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1.  Modeling Learning and Memory Using Verbal Learning Tests: Results From ACTIVE 
To investigate the influence of memory training on initial recall and learning.
The Advanced Cognitive Training for Independent and Vital Elderly study of community-dwelling adults older than age 65 (n = 1,401). We decomposed trial-level recall in the Auditory Verbal Learning Test (AVLT) and Hopkins Verbal Learning Test (HVLT) into initial recall and learning across trials using latent growth models.
Trial-level increases in words recalled in the AVLT and HVLT at each follow-up visit followed an approximately logarithmic shape. Over the 5-year study period, memory training was associated with slower decline in Trial 1 AVLT recall (Cohen’s d = 0.35, p = .03) and steep pre- and posttraining acceleration in learning (d = 1.56, p < .001). Findings were replicated using the HVLT (decline in initial recall, d = 0.60, p = .01; pre- and posttraining acceleration in learning, d = 3.10, p < .001). Because of the immediate training boost, the memory-trained group had a higher level of recall than the control group through the end of the 5-year study period despite faster decline in learning.
This study contributes to the understanding of the mechanisms by which training benefits memory and expands current knowledge by reporting long-term changes in initial recall and learning, as measured from growth models and by characterization of the impact of memory training on these components. Results reveal that memory training delays the worsening of memory span and boosts learning.
PMCID: PMC3693605  PMID: 22929389
AVLT; Growth modeling; HVLT; Memory training; Older adults
2.  Four-Year Outcome of Mild Cognitive Impairment: The Contribution of Executive Dysfunction 
Neuropsychology  2012;27(1):95-106.
The contribution of executive cognition (EC) to the prediction of incident dementia remains unclear. This prospective study examined the predictive value of EC for subsequent cognitive decline in persons with mild cognitive impairment (MCI) over a 4-year period.
141 persons with MCI (amnestic and non-amnestic, single- and multiple-domain) received a baseline and two biennial follow-up assessments. Eighteen tests, assessing six different aspects of EC, were administered at baseline and at 2-year follow-up, together with screening cognitive and daily functioning measures. Longitudinal logistic regression models and generalized estimating equations (GEE) were used to examine whether EC could predict progression to a Clinical Dementia Rating Scale (CDR) score of 1 or more over the 4-year period, first at the univariate level and then in the context of demographic and clinical characteristics, daily functioning measures and other neurocognitive factors.
Over the 4-year period, 56% of MCI patients remained stable, 35% progressed to CDR≥1, and 8% reverted to normal (CDR=0). Amnestic MCI subtypes were not associated with higher rates of progression to dementia, whereas subtypes with multiple impairments were so associated. Eight out of the 18 EC measures, including all three measures assessing inhibition of prepotent responses, predicted MCI outcome at the univariate level. However, the multivariate GEE model indicated that age, daily functioning, and overall cognitive functioning best predicted progression to dementia.
Measures of EC (i.e., inhibitory control) are associated with MCI outcome. However, age and global measures of cognitive and functional impairment are better predictors of incident dementia.
PMCID: PMC3933818  PMID: 23106114
mild cognitive impairment; predictors; executive cognition; dementia
3.  Screening by Telephone in the Alzheimer's Disease Anti-inflammatory Prevention Trial 
Compared with in-person assessment methods, telephone screening for dementia and other cognitive syndromes may improve efficiency of large population studies or prevention trials. We used data from the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) to compare performance of a four-test Telephone Assessment Battery (TAB) that included the Telephone Interview for Cognitive Status (TICS) to that of a traditional in-person Cognitive Assessment Battery (CAB). Among 1,548 elderly participants with valid telephone and in-person screening results obtained within 90 days of each other, 225 persons were referred for a full cognitive diagnostic evaluation (DE) that was completed within six months of screening. Drawing on results from this panel of 225 individuals, we used the Capture-Recapture method to estimate population numbers of cognitively impaired participants. The latter estimates enabled us to compare the performance characteristics of the two screening batteries at specified cut-offs for detection of dementia and milder forms of impairment. Although our results provide relatively imprecise estimates of the performance characteristics of the two batteries, a comparison of their relative performance suggests that, at selected cut-off points, the TAB produces results broadly comparable to in-person screening and may be slightly more sensitive in detecting mild impairment. TAB performance characteristics also appeared slightly better than those of the TICS alone. Given its benefits in time and cost when screening for cognitive disorders, telephone screening should be considered for large samples.
PMCID: PMC3913728  PMID: 23645097
Telephone; neuropsychology; dementia; Alzheimer disease; mild cognitive impairment; prodromal period; memory disorders; geriatric assessment
4.  Memory Training in the ACTIVE study: How Much is Needed and Who Benefits? 
Journal of aging and health  2012;25(0):10.1177/0898264312461937.
Objectives and Methods
Data from the memory training arm (n = 629) of the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial were examined to characterize change in memory performance through five years of follow-up as a function of memory training, booster training, adherence to training, and other characteristics.
Latent growth model analyses revealed that memory training was associated with improved memory performance through year five, but that neither booster training nor training adherence significantly influenced this effect. Baseline age was associated with change in memory performance attributable to the passage of time alone (i.e., to aging). Higher education and better self-rated health were associated with greater change in memory performance after training.
These findings confirm that memory training can aid in maintaining long-term improvements in memory performance. Booster training and adherence to training do not appear to attenuate rates of normal age-related memory decline.
PMCID: PMC3825774  PMID: 23103452
ACTIVE trial; memory training; training adherence; cognitive training; aging; memory decline
5.  A new algorithm for predicting time to disease endpoints in Alzheimer's patients 
Journal of Alzheimer's disease : JAD  2014;38(3):10.3233/JAD-131142.
The ability to predict the length of time to death and institutionalization has strong implications for Alzheimer’s disease patients and caregivers, health policy, economics, and the design of intervention studies.
To develop and validate a prediction algorithm that uses data from a single visit to estimate time to important disease endpoints for individual Alzheimer’s disease patients.
Two separate study cohorts (Predictors 1, N = 252; Predictors 2, N = 254), all initially with mild Alzheimer’s disease, were followed for 10 years at three research centers with semiannual assessments that included cognition, functional capacity, and medical, psychiatric and neurologic information. The prediction algorithm was based on a longitudinal Grade of Membership model developed using the complete series of semiannually-collected Predictors 1 data. The algorithm was validated on the Predictors 2 data using data only from the initial assessment to predict separate survival curves for three outcomes.
For each of the three outcome measures, the predicted survival curves fell well within the 95% confidence intervals of the observed survival curves. Patients were also divided into quintiles for each endpoint to assess the calibration of the algorithm for extreme patient profiles. In all cases, the actual and predicted survival curves were statistically equivalent. Predictive accuracy was maintained even when key baseline variables were excluded, demonstrating the high resilience of the algorithm to missing data.
The new prediction algorithm accurately predicts time to death, institutionalization, and need for full-time care in individual Alzheimer’s disease patients; it can be readily adapted to predict other important disease endpoints. The algorithm will serve an unmet clinical, research, and public health need.
PMCID: PMC3864687  PMID: 24064468
Alzheimer’s disease; prediction algorithm; time to death; nursing home; full-time care; grade of membership model
6.  Brain metabolite alterations and cognitive dysfunction in early Huntington’s Disease 
Movement Disorders  2012;27(7):895-902.
Huntington’s Disease (HD) is a neurodegenerative disorder characterized by early cognitive decline, which progresses at later stages to dementia and severe movement disorder. HD is caused by a cytosine-adenine-guanine triplet-repeat expansion mutation in the Huntingtin gene, allowing early diagnosis by genetic testing. This study aims to identify the relationship of N-acetylaspartate and other brain metabolites to cognitive function in HD-mutation carriers by using high field strength magnetic-resonance-spectroscopy at 7-Tesla.
Twelve individuals with the HD-mutation in premanifest or early stage of disease versus twelve healthy controls underwent 1H magnetic-resonance-spectroscopy (7.2ml voxel in the posterior cingulate cortex) at 7-Tesla, and also T1-weighted structural magnetic-resonance-imaging. All participants received standardized tests of cognitive functioning including the Montreal Cognitive Assessment and standardized quantified neurological examination within an hour before scanning.
Individuals with the HD mutation had significantly lower posterior cingulate cortex N-acetylaspartate (−9.6%, p=0.02) and glutamate levels (−10.1%, p=0.02) than controls. By contrast, in this small group, measures of brain morphology including striatal and ventricle volumes did not differ significantly. Linear regression with Montreal Cognitive Assessment scores revealed significant correlations with N-acetylaspartate (r2=0.50, p=0.01) and glutamate (r2=0.64, p=0.002) in HD subjects.
Our data suggest a relationship between reduced N-acetylaspartate and glutamate levels in the posterior cingulate cortex with cognitive decline in early stages of HD. N-acetylaspartate and glutamate magnetic-resonance-spectroscopy signals of the posterior cingulate cortex region may serve as potential biomarkers of disease progression or treatment outcome in HD and other neurodegenerative disorders with early cognitive dysfunction, when structural brain changes are still minor.
PMCID: PMC3383395  PMID: 22649062
MRS; NAA; glutamate; cognition; neurodegeneration; biomarker
7.  12-month incidence, prevalence, persistence, and treatment of mental disorders among individuals recently admitted to assisted living facilities in Maryland 
To estimate the 12-month incidence, prevalence, and persistence of mental disorders among recently admitted assisted living (AL) residents and to describe the recognition and treatment of these disorders.
Two hundred recently admitted AL residents in 21 randomly selected AL facilities in Maryland received comprehensive physician-based cognitive and neuropsychiatric evaluations at baseline and 12 months later. An expert consensus panel adjudicated psychiatric diagnoses (using DSM-IV-TR criteria) and completeness of workup and treatment. Incidence, prevalence, and persistence were derived from the panel's assessment. Family and direct care staff recognition of mental disorders was also assessed.
At baseline, three-quarters suffered from a cognitive disorder (56% dementia, 19% Cognitive Disorders Not Otherwise Specified) and 15% from an active non-cognitive mental disorder. Twelve-month incidence rates for dementia and non-cognitive psychiatric disorders were 17% and 3% respectively, and persistence rates were 89% and 41% respectively. Staff recognition rates for persistent dementias increased over the 12-month period but 25% of cases were still unrecognized at 12 months. Treatment was complete at 12 months for 71% of persistent dementia cases and 43% of persistent non-cognitive psychiatric disorder cases.
Individuals recently admitted to AL are at high risk for having or developing mental disorders and a high proportion of cases, both persistent and incident, go unrecognized or untreated. Routine dementia and psychiatric screening and reassessment should be considered a standard care practice. Further study is needed to determine the longitudinal impact of psychiatric care on resident outcomes and use of facility resources.
PMCID: PMC3648853  PMID: 23290818
incidence; dementia; psychiatric disorder; treatment; recognition
8.  Parallel But Not Equivalent: Challenges and Solutions for Repeated Assessment of Cognition over Time 
Analyses of individual differences in change may be unintentionally biased when versions of a neuropsychological test used at different follow-ups are not of equivalent difficulty. This study’s objective was to compare mean, linear, and equipercentile equating methods and demonstrate their utility in longitudinal research.
Study Design and Setting
The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE, N=1,401) study is a longitudinal randomized trial of cognitive training. The Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=819) is an observational cohort study. Nonequivalent alternate versions of the Auditory Verbal Learning Test (AVLT) were administered in both studies.
Using visual displays, raw and mean-equated AVLT scores in both studies showed obvious nonlinear trajectories in reference groups that should show minimal change, poor equivalence over time (ps≤0.001), and raw scores demonstrated poor fits in models of within-person change (RMSEAs>0.12). Linear and equipercentile equating produced more similar means in reference groups (ps≥0.09) and performed better in growth models (RMSEAs<0.05).
Equipercentile equating is the preferred equating method because it accommodates tests more difficult than a reference test at different percentiles of performance and performs well in models of within-person trajectory. The method has broad applications in both clinical and research settings to enhance the ability to use nonequivalent test forms.
PMCID: PMC3574868  PMID: 22540849
equating; equipercentile; neuropsychology; longitudinal analysis; alternate forms; parallel forms
9.  Assessment of cognition in early dementia 
Better tools for assessing cognitive impairment in the early stages of Alzheimer’s disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer’s Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.
PMCID: PMC3613863  PMID: 23559893
10.  Internet-Based Screening for Dementia Risk 
PLoS ONE  2013;8(2):e57476.
The Dementia Risk Assessment (DRA) is an online tool consisting of questions about known risk factors for dementia, a novel verbal memory test, and an informant report of cognitive decline. Its primary goal is to educate the public about dementia risk factors and encourage clinical evaluation where appropriate. In Study 1, more than 3,000 anonymous persons over age 50 completed the DRA about themselves; 1,000 people also completed proxy reports about another person. Advanced age, lower education, male sex, complaints of severe memory impairment, and histories of cerebrovascular disease, Parkinson's disease, and brain tumor all contributed significantly to poor memory performance. A high correlation was obtained between proxy-reported decline and actual memory test performance. In Study 2, 52 persons seeking first-time evaluation at dementia clinics completed the DRA prior to their visits. Their responses (and those of their proxy informants) were compared to the results of independent evaluation by geriatric neuropsychiatrists. The 30 patients found to meet criteria for probable Alzheimer's disease, vascular dementia, or frontotemporal dementia differed on the DRA from the 22 patients without dementia (most other neuropsychiatric conditions). Scoring below criterion on the DRA's memory test had moderately high predictive validity for clinically diagnosed dementia. Although additional studies of larger clinical samples are needed, the DRA holds promise for wide-scale screening for dementia risk.
PMCID: PMC3578821  PMID: 23437393
11.  Measurement Equivalence in ADL and IADL Difficulty Across International Surveys of Aging: Findings From the HRS, SHARE, and ELSA 
To examine the measurement equivalence of items on disability across three international surveys of aging.
Data for persons aged 65 and older were drawn from the Health and Retirement Survey (HRS, n = 10,905), English Longitudinal Study of Aging (ELSA, n = 5,437), and Survey of Health, Ageing and Retirement in Europe (SHARE, n = 13,408). Differential item functioning (DIF) was assessed using item response theory (IRT) methods for activities of daily living (ADL) and instrumental activities of daily living (IADL) items.
HRS and SHARE exhibited measurement equivalence, but 6 of 11 items in ELSA demonstrated meaningful DIF. At the scale level, this item-level DIF affected scores reflecting greater disability. IRT methods also spread out score distributions and shifted scores higher (toward greater disability). Results for mean disability differences by demographic characteristics, using original and DIF-adjusted scores, were the same overall but differed for some subgroup comparisons involving ELSA.
Testing and adjusting for DIF is one means of minimizing measurement error in cross-national survey comparisons. IRT methods were used to evaluate potential measurement bias in disability comparisons across three international surveys of aging. The analysis also suggested DIF was mitigated for scales including both ADL and IADL and that summary indexes (counts of limitations) likely underestimate mean disability in these international populations.
PMCID: PMC3267026  PMID: 22156662
Activities of daily living; Differential item functioning; Disability
12.  Cognitive Predictors of Everyday Functioning in Older Adults: Results From the ACTIVE Cognitive Intervention Trial 
The present study sought to predict changes in everyday functioning using cognitive tests.
Data from the Advanced Cognitive Training for Independent and Vital Elderly trial were used to examine the extent to which competence in different cognitive domains—memory, inductive reasoning, processing speed, and global mental status—predicts prospectively measured everyday functioning among older adults. Coefficients of determination for baseline levels and trajectories of everyday functioning were estimated using parallel process latent growth models.
Each cognitive domain independently predicts a significant proportion of the variance in baseline and trajectory change of everyday functioning, with inductive reasoning explaining the most variance (R2 = .175) in baseline functioning and memory explaining the most variance (R2 = .057) in changes in everyday functioning.
Inductive reasoning is an important determinant of current everyday functioning in community-dwelling older adults, suggesting that successful performance in daily tasks is critically dependent on executive cognitive function. On the other hand, baseline memory function is more important in determining change over time in everyday functioning, suggesting that some participants with low baseline memory function may reflect a subgroup with incipient progressive neurologic disease.
PMCID: PMC3155028  PMID: 21558167
Cognition; Cognitive training; Everyday functioning; Structural equation modeling
13.  Extended results of the Alzheimer disease anti-inflammatory prevention trial (ADAPT) 
Epidemiologic evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer’s dementia (AD), but randomized trials show no benefit from NSAIDs in symptomatic AD. ADAPT randomized 2,528 elderly persons to naproxen or celecoxib vs. placebo for two years (s.d. 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups.
We continued the double-masked ADAPT protocol for two additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ1–42.
Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were now 72 AD cases. Overall NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with Cognitive Impairment – No Dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration.
These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, thus: NSAIDs have an adverse effect in later stages of AD pathogenesis, while asymptomatic individuals treated with conventional NSAIDs like naproxen experience reduced AD incidence, but only after 2 – 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.
PMCID: PMC3149804  PMID: 21784351
14.  Utilization of Antihypertensives, Antidepressants, Antipsychotics, and Hormones in Alzheimer’s Disease 
This study explores the longitudinal relationship between patient characteristics and use of four drug classes (antihypertensives, antidepressants, antipsychotics, and hormones) that showed significant changes in use rates over time in patients with Alzheimer’s disease (AD). Patient/caregiver-reported prescription medication usage was categorized by drug class for 201 patients from the Predictors Study. Patient characteristics included use of cholinesterase inhibitors and/or memantine, function, cognition, living situation, baseline age, and gender. Assessment interval, year of study entry, and site were controlled for. Before adjusting for covariates, use increased for antihypertensives (47.8% to 62.2%), antipsychotics (3.5% to 27.0%), and antidepressants (32.3% to 40.5%); use of hormones decreased (19.4% to 5.4%). After controlling for patient characteristics, effects of time on the use of antidepressants were no longer significant. Antihypertensive use was associated with poorer functioning, concurrent use of memantine, and older age. Antipsychotic use was associated with poorer functioning and poorer cognition. Antidepressant use was associated with younger age, poorer functioning, and concurrent use of cholinesterase inhibitors and memantine. Hormone use was associated with being female and younger age. Findings suggest accurate modeling of the AD treatment paradigm for certain subgroups of patients should include antihypertensives and antipsychotics in addition to cholinesterase inhibitors and memantine.
PMCID: PMC3075380  PMID: 20975515
Alzheimer’s disease; antihypertensive; antidepressant; antipsychotic; hormone; longitudinal studies
15.  The Fate of the 0.5s: Predictors of 2-Year Outcome in Mild Cognitive Impairment 
Impairments in executive cognition (EC) may be predictive of incident dementia in patients with mild cognitive impairment (MCI). The present study examined whether specific EC tests could predict which MCI individuals progress from a Dementia Rating Scale (CDR) score of 0.5 to a score ≥1 over a 2-year period. Eighteen clinical and experimental EC measures were administered at baseline to 104 MCI patients (amnestic and non-amnestic, single- and multiple-domain) recruited from clinical and research settings. Demographic characteristics, screening cognitive measures and measures of everyday functioning at baseline were also considered as potential predictors. Over the two-year period, 18% of the MCI individuals progressed to CDR≥1, 73.1% remained stable (CDR=0.5), and 4.5% reverted to normal (CDR=0). Multiple-domain MCI participants had higher rates of progression to dementia than single-domain, but amnestic and non-amnestic MCIs had similar rates of conversion. Only three EC measures were predictive of subsequent cognitive and functional decline at the univariate level, but they failed to independently predict progression to dementia after adjusting for demographic, other cognitive characteristics, and measures of everyday functioning. Decline over 2 years was best predicted by informant ratings of subtle functional impairments and lower baseline scores on memory, category fluency and constructional praxis.
PMCID: PMC3078700  PMID: 21205413
Mild cognitive impairment; dementia; predictors of decline; executive cognition; Clinical Dementia Rating scale; MCI outcome
16.  Word List Memory Predicts Everyday Function and Problem-Solving in the Elderly: Results from the ACTIVE Cognitive Intervention Trial 
Data from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial (N=2,802) were analyzed to examine whether word list learning predicts future everyday functioning. Using stepwise random effects modeling, measures from the modified administrations of the Hopkins Verbal Learning Test (HVLT) and the Auditory Verbal Learning Test (AVLT) were independently predictive of everyday IADL functioning, problem-solving, and psychomotor speed. Associations between memory scores and everyday functioning outcomes remained significant across follow-up intervals spanning five years. HVLT total recall score was consistently the strongest predictor of each functional outcome. Results suggest that verbal memory measures are uniquely associated with both current and future functioning and that specific verbal memory tests like the HVLT and AVLT have important clinical utility in predicting future functional ability among older adults.
PMCID: PMC3265385  PMID: 21069610
functional ability; HVLT; AVLT; verbal memory
17.  Longitudinal Medication Usage in Alzheimer Disease Patients 
This study examined in detail patterns of cholinesterase inhibitors (ChEIs) and memantine use and explored the relationship between patient characteristics and such use. Patients with probable Alzheimer disease AD (n = 201) were recruited from the Predictors Study in 3 academic AD centers and followed from early disease stages for up to 6 years. Random effects logistic regressions were used to examine effects of patient characteristics on ChEIs/memantine use over time. Independent variables included measures of function, cognition, comorbidities, the presence of extrapyramidal signs, psychotic symptoms, age, sex, and patient’s living situation at each interval. Control variables included assessment interval, year of study entry, and site. During a 6-year study period, rate of ChEIs use decreased (80.6% to 73.0%) whereas memantine use increased (2.0% to 45.9%). Random effects logistic regression analyses showed that ChEI use was associated with better function, no psychotic symptoms, and younger age. Memantine use was associated with better function, poorer cognition, living at home, later assessment interval, and later year of study entry. Results suggest that high rate of ChEI use and increasing memantine use over time are consistent with current practice guidelines of initiation of ChEIs in mild-to-moderate AD patients and initiation of memantine in moderate-to-severe patients.
PMCID: PMC3087865  PMID: 20625271
Alzheimer disease; cholinesterase inhibitors; memantine; longitudinal studies
18.  Clinical Characteristics and Longitudinal Changes of Informal Cost of Alzheimer’s Disease in the Community 
Most estimates of the cost of informal caregiving in patients with Alzheimer’s disease (AD) remain cross-sectional. Longitudinal estimates of informal caregiving hours and costs are less frequent and are from assessments covering only short periods of time. The objectives of this study were to estimate long-term trajectories of the use and cost of informal caregiving for patients with AD and the effects of patient characteristics on the use and cost of informal caregiving. The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed annually for up to 7 years in three university-based AD centers in the United States (n = 170). Generalized linear mixed models were used to estimate the effects of patient characteristics on use and cost of informal caregiving. Patients’ clinical characteristics included cognitive status (Mini-Mental State Examination), functional capacity (Blessed Dementia Rating Scale (BDRS)), comorbidities, psychotic symptoms, behavioral problems, depressive symptoms, and extrapyramidal signs. Results show that rates of informal care use and caregiving hours (and costs) increased substantially over time but were related differently to patients’ characteristics. Use of informal care was significantly associated with worse cognition, worse function, and higher comorbidities. Conditional on receiving informal care, informal caregiving hours (and costs) were mainly associated with worse function. Each additional point on the BDRS increased informal caregiving costs 5.4%. Average annual informal cost was estimated at $25,381 per patient, increasing from $20,589 at baseline to $43,030 in Year 4.
PMCID: PMC3229197  PMID: 17038080
informal care; costs; Alzheimer’s disease; longitudinal study
19.  A Recommended Scale for Cognitive Screening in Clinical Trials of Parkinson’s Disease 
Cognitive impairment is common in Parkinson’s disease (PD). There is a critical need for a brief, standard cognitive screening measure for use in PD trials whose primary focus is not on cognition.
The Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group formed a Task Force to make recommendations for a cognitive scale that could screen for dementia and mild cognitive impairment in clinical trials of PD where cognition is not the primary outcome. This Task Force conducted a systematic literature search for cognitive assessments previously used in a PD population. Scales were then evaluated for their appropriateness to screen for cognitive deficits in clinical trials, including brief administration time (<15 minutes), assessment of the major cognitive domains, and potential to detect subtle cognitive impairment in PD.
Five scales of global cognition met the predetermined screening criteria and were considered for review. Based on the Task Force’s evaluation criteria the Montreal Cognitive Assessment (MoCA), appeared to be the most suitable measure.
This Task Force recommends consideration of the MoCA as a minimum cognitive screening measure in clinical trials of PD where cognitive performance is not the primary outcome measure. The MoCA still requires further study of its diagnostic utility in PD populations but appears to be the most appropriate measure among the currently available brief cognitive assessments. Widespread adoption of a single instrument such as the MoCA in clinical trials can improve comparability between research studies on PD.
PMCID: PMC2978783  PMID: 20878991
20.  Auditory Confrontation Naming in Alzheimer’s Disease 
The Clinical neuropsychologist  2010;24(8):1326-1338.
Naming is a fundamental aspect of language and is virtually always assessed with visual confrontation tests. Tests of the ability to name objects by their characteristic sounds would be particularly useful in the assessment of visually impaired patients, and may be particularly sensitive in Alzheimer’s disease (AD). We developed an Auditory Naming Task, requiring the identification of the source of environmental sounds (i.e., animal calls, musical instruments, vehicles) and multiple-choice recognition of those not identified. In two separate studies, mild-to-moderate AD patients performed more poorly than cognitively normal elderly on the Auditory Naming Task. This task was also more difficult than two versions of a comparable Visual Naming Task, and correlated more highly with Mini-Mental State Exam score. Internal consistency reliability was acceptable, although ROC analysis revealed auditory naming to be slightly less successful than visual confrontation naming in discriminating AD patients from normal subjects. Nonetheless, our Auditory Naming Test may prove useful in research and clinical practice, especially with visually-impaired patients.
PMCID: PMC2992092  PMID: 20981630
21.  Episodic Memory in Dementia: Characteristics of New Learning that Differentiate Alzheimer's, Huntington's, and Parkinson's Diseases 
Differences in the memory characteristics of patients with Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD) were investigated with tests that assess learning and retention of words, line-drawn objects, and locations. Large groups of AD, HD, and PD patients were administered the Hopkins Verbal Learning Test-Revised (HVLT-R) and the Hopkins Board (HB). Eight learning and memory measures were subjected to discriminant function analysis. A 91% classification accuracy was achieved for the separation of cortical and subcortical dementias and 79% accuracy for the discrimination of the three groups. The delayed recall of items was the best discriminator. Receiver-operating curve analysis indicated up to 90% sensitivity and 90% specificity in differentiating the three diseases using the discriminant scores. Individual learning and memory measures of the HVLT-R and the HB provided very high sensitivity and specificity in distinguishing cortical versus subcortical dementias and modest accuracy in separating the two subcortical diseases.
PMCID: PMC2904670  PMID: 20530592
Episodic memory; Alzheimer's disease; Huntington's disease; Parkinson's disease
22.  The physical environment influences neuropsychiatric symptoms and other outcomes in assisted living residents 
Although the number of elderly residents living in assisted living (AL) facilities is rising, few studies have examined the AL physical environment and its impact on resident well-being. We sought to quantify the relationship of AL physical environment with resident outcomes including neuropsychiatric symptoms (NPS), quality of life (QOL), and fall risk, and to compare the effects for demented and non-demented residents.
Prospective cohort study of a stratified random sample of 326 AL residents living in 21 AL facilities. Measures included the Therapeutic Environmental Screening Scale for Nursing Homes and Residential Care (TESS-NH/RC) to rate facilities and in-person assessment of residents for diagnosis (and assessment of treatment) of dementia, ratings on standardized clinical, cognitive, and QOL measures. Regression models compared environmental measures with outcomes. TESS-NH/RC is modified into a scale for rating the AL physical environment AL-EQS.
The AL Environmental Quality Score (AL-EQS) was strongly negatively associated with Neuropsychiatric Inventory (NPI) total score (p <0.001), positively associated with Alzheimer Disease Related Quality of Life (ADRQL) score (p = 0.010), and negatively correlated with fall risk (p = 0.042). Factor analysis revealed an excellent two-factor solution, Dignity and Sensory. Both were strongly associated with NPI and associated with ADRQL.
The physical environment of AL facilities likely affects NPS and QOL in AL residents, and the effect may be stronger for residents without dementia than for residents with dementia. Environmental manipulations that increase resident privacy, as well as implementing call buttons and telephones, may improve resident well-being.
PMCID: PMC3143504  PMID: 20077498
physical environment; neuropsychiatric symptoms; assisted living; behavior; dementia
23.  Gray matter in amnestic mild cognitive impairment: voxel-based morphometry 
Neuroreport  2010;21(4):259-263.
Multiple regression voxel-based morphometry analyses were used to examine the relationship between regional gray matter volumes and neurocognitive performance in 10 patients with amnestic mild cognitive impairment and 20 healthy age-matched controls. Cognitive functioning was assessed with seven standardized neuropsychological tests. Patients with amnestic mild cognitive impairment exhibited impaired cognitive performance (on the Mini Mental State Examination, tests of verbal fluency, verbal and spatial learning and memory, and visual-motor abilities) and reduced gray matter volume in the right temporal pole. Across all participants, better performance on several neuropsychological tests was associated with higher regional gray matter volumes. Voxel-based morphometry provides an operator-unbiased means to investigate volumetric differences, which may be related to impaired neuropsychological functioning.
PMCID: PMC3041512  PMID: 20042900
aging; gray matter volume; mild cognitive impairment; neuropsychological assessment; temporal lobe; voxel-based morphometry
24.  Delusions and Hallucinations Are Associated With Worse Outcome in Alzheimer Disease 
Archives of neurology  2005;62(10):1601-1608.
Delusions and hallucinations are common in Alzheimer disease (AD) and there are conflicting reports regarding their ability to predict cognitive decline, functional decline, and institutionalization. According to all previous literature, they are not associated with mortality.
To examine whether the presence of delusions or hallucinations has predictive value for important outcomes in AD.
Design, Setting, and Participants
A total of 456 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] score of 21 of 30 at entry) were recruited and followed up semiannually for up to 14 years (mean, 4.5 years) in 5 university-based AD centers in the United States and Europe. Using the Columbia University Scale for Psychopathology in AD (administered every 6 months, for a total of 3266 visit-assessments, average of 7.2 per patient), the presence of delusions and hallucinations was extracted and examined as time-dependent predictors in Cox models. The models controlled for cohort effect, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and baseline functional performance, behavioral symptoms, and use of neuroleptics and cholinesterase inhibitors.
Main Outcome Measures
Cognitive (Columbia MMSE score of ≤20/57 [approximate Folstein MMSE score of ≤10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of ≥10), institutionalization equivalent index, and death.
During the full course of follow-up, 38% of patients reached the cognitive, 41% the functional, 54% the institutionalization, and 49% the mortality end point. Delusions were noted for 34% of patients at baseline and 70% at any evaluation. Their presence was associated with increased risk for cognitive (risk ratio [RR], 1.50; 95% confidence interval [CI], 1.07-2.08) and functional decline (RR, 1.41; 95% CI, 1.02-1.94). Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline (RR, 1.62; 95% CI, 1.06-2.47), functional decline (RR, 2.25; 95% CI, 1.54-2.27), institutionalization (RR, 1.60; 95% CI, 1.13-2.28), and death (RR, 1.49; 95% CI, 1.03-2.14).
Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.
PMCID: PMC3028538  PMID: 16216946
25.  Everyday functioning in mild cognitive impairment and its relationship with executive cognition 
Elderly persons with mild cognitive impairment (MCI) are at increased risk of dementia and functional impairments. The present study investigated the contribution of three domains of executive cognition to everyday functioning among persons with MCI.
124 MCI patients and 68 cognitively normal elderly participants were administered a cognitive screening battery. These tests were used to divide patients into four subgroups (amnestic single domain, amnestic multiple domain, non-amnestic single domain, and non-amnestic multiple domain). Subjects were then administered 18 executive function tests that assess planning/problem-solving, working memory, and judgment. Performance of everyday activities and everyday cognition was rated with two informant-reported measures.
All MCI subtypes had more difficulties in everyday activities than cognitively normal elderly participants. Multiple domain MCI patients had more functional impairments than single domain MCI patients. Contrary to our expectations, only one executive function component, working memory, contributed significantly to functional status after controlling for demographic, health-related and other cognitive factors.
Functional abilities are compromised in all MCI subtypes. Working memory may be associated with functional impairments, but general cognitive measures account for more unique variance.
PMCID: PMC2987652  PMID: 19650160
everyday functioning; executive cognition; working memory; mild cognitive impairment

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