in dementia. Twenty participants with dementia due to Alzheimer's disease (n = 12) or subcortical vascular disease (n = 8) were videotaped while they performed 3 discrete tasks: (1) make a cup of coffee, (2) wrap a gift, and (3) pack a lunch under two conditions that were counterbalanced across participants. The conditions differed in terms of the type of distractor objects included in the workspace: (1) Target-Related Distractor Condition - distractor objects were functionally and visually similar to target objects (e.g., salt for sugar) (2) Unrelated Distractor Condition - distractors were neither visually nor functionally similar to targets (e.g., glue for sugar). Participants touched (t = 4.19; p < .01) and used (z = 3.00; p < .01) significantly more distractors, made more distractor errors (i.e., substitutions; t = 2.93; p < .01), and took longer to complete tasks (t = 2.27; p < .05) in the Target-Related Distractor condition. The percent of steps accomplished and non-distractor errors did not differ across conditions (t < 1.26; p > .05 for both). In summary, distractors that were similar to targets elicited significant interference effects circumscribed to object selection.

Leukoaraiosis severity and list-learning in dementia.

In patients with dementia, leukoaraiosis (LA) was hypothesized to result in differential patterns of impairment on a verbal serial list-learning test. Using a visual rating scale, 144 dementia patients with ischemic scores <4 were re-categorized as having mild (n = 73), moderate (n = 44), or severe LA (n = 27). Mild LA was predicted to be associated with an amnestic list-learning profile, while severe LA was predicted to be associated with a dysexecutive profile. List-learning performances were standardized to a group of healthy older adults (n = 24). Analyses were conducted on a set of four factors derived from the list-learning paradigm, as well as error scores. Data indicate that LA severity is an important marker for understanding list learning in dementia.

From cognitive neuroscience to geriatric neuropsychology: what do current conceptualizations of the action error handling process mean for older adults?

The fields of cognitive neuroscience and neuropsychology have contributed an extensive corpus of research to the study of error monitoring processes in younger adults; however, less is known about error handling in older adults. This paper highlights current conceptualizations of error detection and correction in healthy and impaired older adult populations. The literature suggests that some error handling processes require fewer processing resources than others and may be performed relatively automatically. Compared with young adults, older adults demonstrate a reduced ability to recognize errors, but exhibit similar rates of correction. Older adults diagnosed with a neurodegenerative disease (e.g. Alzheimer's disease) show a reduced ability to detect and correct their action errors. Thus, neurodegenerative disease processes amplify the impairments in error identification associated with normal aging by disrupting both automatic and controlled error corrections. The clinical implications of our current knowledge are discussed, and directions for future neuropsychological research are offered.

The impact of goal cues on everyday action performance in dementia.

Everyday action performance is impaired as a consequence of dementia. Omissions (i.e., not performing task steps) are a frequent source of error in everyday tasks among dementia patients. External cues or notes are often suggested to improve everyday functioning and might specifically address omission errors; however, the efficacy of such strategies has not been evaluated. Thus, the primary aim of this study was to assess the efficacy of goal cues (i.e., reminders of everyday task objectives) for improving dementia patients' everyday action performance. Forty-four participants with mild to moderate dementia were administered the Naturalistic Action Test (NAT), a performance-based test that includes three everyday tasks. After participants indicated that they had completed each task, they were presented with a cue card restating the task goals. Videotapes were used to code task performance as well as responses to the cues. Most participants checked their work and showed significant improvement in task accomplishment/omission errors, but not commission errors, after the cues. However, effect sizes for the differences were small, and the proportion of cases in the impaired range did not differ before versus after the cues. Therefore, although statistically significant, we concluded that the goal cues did not meaningfully or clinically improve everyday functioning.

Syntactic comprehension deficits are associated with MRI white matter alterations in dementia.

Comprehension difficulties associated with periventricular and deep white matter alterations (WMA) in mild dementia were investigated using portions of the Boston Diagnostic Aphasia Examination (BDAE) Complex Ideation subtest and Syntax subtests. Mild dementia participants were grouped according to the extent of their WMA as observed on magnetic resonance imaging (mild WMA n = 45 vs. moderate to severe WMA n = 52). Correlation and regression analyses also were performed to examine the link between WMA and comprehension abilities, as well as the link between comprehension abilities and neuropsychological measures of executive functioning, language, episodic memory, and overall dementia severity. Results showed that the WMA groups differed on the BDAE-Syntax subtests, with the severe WMA group demonstrating more impairment. Correlation and regression analyses including the entire sample also demonstrated that the extent of WMA was significantly linked to Syntax test scores but not Complex Ideation scores. Regression analyses including neuropsychological measures showed that the BDAE-Complex Ideation score was marginally predicted by only overall dementia severity, whereas the BDAE-Syntax scores were significantly predicted by independent measures of working memory/executive functioning. In conclusion, greater subcortical WMA and executive deficits are associated with greater difficulties in syntactic comprehension in individuals with mild dementia.

Characterization of everyday functioning in mild cognitive impairment: a direct assessment approach.

AIMS: To evaluate the degree and pattern of functional difficulties in mild cognitive impairment (MCI) via direct observation of everyday task performance. METHODS: MCI (n = 25), mild Alzheimer's disease (AD; n = 25), and control (n = 18) participants performed three everyday tasks of increasing complexity. RESULTS: Although caregivers reported no functional difficulties in MCI, direct observation measures of overall impairment and total errors showed MCI participants performed worse than controls, but better than AD participants, even on simple tasks. MCI and control participants exhibited significantly more difficulty performing steps accurately (i.e. commission errors) than completing task steps (i.e. omission errors), but AD participants showed an even distribution of commissions and omissions. CONCLUSIONS: Diagnostic criteria for MCI should specify mild functional deficits due to the inefficient and imprecise execution of task steps. Functional deficits characterized by omission of major task segments may indicate a diagnosis of dementia.

Coffee with jelly or unbuttered toast: commissions and omissions are dissociable aspects of everyday action impairment in Alzheimer's disease.

Relative to our understanding of the memory and language deficits associated with Alzheimer's disease (AD), little is known about problems with everyday action performance (i.e., meal preparation, grooming). The resource theory proposes that everyday action problems are best explained by a unitary deficit in general cognitive resources. However, recent research suggests that omission and commission errors may reflect dissociable aspects of action impairment, with only omissions associated with resource limitations. This study examined everyday action performance in 70 participants with AD who also underwent a neuropsychological evaluation. First, correlation and principal component analyses were performed to examine the construct(s) that might explain everyday action impairment. Second, relations between everyday task component(s) and neuropsychological tests were examined by using correlation and regression analyses. Third, differences in everyday action error patterns were examined among participants of comparable overall impairment levels. Results showed omission and commission errors were uncorrelated and distinct components of everyday action performance, predicted by different neuropsychological tests, and differentially distributed even among participants with comparable overall impairment.

Linking MRI hyperintensities with patterns of neuropsychological impairment: evidence for a threshold effect.

BACKGROUND AND PURPOSE: Leukoaraiosis (LA) might interrupt intra- and interhemispheric communication and thus induce cognitive impairments and dementia. It remains unclear, however, if there is a volume threshold of LA that is needed before either the signs of dementia and/or a specific pattern of neuropsychological impairment become manifest. Roman et al has suggested that 25% of white matter may need to be involved before white matter alterations influence the clinical signs associated with dementia. The purpose of this study is to ascertain the threshold of MRI-LA as measured with a visual rating scale needed to induce specific patterns of neuropsychological impairment associated with dementia. METHODS: One hundred fifteen patients with dementia received a comprehensive neuropsychological examination and the severity of MRI-LA was measured using a 40-point LA scale. RESULTS: Patients were categorized into low (mean LA=4.21+/-2.92; 3.22%-17.82%), moderate (mean LA=12.58+/-2.54; 25.01%-37.80%), and severe (mean LA=22.36+/-4.04; 45.80%-66.00%) LA groups. Patients in the mild LA group obtained markedly lower scores on tests of episodic memory compared with working memory, a neuropsychological profile often associated with Alzheimer disease. Patients with moderate LA displayed equal impairment on neuropsychological tests. Patients in the severe LA group obtained significantly lower scores on tests of working memory as compared with episodic memory. CONCLUSIONS: These data provide evidence that a threshold of moderate MRI-LA as measured with a visual rating scale is associated with greater and/or equal impairment on tests of working memory versus episodic memory and provides a benchmark to assess the effect of MRI-LA on the clinical presentation of dementia.

Error detection and correction patterns in dementia: a breakdown of error monitoring processes and their neuropsychological correlates.

Error monitoring is critical to an individual's ability to function autonomously. This study characterized error detection and correction behaviors within the service of everyday tasks in individuals with dementia. Also, the impact of neuropsychological functioning on error detection and correction was examined. Fifty-three participants diagnosed with Alzheimer's disease (AD) or vascular dementia (VaD) were administered a neuropsychological protocol and the Naturalistic Action Test, which requires performance of three everyday tasks. Error detection, correction, and the point at which correction occurred (i.e., microslip--before the error was completed, immediate--just after the error was made, delayed--after performing other task steps) was coded. Dementia participants detected 32.7% of their errors and corrected 75.8% of detected errors. Participants were more likely to engage in microslips than delayed corrections. Tests of executive control and language predicted detection and correction variables; moreover, detection and correction were each related to different aspects of executive functioning. Microslips were related to naming ability. AD and VaD patients did not differ on detection/correction variables, and regression analyses indicated that dementia severity and memory abilities were unrelated to detection/correction. The results specify the error monitoring deficits in AD and VaD and have implications for improving functional abilities in dementia.

Environmental adaptations improve everyday action performance in Alzheimer's disease: empirical support from performance-based assessment.

Neuropsychologists often recommend that patients with dementia and their caregivers use environmental adaptations to improve everyday functioning. Although these recommendations are intuitive (e.g., reduce clutter), most have never been experimentally tested. This study examined whether and how environmental adaptations improved everyday action in Alzheimer's disease (AD). Forty-six outpatients completed the Naturalistic Action Test (NAT; M. F. Schwartz, L. J. Buxbaum, M. Ferraro, T. Veramonti, & M. Segal, 2003), which requires completion of 3 everyday tasks. The NAT was administered under 2 conditions: standard and user centered. The standard NAT followed the procedures of the manual; object placement was standardized, but objects were not meaningfully arranged on the tabletop. In the user-centered NAT, objects were arranged in the order needed in the task, and a visual cue to monitor performance was placed on the table. These conditions were counterbalanced across participants. The user-centered condition improved performance on all NAT items and reduced commission and omission error rates. However, post hoc examination of commission error types showed improvement of substitution and off-task errors but no difference in anticipation and perseveration errors. Thus, environmental adaptations improved everyday performance in AD by facilitating task accomplishment, object selection, and task-congruent actions.

Sexual dysfunction associated with second-generation antipsychotics in outpatients with schizophrenia or schizoaffective disorder: an empirical evaluation of olanzapine, risperidone, and quetiapine.

OBJECTIVE: Evaluate sexual dysfunction, as measured by the Arizona Sexual Experience Scale (ASEX), in olanzapine-, quetiapine-, and risperidone-treated outpatients with schizophrenia or schizoaffective disorder. METHOD: The sexual functioning of 238 outpatients (age> or =18 years) with diagnoses of schizophrenia or schizoaffective disorder who took quetiapine (n=57), olanzapine (n=94), or risperidone (n=87) was evaluated with a one-time rating of the ASEX. The dose range for each treatment group was 5 to 40 mg/day (M=16.6 mg/day, SD=7.4) for olanzapine; 1 to 8 mg/day (M=3.9 mg/day, SD=1.6) for risperidone; and 50 to 900 mg/day (M=376.8 mg/day, SD=213.4) for quetiapine. Antipsychotic group designation was based on medication treatment at study entry (i.e., non-random assignment). Participant characteristics were collected to test for treatment group differences and for potential associations with severity of sexual dysfunction. The primary data analysis was a mixed linear model analysis of covariance with age, gender, and presence/absence of antidepressant known to cause sexual dysfunction included as covariates. RESULTS: There was a significant treatment effect on severity of sexual dysfunction, as measured by ASEX total scores (p=.04). The adjusted average ASEX total scores were lower in the quetiapine (M=17.80) than in the risperidone (M=19.69) or olanzapine (M=20.34) groups. Individual comparisons of the treatments on adjusted average ASEX total scores indicated a significant difference between olanzapine and quetiapine (p=.04), but no difference between risperidone and quetiapine (p=.17) or olanzapine and risperidone (p=.76). CONCLUSIONS: Quetiapine was associated with less severe sexual dysfunction than olanzapine and risperidone (albeit the effect between risperidone and quetiapine was not statistically significant). Olanzapine and risperidone were associated with a comparable degree of sexual dysfunction. Patients in all three treatment groups, nonetheless, experienced a moderately high degree of sexual dysfunction. Because the patients were not randomized, conclusions must be interpreted within the context of the quasi-experimental design.