Predictors of rate of cognitive decline in patients with amnestic mild cognitive impairment.

OBJECTIVE: Amnestic mild cognitive impairment (MCI) is a known risk factor for conversion to Alzheimer's disease (AD). Although substantial research has been conducted on the general profile of amnestic MCI subjects and predictors of conversion to AD, research on predictors of rate of decline has been considerably less extensive. The present study sought to more systematically and comprehensively examine predictors of rate of cognitive decline in a longitudinal sample of individuals with MCI, including age, genetic vulnerability, baseline cognitive performance, and baseline neuropsychiatric severity. METHOD: Participants with single or multi-domain amnestic MCI (N = 151) were assessed at baseline and for a mean of 1.32 follow-up visits (mean interval from baseline to last follow-up = 1.61 years). RESULTS: Results showed that carriers of the ApoE ε4 allele declined more quickly on all three dementia severity measures compared to non-carriers. Older individuals did not decline more rapidly in dementia severity. Participants with lower executive functions composite scores and greater memory impairment severity at baseline predicted faster decline on dementia severity measures. Contrary to hypotheses, those with lower levels of depression at baseline declined more rapidly on dementia severity measures compared to those with higher levels of depression. CONCLUSION: Identifying potential predictors of rate of decline from amnestic MCI to AD could be clinically meaningful for prognostic purposes, understanding risk and protective factors, as well as guiding future treatments and clinical trials that could aim to target and delay progression among those patients who are vulnerable to more quickly convert to AD.

Benefit of phonemic cueing on confrontation naming in Alzheimer's disease.

Objective: Deficits in confrontation naming vary among persons with Alzheimer's disease (AD), including the extent to which phonemic cueing is helpful in generating the target word. This study examined neuropsychological correlates of phonemic cueing benefit and the influential effects of AD severity, estimated premorbid intellectual functioning, and apolipoprotein E genotype status.Method: Participants were 1104 individuals with mild to moderate AD who were administered the Boston Naming Test (BNT) as part of their initial neuropsychological evaluation.Results: Mild AD subjects benefited from phonemic cues significantly more than moderate AD subjects. Individuals with higher estimated premorbid IQ benefited more from phonemic cueing. Differences in phonemic cueing benefit between carriers and noncarriers of the ApoE ε4 allele were accounted for by naming ability, with carriers performing better on naming tasks compared to noncarriers. Phonemic cueing benefit uniquely contributed to cognitive performance on some semantic measures, phonemic fluency, and one nonsemantic visuospatial task.Conclusion: Individuals with probable AD who benefit more from phonemic cueing during confrontation naming tend to have higher estimated premorbid IQ and are milder in dementia severity. There is a positive association between phonemic cueing benefit and performance on select semantic measures and verbal fluency. Differences in phonemic cueing benefit between carriers and noncarriers of APOE ε4 allele can be explained by spontaneous naming performance. Results suggest complexity of underlying mechanisms involving confrontation naming, phonemic cueing, and lexical access and the factors that influence them.

Cognitive impairment and postural control deficit in adults with Type 2 diabetes.

BACKGROUND: Diseases induced by metabolic disorders, eg, Type 2 diabetes, has recently been linked to both sensory and motor deficit in the absence of a formal clinical diagnosis of peripheral neuropathy. Studies have demonstrated mild cognitive impairment in diabetic patients, which also plays a role in one's loss of ability to successfully perform basic motor activities. This project focused on evaluating cognitive function while maintaining balance. We hypothesized that simultaneous cognitive and motor deficit would occur among adults with Type 2 diabetes versus healthy age- and sex-matched control during a balance task. METHODS: A sample of 10 Type 2 diabetes patients and 10 age-matched and sex-matched controls underwent a series of sensory, motor, cognitive, and cognitive-motor evaluations. Blood pressure and A1c levels were assessed. RESULTS: Significantly lower cognitive function scores, particularly in the domain of working memory, were exhibited in the diabetic group than controls. Balance in the diabetic group was overall poorer in both single- and dual-tasks than controls. When diabetic patients were asked to verbally recall different words while maintaining their balance, their accuracy rate was significantly lower than controls. Some health state measures were found to co-vary with motor function. Increased body mass index in the diabetic group did not account for motor function deficit. SIGNIFICANCE: Our data suggest that: (1) systemic deficit beyond tactile dysfunction and increased body mass index contribute to reduced motor function in diabetes, and (2) both balance and working memory functions are simultaneously impaired in patients with Type 2 diabetes.

Frequency and Correlates of Subjective Cognitive Impairment in HIV Disease.

The increasing prevalence of older adults living with HIV has raised growing concerns about a possible rise in the incidence of neurocognitive disorders due to HIV and other age-related factors. In typical aging, subjective cognitive impairment (SCI) among individuals with normal neurocognitive functioning may be an early manifestation of an incipient neurocognitive disorder. The current study examined the frequency and correlates of SCI in 188 HIV-infected adults without performance-based neurocognitive deficits or a current psychiatric disorder and 133 HIV seronegative comparison participants. All participants completed the Prospective and Retrospective Memory Questionnaire and Profile of Mood States Confusion/Bewilderment scale. Consistent with the diagnostic criteria proposed by Jessen et al. (Alzheimers Dement 10(6):844-852, 2014), participants were classified with SCI if their scores on either of the self-reported measures was greater than 1.5 SD above the normative mean. A logistic regression controlling for current mood complaints and lifetime history of substance use disorders revealed that HIV infection increased the odds of SCI (odds ratio= 4.5 [1.6, 15.4], p = 0.004). Among HIV+ individuals, SCI was associated with lower performance-based learning and delayed memory scores (Cohen's d range 0.41-0.42.) and poorer global everyday functioning (odds ratio= 8.5 [2.6, 15.9]), but not HIV disease severity (ps > 0.10). In a sample of individuals without neurocognitive impairment or elevated mood symptoms, HIV disease was associated with a nearly fivefold increased odds of SCI compared to seronegative individuals, which may indicate an increased risk for developing major neurocognitive disorders as these HIV+ individuals age.

Semantic Memory in HIV-associated Neurocognitive Disorders: An Evaluation of the "Cortical" Versus "Subcortical" Hypothesis.

OBJECTIVE: HIV-associated neurocognitive disorders (HAND) have historically been characterized as a subcortical condition that does not affect semantic memory; however, recent evidence suggests that the cortical regions that support semantic memory may be affected in HIV. METHOD: The current study examined the effects of HAND on semantic memory in 85 HIV+ individuals with HAND, 193 HIV+ individuals without HAND, and 181 HIV- individuals who completed the Boston Naming Test (BNT) and the Famous Faces subtest of the Kauffman Adolescent and Adult Intelligence Test (KAIT-FF). RESULTS: Linear regressions revealed a significant adverse effect of HAND on total scores on the BNT and the KAIT-FF (all ps < .01). Analyses of BNT errors showed that individuals with HAND committed more semantically related errors as compared to the other two study groups (all ps < .05). However, there were no group differences in rates of visually based errors, which are more commonly observed in traditional subcortical diseases (all ps > .10). CONCLUSIONS: Results indicate that HAND may impose adverse effects on individuals' object naming and identification abilities suggestive of mild semantic deficits that parallel traditional cortical diseases such as Alzheimer's disease.

Prevalence and correlates of cognitive asymmetry in a large sample of Alzheimer's disease patients.

Previous research has suggested that a significant minority of patients with Alzheimer's disease (AD) exhibit asymmetric cognitive profiles (greater verbal than visuospatial impairment or vice versa) and that these patient subgroups may differ in demographic and other characteristics. Prior studies have been relatively small, and this investigation sought to examine correlates of asymmetry in a large patient sample (N = 438). Patients were classified into the following cognitive profile groups: low verbal, symmetric, and low visuospatial. Consistent with past research, 28.3% of participants were classified as having asymmetric cognitive profiles, with more participants in the low visuospatial subgroup. Low visuospatial participants were younger than members of the other subgroups, and low verbal participants performed worse on a measure estimating premorbid verbal intelligence. Findings regarding apolipoprotein E (ApoE) ε4 genotype were equivocal, although results provided some evidence for an effect of the ɛ4 allele on cognitive asymmetry. These results suggest systematic differences between neuropsychological asymmetry profiles that support the possibility of distinct subgroups of the disease.

Cognitive and Functional Correlates of NPI-Q Scores and Symptom Clusters in Mildly Demented Alzheimer Patients.

Previous research has demonstrated an association between the emotional and behavioral symptoms of dementia, known as neuropsychiatric symptoms, and cognitive and functional decline among patients with Alzheimer disease (AD). The present study aimed to identify associations between neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and cognitive and functional performance. Participants were 256 AD patients enrolled in the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine. An exploratory factor analysis of the NPI-Q indicated a 2-factor structure consisting of Negative/Oppositional and Anxiety/Restlessness factors. Regression analyses revealed significant associations between greater total severity of neuropsychiatric symptoms and poorer performance on basic and Instrumental Activities of Daily Living. Greater severity of Anxiety/Restlessness symptoms was associated with poor performance on measures of visuospatial functioning and basic and instrumental activities of daily living. The Negative/Oppositional factor was not related to cognition or functioning. In summary, neuropsychiatric symptoms (particularly Anxiety/Restlessness symptoms) were related to cognition and everyday functioning. Proper assessment and treatment of these symptoms is essential for improving cognition and functioning in AD patients.

Rapidly Versus Slowly Progressing Patients With Alzheimer's Disease: Differences in Baseline Cognition.

Rate of progression of cognitive deficits is variable among patients with Alzheimer's disease (AD). The purpose of the current study was to compare demographic characteristics and performance on neuropsychological measures at baseline evaluation between rapidly and slowly progressing patients. Participants were divided into 2 groups based on change in Alzheimer's Disease Assessment Scale-Cognitive subscale score from baseline to 2-year follow-up, and baseline performance was compared between the groups. Participants were 55 rapidly progressing and 55 slowly progressing patients with probable AD who had a follow-up evaluation 21 to 27 months after the baseline evaluation. The groups differed in age and initial Clinical Dementia Rating. Performance differed significantly between the groups on Verbal Series Attention Test time, Logical Memory I, Visual Reproduction I, Block Design, and Controlled Oral Word Association Test. Differences were found between rapidly and slowly progressing patients on baseline neuropsychological testing.

Binomial regression with a misclassified covariate and outcome.

Misclassification occurring in either outcome variables or categorical covariates or both is a common issue in medical science. It leads to biased results and distorted disease-exposure relationships. Moreover, it is often of clinical interest to obtain the estimates of sensitivity and specificity of some diagnostic methods even when neither gold standard nor prior knowledge about the parameters exists. We present a novel Bayesian approach in binomial regression when both the outcome variable and one binary covariate are subject to misclassification. Extensive simulation results under various scenarios and a real clinical example are given to illustrate the proposed approach. This approach is motivated and applied to a dataset from the Baylor Alzheimer's Disease and Memory Disorders Center.

Does Older Age Confer an Increased Risk of Incident Neurocognitive Disorders Among Persons Living with HIV Disease?

OBJECTIVE: This study aimed to determine the combined effects of age and HIV infection on the risk of incident neurocognitive disorders. METHOD: A total of 146 neurocognitively normal participants were enrolled at baseline into one of four groups based on age (≤ 40 years and ≥ 50 years) and HIV serostatus resulting in 24 younger HIV-, 27 younger HIV+, 39 older HIV-, and 56 older HIV+ individuals. All participants were administered a standardized clinical neuropsychological battery at baseline and 14.3 ± .2 months later. RESULTS: A logistic regression predicting incident neurocognitive disorders from HIV, age group, and their interaction was significant (χ(2)[4] = 13.56, p = .009), with a significant main effect of HIV serostatus (χ(2)[1] = 5.01, p = .025), but no main effect of age or age by HIV interaction (ps > .10). Specifically, 15.7% of the HIV+ individuals had an incident neurocognitive disorder as compared to 3.2% of the HIV- group (odds ratio = 4.8 [1.2, 32.6]). Among older HIV+ adults, lower baseline cognitive reserve, prospective memory, and verbal fluency each predicted incident neurocognitive disorders at follow-up. CONCLUSIONS: Independent of age, HIV infection confers a nearly fivefold risk for developing a neurocognitive disorder over approximately one year. Individuals with lower cognitive reserve and mild weaknesses in higher-order neurocognitive functions may be targeted for closer clinical monitoring and preventative measures.

Elevated rates of mild cognitive impairment in HIV disease.

With the rising number of individuals in their 50s and 60s who are infected with HIV, concerns have emerged about possible increases in the rates of non-HIV-associated dementias. The current study examined the prevalence of mild cognitive impairment (MCI) in older HIV-infected adults, since MCI is an intermediate state between typical cognitive aging and dementia that emerges in this age range. Participants included 75 adults with HIV disease aged 50 years and older who were on combination antiretroviral therapy (cART) and had undetectable plasma viral loads and 80 demographically similar HIV-seronegative comparison subjects. Participants completed a research neuropsychological evaluation that was used to classify MCI according to the comprehensive diagnostic scheme described by Bondi et al. (J Alzheimers Dis 42:275-289, 2014). HIV-infected persons were over seven times more likely to have an MCI designation (16 %) than their seronegative counterparts (2.5 %). Within the HIV+ cohort, MCI had minimal overlap with diagnoses of asymptomatic neurocognitive impairment and was significantly associated with older age, lower Karnofsky Scale of Performance Scores, and mild difficulties performing instrumental activities of daily living (iADLs). HIV infection in older adults is associated with a notably elevated concurrent risk of MCI, which may increase the likelihood of developing non-HIV-associated dementias as this population ages further.

Relationships between testosterone levels and cognition in patients with Alzheimer disease and nondemented elderly men.

BACKGROUND/AIMS: Previous research suggests that low levels of testosterone may be associated with the development of Alzheimer disease (AD), as well as poorer performance on certain neuropsychological tests and increased risk of depression. METHODS: This study utilized data from 61 nondemented older men and 68 men with probable AD. RESULTS: Testosterone levels did not differ between the groups. Regression analyses in men with AD revealed that testosterone levels did not significantly predict performance on neuropsychological tests or a measure of depression. Among controls, testosterone levels predicted estimated premorbid verbal IQ and performance on a verbal fluency test. CONCLUSION: Findings suggest that testosterone is not associated with most neuropsychological test performances in patients with AD.

Differences in the association of peripheral insulin and cognitive function in non-diabetic Alzheimer's disease cases and normal controls.

Insulin resistance increases the risk of cognitive impairment and dementia, but higher insulin levels may be cognitively protective after a diagnosis of Alzheimer's disease (AD). The role of peripheral insulin as a predictor of cognitive decline both before and after an AD diagnosis needs further elucidation. We studied 197 AD cases and 198 normal controls enrolled in the Texas Alzheimer's Research and Care Consortium. Standardized protocols were used to collect age, gender, education, body mass index (BMI), serum insulin (not restricted to fasting), hemoglobin A1c (HbA1c), lipids, smoking and cardiovascular disease history, and neuropsychological tests including Mini-Mental State Examination, American National Adult Reading Test (AMNART) errors, Controlled Word Association Test (COWAT), Boston Naming Test, Wechsler Memory Scale-Revised (WMSR) Digit Span, Trails A and B, WMSR Logical Memory (LM) I and II, and Visual Reproduction (VR) I and II. We used linear regression to test the contribution of log-transformed serum insulin to each score, adjusting for age, gender, education, and BMI. In the AD cases, higher serum insulin was associated with worse performance on the COWAT (p < 0.001) and Trails B (p = 0.04). In controls, higher serum insulin was associated with worse performance on the AMNART (p = 0.001), COWAT (p = 0.007), Digit Span (p = 0.004), LM I (p = 0.004), LM II (p = 0.009), and marginally with VR II (p = 0.076). Adjustment for HbA1c, APOE4, and cardiovascular disease, or restricting the sample to mild AD, did not alter these associations. In non-demented older individuals, higher peripheral insulin appears to be associated with worse cognitive performance in multiple domains, but is not a consistent predictor in AD cases. These findings indicate the need for additional research on the role of insulin in the transition between normal and impaired cognitive function.

Factor structure of the Geriatric Depression Scale and relationships with cognition and function in Alzheimer's disease.

BACKGROUND/AIMS: No study to date has systematically explored whether the Geriatric Depression Scale (GDS) measures symptoms of apathy and dysphoria in patients with Alzheimer's disease (AD) or related these constructs to cognitive and functional status. METHODS: Exploratory factor analysis (EFA) was used to identify factors of the GDS in a sample of 569 patients with probable AD. Two-way ANOVAs were used to determine the relationship of apathy and dysphoria to neuropsychological and functional measures. RESULTS: The EFA yielded four factors associated with apathy, dysphoria, social withdrawal and cognitive impairment. Apathy was associated with greater impairments in verbal memory, motor speed, and functional abilities. CONCLUSION: Apathy, but not dysphoria, was associated with some cognitive and functional variables. Results suggest that the GDS may be used as a screening measure for symptoms of apathy in AD.

An examination of the Boston Naming Test: calculation of "estimated" 60-item score from 30- and 15-item scores in a cognitively impaired population.

OBJECTIVE: Multiple versions of the Boston Naming Test (BNT) exist, which makes comparison of findings from different studies difficult. The current project sought to determine if estimated 60-item BNT scores could be reliably calculated from 30- and 15-item administrations with patients diagnosed with Alzheimer's disease (AD). METHODS: Estimated 60-item scores were created for 30-item (even and odd) and 15-item Consortium to Establish a Registry for Alzheimer's disease (CERAD) versions of the BNT from a database containing item-level responses for all BNT items. Correlations were conducted between all three estimated 60-item scores and full 60-item version scores administered to all participants in the sample. RESULTS: The estimated versions were all highly correlated with the standard 60-item version of the BNT across the sample and these findings held when the sample was separated out by case (AD) and control status. Mean difference scores were very small for scores estimated from 30-item administrations; however, difference scores for the 15-item CERAD were much larger. CONCLUSIONS: Estimated 60-item versions of the BNT can be created from 30-item BNT administrations, which will enable comparisons across studies and allow integration of data from various AD research groups for increased power in analytic protocols. Creation of an estimated score from the 15-item CERAD version is not warranted.

Validation of the new interpretive guidelines for the clinical dementia rating scale sum of boxes score in the national Alzheimer's coordinating center database.

BACKGROUND: It was recently demonstrated that the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) score can be used to accurately stage severity of Alzheimer dementia and mild cognitive impairment (MCI). However, to our knowledge, the utility of those interpretive guidelines has not been cross-validated or applied to a heterogeneous sample of dementia cases. OBJECTIVE: To cross-validate the staging guidelines proposed in a previous study using the National Alzheimer's Coordinating Center (NACC) database. DESIGN: The previously published cut scores were applied to the NACC sample and diagnostic accuracy estimates obtained. Next, analyses were restricted to NACC participants with a CDR global score (CDR-GS) of 0.5 and receiver operating characteristic curves generated to determine optimal CDR-SB cut scores for distinguishing MCI from very early dementia. SETTING: The 2008 NACC uniform data set. PARTICIPANTS: There were 12 462 participants (5115 controls; 2551 patients with MCI; 4796 patients with dementia, all etiologies) in the NACC data set used for the current analysis. Main Outcome Measure Accurate prediction of diagnoses (MCI or dementia) using the CDR-SB score. RESULTS: The previously proposed CDR-SB ranges successfully classified the vast majority of patients across all impairment ranges with a kappa of 0.91 and 94% overall correct classification rate. Additionally, the CDR-SB score discriminated between patients diagnosed with MCI and dementia when CDR-GS was restricted to 0.5 (overall area under the curve = 0.83). CONCLUSIONS: These findings cross-validate the previously published CDR-SB interpretative guidelines for staging dementia severity and extend those findings to a large heterogeneous sample of patients with dementia. Additionally, the CDR-SB scores distinguished MCI from dementia in patients with reasonable accuracy when CDR-GS was restricted to 0.5.

Predicting progression of Alzheimer's disease.

INTRODUCTION: Clinicians need to predict prognosis of Alzheimer's disease (AD), and researchers need models of progression to develop biomarkers and clinical trials designs. We tested a calculated initial progression rate to see whether it predicted performance on cognition, function and behavior over time, and to see whether it predicted survival. METHODS: We used standardized approaches to assess baseline characteristics and to estimate disease duration, and calculated the initial (pre-progression) rate in 597 AD patients followed for up to 15 years. We designated slow, intermediate and rapidly progressing groups. Using mixed effects regression analysis, we examined the predictive value of a pre-progression group for longitudinal performance on standardized measures. We used Cox survival analysis to compare survival time by progression group. RESULTS: Patients in the slow and intermediate groups maintained better performance on the cognitive (ADAScog and VSAT), global (CDR-SB) and complex activities of daily living measures (IADL) (P values < 0.001 slow versus fast; P values < 0.003 to 0.03 intermediate versus fast). Interaction terms indicated that slopes of ADAScog and PSMS change for the slow group were smaller than for the fast group, and that rates of change on the ADAScog were also slower for the intermediate group, but that CDR-SB rates increased in this group relative to the fast group. Slow progressors survived longer than fast progressors (P = 0.024). CONCLUSIONS: A simple, calculated progression rate at the initial visit gives reliable information regarding performance over time on cognition, global performance and activities of daily living. The slowest progression group also survives longer. This baseline measure should be considered in the design of long duration Alzheimer's disease clinical trials.

Decreased C-reactive protein levels in Alzheimer disease.

C-reactive protein (CRP) is an acute-phase reactant that has been found to be associated with Alzheimer disease (AD) in histopathological and longitudinal studies; however, little data exist regarding serum CRP levels in patients with established AD. The current study evaluated CRP levels in 192 patients diagnosed with probable AD (mean age = 75.8 +/- 8.2 years; 50% female) as compared to 174 nondemented controls (mean age = 70.6 +/- 8.2 years; 63% female). Mean CRP levels were found to be significantly decreased in AD (2.9 microg/mL) versus controls (4.9 microg/mL; P = .003). In adjusted models, elevated CRP significantly predicted poorer (elevated) Clinical Dementia Rating Scale sum of boxes (CDR SB) scores in patients with AD. In controls, CRP was negatively associated with Mini-Mental State Examination (MMSE) scores and positively associated with CDR SB scores. These findings, together with previously published results, are consistent with the hypothesis that midlife elevations in CRP are associated with increased risk of AD development though elevated CRP levels are not useful for prediction in the immediate prodrome years before AD becomes clinically manifest. However, for a subgroup of patients with AD, elevated CRP continues to predict increased dementia severity suggestive of a possible proinflammatory endophenotype in AD.

Cognitive and affective sequelae of primary hyperparathyroidism and early response to parathyroidectomy.

Cognitive and affective complaints are common in patients with primary hyperparathyroidism (PHPT), but few studies have used psychometric testing to document these symptoms and their response to parathyroidectomy. The current study sought to clarify the nature of cognitive and affective impairments in PHPT and changes postparathyroidectomy. One hundred eleven patients with PHPT underwent neuropsychological evaluation prior to parathyroidectomy with 68 returning for an early postsurgical evaluation. Changes in cognition were assessed using practice effect corrected reliable change indices. Biochemical and anesthesia variables were compared between groups who improved and declined. In a subset of patients, assessment revealed a significant pattern of cognitive slowing, reductions in psychomotor speed, memory impairment, and depression prior to parathyroidectomy. Postsurgical evaluations revealed a trend for improvements on timed tests and depression but a decline in memory. Older patients responded less well to surgical intervention, as did patients who experienced more dramatic changes in biochemical status following surgery. Cognitive changes early postparathyroidectomy are characterized by improved information processing speed and decline in verbal memory, with younger patients more likely to recover during this acute phase. The need for longer-term follow-up studies and increasing utilization of neuropsychological assessments in this population are discussed.