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Free-water: A promising structural biomarker for cognitive decline in aging and mild cognitive impairment.

Diffusion MRI derived free-water (FW) metrics show promise in predicting cognitive impairment and decline in aging and Alzheimer's disease (AD). FW is sensitive to subtle changes in brain microstructure, so it is possible these measures may be more sensitive than traditional structural neuroimaging biomarkers. In this study, we examined the associations among FW metrics (measured in the hippocampus and two AD signature meta-ROIs) with cognitive performance, and compared FW findings to those from more traditional neuroimaging biomarkers of AD. We leveraged data from a longitudinal cohort (nparticipants = 296, nobservations = 870, age at baseline: 73 ± 7 years, 40% mild cognitive impairment [MCI]) of older adults who underwent serial neuropsychological assessment (episodic memory, information processing speed, executive function, language, and visuospatial skills) and brain MRI over a maximum of four time points, including baseline (n = 284), 18-month (n = 246), 3-year (n = 215), and 5-year (n = 125) visits. The mean follow-up period was 2.8 ± 1.3 years. Structural MRI was used to quantify hippocampal volume, in addition to Schwarz and McEvoy AD Signatures. FW and FW-corrected fractional anisotropy (FAFWcorr) were quantified in the hippocampus (hippocampal FW) and the AD signature areas (SchwarzFW, McEvoyFW) from diffusion-weighted (dMRI) images using bi-tensor modeling (FW elimination and mapping method). Linear regression assessed the association of each biomarker with baseline cognitive performance. Additionally, linear mixed-effects regression assessed the association between baseline biomarker values and longitudinal cognitive performance. A subsequent competitive model analysis was conducted on both baseline and longitudinal data to determine how much additional variance in cognitive performance was explained by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein-ε4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. All analyses were corrected for multiple comparisons using an FDR procedure. Cross-sectional results indicate that hippocampal volume, hippocampal FW, Schwarz and McEvoy AD Signatures, and the SchwarzFW and McEvoyFW metrics are all significantly associated with memory performance. Baseline competitive model analyses showed that the McEvoy AD Signature and SchwarzFW explain the most unique variance beyond covariates for memory (ΔRadj 2 = 3.47 ± 1.65%) and executive function (ΔRadj 2 = 2.43 ± 1.63%), respectively. Longitudinal models revealed that hippocampal FW explained substantial unique variance for memory performance (ΔRadj 2 = 8.13 ± 1.25%), and outperformed all other biomarkers examined in predicting memory decline (pFDR = 1.95 x 10-11). This study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.

Alzheimer’s disease (AD)↗

Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a disease of acute respiratory failure manifested by severe hypoxemia with a high mortality rate. Previous outcome studies of ARDS have assessed survival and/or pulmonary function as the primary outcome variables. Cognitive or psychological outcomes following ARDS have not been described, despite the possibility that ARDS patients are at risk for brain injury through hypoxemia or other mechanisms. In the current study 55 consecutive ARDS survivors completed a battery of neuropsychological tests and questionnaires regarding health status, cognitive and psychological outcomes at the time of hospital discharge and 1 yr after onset of ARDS. At hospital discharge, 100% (55 of 55) of survivors exhibited cognitive and affective impairments, as well as problems with health status which affected their quality of life. At 1 yr after ARDS, 17 of 55 (30%) patients still exhibited generalized cognitive decline. Forty-three of 55 (78%) patients had all or at least one of the following: impaired memory, attention, concentration and/or decreased mental processing speed. One year after ARDS a substantial portion of ARDS survivors exhibit impaired health status and cognitive sequelae which may be due to hypoxemia, emboli, inflammation, drug toxicity, and/or other etiologies.

Adolescent↗

Longitudinal neuropsychological follow-up study of patients with first-episode schizophrenia.

OBJECTIVE: The primary purpose of this article was to determine if cognitive abilities decline, remain unchanged, or modestly improve throughout the course of schizophrenic illness. METHOD: Forty-two patients with a first hospitalization for schizophrenia or schizophreniform disorder and 16 normal comparison subjects had a battery of neuropsychological tests and a magnetic resonance imaging (MRI) brain scan at approximate yearly intervals for the first 2 to 5 years of illness. Summary rating scales for language, executive, memory, processing speed, and sensory-perceptual functions were constructed. RESULTS: Patients with schizophrenia scored 1 to 2 standard deviations below normal comparison subjects on neuropsychological test measures during the course of the study. Patients exhibited less improvement than comparison subjects on measures of verbal memory. In general, improvement in positive symptoms over the time interval was associated with improvement in cognition. No changes in regional brain measurements were correlated with cognitive change in the patient group. CONCLUSIONS: Patients with schizophrenia have considerable cognitive dysfunction in the first 4 to 5 years of illness, which is stable at a level of 1 to 2 standard deviations below that of comparison subjects. There is little evidence for deterioration of cognitive abilities over the first few years of illness, with the exception of verbal memory, which shows significantly less improvement in patients over time relative to that of comparison subjects.

Adult↗

Effects of anxiety versus depression on cognition in later life.

OBJECTIVE: The authors investigated the relationship between anxiety and cognition in older persons, taking account of comorbid depression. METHODS: Data were used from the Longitudinal Aging Study Amsterdam (LASA), a large epidemiological study of 3,107 elderly citizens in The Netherlands. Anxiety and depression were measured with the Hospital Anxiety and Depression Scale-Anxiety subscale and the Center for Epidemiologic Studies-Depression Scale. In measuring cognitive performance, general cognitive functioning was measured by means of Mini-Mental State Exam, episodic memory was measured with the Auditory Verbal Learning Test (AVLT), fluid intelligence by using the RAVEN, and information-processing speed by the coding task. Analysis of variance examined the association between anxiety symptoms and cognition in persons with and without depression. RESULTS: Main effects of anxiety symptoms were found for learning and delayed recall of the AVLT. Depression symptoms showed significant main effects on almost all cognitive performance tests. Mild anxiety symptoms were associated with better cognitive performance, whereas severe anxiety symptoms were negatively associated with cognitive functioning. In contrast, depressive symptoms showed a linear association with cognition; more depression was associated with worse cognition. CONCLUSION: This study suggests that anxiety has a curvilinear relationship with cognition. Depressive symptoms, however, were always negatively associated with cognitive performance.

Aged↗

Treatment of cognitive impairment in early psychosis: a comparison of risperidone and haloperidol in a large long-term trial.

OBJECTIVE: Cognitive impairment is a major determinant of functional outcome in schizophrenia. Treatment of cognitive impairment at the time of the first episode may have the potential to change functional outcomes of the illness. This study examined changes associated with treatment with risperidone compared with haloperidol in aspects of cognitive functioning known to be associated with functional outcomes. The study was conducted in a large group of patients experiencing their first episode of schizophrenia. METHOD: Cognitive assessments were conducted in 533 patients experiencing their first episode of schizophrenia or a related psychosis who had been randomly assigned to receive low doses of risperidone or haloperidol. The cognitive assessments were repeated at several different follow-up intervals; 359 patients were reexamined at the 3-month follow-up. The assessments included examinations of verbal and visuospatial episodic memory, vigilance, executive functioning, processing speed, and verbal fluency. Patients' clinical symptoms were also rated with the Positive and Negative Syndrome Scale. RESULTS: Improvements from baseline were found in the risperidone-treated patients for episodic memory, verbal fluency, vigilance, executive functioning, and visuomotor speed. Haloperidol-treated patients also showed improvements from baseline in episodic memory, vigilance, and visuomotor speed but not in executive functioning or verbal fluency. Comparison of differential treatment effects on a composite measure of cognitive functioning found that risperidone was significantly more beneficial than haloperidol after 3 months of treatment. Changes in Positive and Negative Syndrome Scale scores were correlated overall with improvement in the haloperidol-treated patients but not in the risperidone-treated patients. CONCLUSIONS: Treatment with risperidone at the time of the first episode of schizophrenia is associated with wide-ranging improvements in cognitive functioning. Overall improvement is significantly greater with risperidone than with haloperidol. Further, cognitive improvement associated with treatment with risperidone was not influenced by changes in symptoms, but that relationship was significant in haloperidol-treated patients.

Adult↗

Neurobehavioral correlates of perceived mental and motor slowness in HIV infection and AIDS.

The authors assessed 72 human immunodeficiency virus (HIV)-infected patients with a self-rating slowness scale (SRSS) concerning mental and motor slowness in their activities of daily living. In order to understand the relationship between complaints of slowness and predictor variables, the investigators developed a preliminary model using multiple regression analysis. Reports of slowness on the SRSS were independently associated with self-reported cognitive and neurological symptoms and with peripheral neurological syndromes (e.g., neuropathy, myopathy). Lesser contributions to self-perceived mental and motor slowness were found for neuropsychological measures of information processing speed, severity of the infection, depression, HIV encephalopathy, and sociodemographic factors (e.g., age, education). The relationship among the predictor variables showed that complaints of slowness reflect neurological, psychiatric/psychological, and cognitive symptomatology of the HIV infection.

AIDS Dementia Complex↗

Cognitive correlates of human brain aging: a quantitative magnetic resonance imaging investigation.

The relations between age-related changes in brain structure and neuropsychological test performance in 320 elderly nonclinical volunteers (ages 66-90) were examined by using quantitative MRI data and measures of attention, information processing speed, language, memory, and visuospatial ability. Final path analyses revealed significant brain-behavior relationships for two of the six cognitive measures: the Trail Making Test part B and visual delayed memory. Poorer performance on Trails B was associated with smaller cerebral hemisphere volumes and larger volumes of peripheral CSF, lateral ventricles, and third ventricle. Poorer recall on visual delayed memory was associated with larger volumes of the lateral ventricles and third ventricle. The findings demonstrate a relationship between age-related changes in brain structure and an age-related decline in attention, psychomotor speed, and visual delayed memory. The neurobiological basis for this relationship requires further investigation.

Aged↗

Cognitive impairment associated with major depression following mild and moderate traumatic brain injury.

Traumatic brain injury (TBI) and major depression are neuropsychiatric conditions that have been associated with cognitive dysfunction. The aim of this study was to explore the relationship between major depression and cognitive impairment following mild and moderate TBI. Seventy-four TBI patients were assessed for the presence of major depression using the Structured Clinical Interview for the DSM-IV and completed a neurocognitive assessment battery. Subjects with major depression (28.4%), compared to those without, were found to have significantly lower scores on measures of working memory, processing speed, verbal memory and executive function. Potential mechanisms and implications for treatment are discussed.

Adolescent↗

Influence of Angiotensin-converting enzyme polymorphism on neuropsychological subacute performance in moderate and severe traumatic brain injury.

Traumatic brain injury (TBI) frequently results in cerebrovascular lesions that may increase secondary damage and cause neuropsychological impairment. Previous studies suggest an association among the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE), cardiovascular disease, and cognitive performance. Clinical and experimental studies have demonstrated the beneficial effects of ACE inhibitor treatment on vascular injury, hypertension, brain ischemia, and cognitive functioning. In a sample of 73 moderate and severe TBI patients, the authors assessed whether cognitive sequelae differed in relation to the ACE I/D polymorphism. D allele carrier patients performed worse than those with I/I polymorphism on tests involving attention and processing speed. Findings suggest that the physiopathological changes associated with TBI may have greater consequences in ACE D allele carriers.

Adolescent↗

Academic outcomes in children with congenital heart disease.

Congenital heart disease (CHD) is often associated with intellectual, developmental, and academic late effects related to the diagnosis itself and treatment. This literature review examines what is currently understood about these intellectual and academic deficits. It appears that children with CHD, and particularly those with cyanotic CHD, are at risk for significant impairments in visual spatial skills, visual motor skills, and overall processing speed. Early neurocognitive interventions, especially with younger children, may prove beneficial for remediating some of these deficits.

Age Factors↗

Self-reported visual problems of older drivers.

We conducted a survey in order to gain insights into the reasons older persons decide to give up driving. Our survey focused on vision. We probed the relationship between visual deficiencies and driving status by asking older people about the problems they encountered while performing routine visual tasks. The results showed that older persons who had recently given up driving reported more visual problems than did their driving counterparts. These problems related to difficulties in dynamic vision, visual processing speed, visual search, light sensitivity, and near vision. The results suggested that older persons are sensitive to their own visual deficits and that this awareness influences decisions about driving.

Activities of Daily Living↗

A nationwide epidemiologic modeling study of LD: risk, protection, and unintended impact.

Through multiple logistic regression modeling, this article explores the relative importance of risk and protective factors associated with learning disabilities (LD). A representative national sample of 6- to 17-year-old students (N = 1,268) was drawn by random stratification and classified by the presence versus absence of LD in reading, spelling, and mathematics according to ability-achievement discrepancies or low achievement levels. The dichotomous classifications were regressed on sets of explanatory variables indicating potential biological, social-environmental, and cognitive factors, problem behavior, and classroom learning behavior. Modeling revealed patterns of high risk for male students and students evincing verbal and nonverbal ability problems and processing speed problems. It was shown that, absent controls for cognitive abilities (such as provided by the ability-achievement discrepancy definition), definitions keyed to low achievement will substantially overidentify ethnic minority and disadvantaged students and will be confounded by significantly higher proportions of students who display oppositional and aggressive behavior problems. Alternatively, good learning behaviors uniformly provide substantial reduction in the risk for LD.

Achievement↗

Neuropsychologic test performance in amateur boxers.

Cognitive functions of 23 amateur boxers were assessed immediately before and after an amateur boxing event. A range of cognitive measures were employed including tasks of verbal, figural, and incidental memory, motor functions, attention and concentration, and information processing speed. Compared to their prefight performance, boxers demonstrated impairments in verbal and incidental memory, but enhanced executive and motor functions postfight. There were no observed differences between winners and losers on any of the measures. The results are compared to other studies that have shown only minor changes in cognitive functions in amateur boxers compared to controls.

Adolescent↗

Correlating brain atrophy with cognitive dysfunction, mood disturbances, and personality disorder in multiple sclerosis.

Neuropsychological impairment is a common feature of multiple sclerosis. Affected patients often have deficits in information-processing speed and memory and exhibit psychopathological states such as depression. A minority of patients have rarer affect/mood disorders such as euphoria sclerotica and pathological laughter/crying. Neuropsychological impairment is a major predictor of low quality of life, unemployment, and caregiver distress. Studies evaluating correlations between neuropsychological impairment and findings on magnetic resonance imaging show that neuropsychological dysfunction is associated with lesion burden and diffuse disease in normal-appearing brain tissue. However, measures of tissue atrophy including whole-brain and central atrophy are especially well correlated with and predictive of cognitive impairment. Moreover, recent studies have shown that conventional measures of brain atrophy explain more variance in neuropsychological dysfunction than do measures of lesion burden. In particular, neuropsychological outcomes correspond highly with linear measures of subcortical atrophy such as ventricle enlargement. Within the domain of emotional dysfunction, both lesion burden and atrophy are related to major depressive disorder. Brain atrophy also predicts euphoria and disinhibition. The preliminary data suggest that although lesion burden primarily predicts depressive disorder, both lesion burden and atrophy predict the presence of euphoria. Euphoria and disinhibition likely represent personality change associated with worsening cognition as the disease progresses. Taken together, this growing body of data on magnetic resonance imaging to neuropsychological correlations supports the clinical relevance and validity of brain atrophy as a measure of disease progression in multiple sclerosis. Continuing research focuses on the possible relationship between measures of regional brain atrophy and cognitive and emotional impairment.

Atrophy↗

Does the letter number sequencing task measure anything more than digit span?

A total of 102 undergraduate students performed the Letter Number Sequencing (LNS) task in addition to a series of other measures of reading, working memory, motor execution, visuo-spatial memory, and executive functions. Performance on the LNS was uniquely contributed to by reading level, digit span forward and backward, arithmetic, visual spatial learning, and by performance on the Symbol Search subtest of the WAIS-III. The results indicate that while much of the variance on the LNS task is explained by performance on the traditional measures of digit span, additional unique contributions to prediction of LNS performance are provided by measures of processing speed and visual spatial working memory.

Adolescent↗

Estimation of Wechsler Adult Intelligence Scale-III index scores with the 7-subtest short form in a clinical sample.

A 7-subtest short form of the Wechsler Adult Intelligence Scale-III (WAIS-III) previously demonstrated good comparability in estimating Full Scale and Verbal IQ summary scores, with adequate comparability in estimating Performance IQ. In a mixed clinical sample of 295 patients, the current study assessed the equivalence of the index scores generated from the full and prorated WAIS-III. The results revealed correlations corrected for redundancy of .90, .86, .87, and .75 for the Verbal Comprehension (VCI), Perceptual Organization (POI), Working Memory (WMI), and Processing Speed (PSI) indexes, respectively. Although the 7-subtest short form of the WAIS-III was not designed to estimate index scores, adequate estimates are viable for VCI, POI, and WMI when the goal is to obtain group, rather than individual, data points.

Adult↗

Second-order confirmatory factor analysis of the WAIS-III. Wechsler Adult Intelligence Scale.

According to Vernon's structure-of-intellect paradigm, abilities can be conceptualized as a hierarchy, with a factor of general intelligence at the top of the hierarchy, and successively more specific abilities toward the bottom. This paradigm has proven useful for interpreting a number of Wechsler intelligence scales. However, most of the research with this paradigm has used exploratory factor analysis, and the validity of the paradigm for the newest Wechsler Adult Intelligence Scale (WAIS-III) has yet to be evaluated. The present study examined the WAIS-III using second-order confirmatory factor analysis, which is a more appropriate analytic tool when specific hypotheses are tested. Using the standardization sample for the WAIS-III (N = 2,450), support was found for the hierarchical factor structure with a second-order factor of general intelligence and four first-order factors of Verbal Comprehension, Perceptual Organization, Working Memory, and Processing Speed.

Adolescent↗

Factor index score patterns in the WAIS-III standardization sample.

Representative profile subtypes, based on factor index scores, were examined in the standardization sample of the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III). Two-stage cluster analysis identified five reliable subtypes. Three clusters were differentiated primarily by level of performance across all factor index scores (ranging from below average, to average, to above average). The other two clusters were characterized by distinct patterns of performance, with relative efficacy on the Processing Speed index being the most prominent distinction (ranging from a relative weakness to a relative strength). The clusters did not differ significantly in age, but ethnicity and income covaried directly with level of WAIS-III performance, whereas gender affected differential patterns of performance. Furthermore, education and memory were associated primarily with level and, to a relatively minor degree, pattern of WAIS-III performance. Implications for clinical practice are discussed.

Chi-Square Distribution↗