Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial.

BACKGROUND: Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials. OBJECTIVE: To evaluate the association between amyloid (Aß) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS). DESIGN: Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis. SETTING: The EARLY study was conducted at 143 centers across 14 countries. PARTICIPANTS: 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with Aß status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aß levels (Aß-, n=2,824) and those with pathological Aß levels (Aß+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aß1-42. MEASUREMENTS: Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aß groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aß status. RESULTS: Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. Aß+ participants performed worse versus Aß- participants on all cognitive composites though the magnitude of the Aß effect was generally small. The Aß+/- effect size for the PACC (Cohen's d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest Aß+/- effect sizes. CONCLUSIONS: Cross-sectional relationships between Aß and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aß+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aß status cross-sectionally cannot be generalized to sensitivity to change over time.

Prospective Evaluation of Cognitive Health and Related Factors in Elderly at Risk for Developing Alzheimer's Dementia: A Longitudinal Cohort Study.

BACKGROUND: The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer's disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD). OBJECTIVES: The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup. DESIGN: This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor. RESULTS: 987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor's or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%). Conclusion (clinical relevance): AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.

Psychometric Evaluation of the Neuropsychological Test Battery in Individuals with Normal Cognition, Mild Cognitive Impairment, or Mild to Moderate Alzheimer's Disease: Results from a Longitudinal Study.

BACKGROUND: The Neuropsychological Test Battery (NTB) is a combination of widely used clinical neuropsychological tests measuring memory and executive function and was designed to overcome some of the limitations of the traditionally used Alzheimer's disease Assessment Scale - Cognitive subscale (ADAS-Cog). A previously reported account indicated high levels of NTB reliability in patients with mild-to-moderate Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVES: We examined capacity of the Neuropsychological Test Battery (NTB) and its component subtests to measure cognitive change over time. Correlations with other cognitive and functional assessments were also determined. Design, Settings, Participants: This was a multicentre, prospective, non-interventional, longitudinal cohort study involving patients with mild-to-moderate AD (n=196), MCI (n=70), or cognitively normal control participants (NC, n=75). INTERVENTION: The NTB, as well as other Clinical Outcome Assessments including, ADAS-Cog, other cognitive measures, functional/behavioral questionnaires, health outcome questionnaires, and resource utilization tools were administered. RESULTS: Mean change from baseline for the NTB composite score and the six individual NTB subtests showed greater reductions in performance over time in the AD and MCI groups, compared with NC group. The ADAS-Cog was found to be more sensitive to change than the NTB in all three populations. CONCLUSIONS: The NTB showed high correlation with the ADAS-Cog and appears to be a sensitive and reliable assessment tool for measuring cognitive decline in patients with mild-to-moderate AD. However, the ADAS-Cog was found to be more sensitive to change over time in both the AD and MCI populations.

A Randomized, Double-Blind, Phase 2 Study of the Effects of the Vaccine Vanutide Cridificar with QS-21 Adjuvant on Immunogenicity, Safety and Amyloid Imaging in Patients with Mild to Moderate Alzheimer's Disease.

BACKGROUND: Vanutide Cridificar (ACC-001), a novel investigational immunotherapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease (AD). OBJECTIVES: To evaluate the immunogenicity, safety and impact of ACC-001 with Quillaja saponaria (QS-21) adjuvant on the reduction of brain fibrillar amyloid burden, assayed by positron emission tomography (PET) imaging, in patients with mild to moderate AD. DESIGN: Randomized, phase 2, interventional study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01284387. PARTICIPANTS: Individuals with mild to moderate Alzheimer's disease (Mini-Mental State Examination scores 18-26; measurable amyloid burden in the expected range, on the screening 18F-florbetapir PET scan; and a Rosen modified Hachinski ischemic score ≤4). INTERVENTION: Participants were randomized to 3 µg or 10 µg ACC-001 (each in combination with 50 µg QS-21) or placebo (without QS-21). MEASUREMENTS: Primary endpoint was the change from baseline to week 104 in cerebral amyloid burden as measured by the global cortical average (GCA) standard value uptake ratio (SUVR) based on the brain 18F-florbetapir PET composite cortical SUVR between each ACC-001+QS-21 dose compared with placebo. Secondary endpoints included safety, immunogenicity and pharmacodynamics. Exploratory endpoints included cognitive and functional efficacy, and health outcome measures. RESULTS: Of 126 randomized patients (placebo: 40; ACC-001 3 µg+QS-21: 43; and ACC-001 10 µg+QS-21: 43), 125 received study treatment; 92 (73%) completed the study. Change in 18F-florbetapir PET GCA SUVR, was not significantly different between either of the two ACC-001+QS-21 treatment groups and placebo (3 µg +QS-21 vs. placebo diff=-0.03, p=0.54; 10 µg +QS-21 vs. placebo diff=-0.08, p=0.07), but the trend was numerically consistent with a dose response. The geometric mean peak anti-Aß IgG titers were slightly higher in the 10 µg than the 3 µg group. The proportion of responders was similar in both dose groups of ACC-001+QS-21. The cerebrospinal fluid (CSF) p-tau changes from baseline in both active treatment groups were not statistically different from placebo, but were numerically consistent with a dose response (3 µg +QS-21 vs. placebo diff=-3.2, p=0.57; 10 µg +QS-21 vs. placebo diff=-7.0, p=0.19). The vMRI showed statistically significant faster treatment-related decrease in brain volume in the 10 µg group but was not significant in the 3 µg group, compared with placebo (3 µg diff =-1.3 mL/year, p=0.50; 10 µg diff=-4.2 mL/year, p=0.02). Measured plasma Aß levels increased in parallel with peak anti-Aß titers after each injection. Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) were more frequent in patients who received ACC-001+QS-21 than placebo (6% vs. 0%) but none were symptomatic. The most common treatment-emergent adverse events in the active groups were injection reactions, and occurred more frequently in the ACC-001+QS-21 groups than the placebo (48% vs 8%), the majority of which were mild and transient. CONCLUSIONS: Primary biomarker efficacy endpoints were not statistically significant in either dose group. The numerical decreases in 18F-florbetapir PET GCA SUVR suggests a dose-related trend for greater reductions in fibrillar amyloid burden in the ACC-001+QS-21 10 µg group compared with placebo. Likewise, while not significant, there was a numerical trend of decreased CSF p-tau levels with ACC-001, possibly consistent with a downstream effect in the ACC-001+QS-21 group. Insufficient antibody titers or quality, insufficient power to detect a difference, or too short duration of follow up may be reasons why a statistically significant response was not observed. Brain volume measures showed faster volume loss in the 10 µg treatment group, similar to the effect seen in few earlier AD immunotherapy trials which may suggest removal of amyloid and resultant decrease in inflammation. No new, unexpected safety signals were detected.

MR imaging features of amyloid-related imaging abnormalities.

BACKGROUND AND PURPOSE: AD is one of the few leading causes of death without a disease-modifying drug; however, hopeful agents are in various phases of development. MR imaging abnormalities, collectively referred to as amyloid-related imaging abnormalities, have been reported for several agents that target cerebral Aß burden. ARIA includes ARIA-E, parenchymal or sulcal hyperintensities on FLAIR indicative of parenchymal edema or sulcal effusions, and ARIA-H, hypointense regions on gradient recalled-echo/T2* indicative of hemosiderin deposition. This report describes imaging characteristics of ARIA-E and ARIA-H identified during studies of bapineuzumab, a humanized monoclonal antibody against Aß. MATERIALS AND METHODS: Two neuroradiologists with knowledge of imaging changes reflective of ARIA reviewed MR imaging scans from 210 bapineuzumab-treated patients derived from 3 phase 2 studies. Each central reader interpreted the studies independently, and discrepancies were resolved by consensus. The inter-reader κ was 0.76, with 94% agreement between neuroradiologists regarding the presence or absence of ARIA-E in individual patients. RESULTS: Thirty-six patients were identified with incident ARIA-E (17.1%, 36/210) and 26 with incident ARIA-H (12.4%, 26/210); of those with incident ARIA-H, 24 had incident microhemorrhages and 2 had incident large superficial hemosiderin deposits. CONCLUSIONS: In 49% of cases of ARIA-E, there was the associated appearance of ARIA-H. In treated patients without ARIA-E, the risk for incident blood products was 4%. This association between ARIA-E and ARIA-H may suggest a common pathophysiologic mechanism. Familiarity with ARIA should permit radiologists and clinicians to recognize and communicate ARIA findings more reliably for optimal patient management.

An MRI rating scale for amyloid-related imaging abnormalities with edema or effusion.

BACKGROUND AND PURPOSE: Immune therapy against amyloid-ß appears to be a promising target in Alzheimer disease. However, a dose-related risk for ARIA on FLAIR images thought to represent parenchymal vasogenic edema or sulcal effusion (termed "ARIA-E"), has been observed in clinical trials. To assess the intensity of ARIA-E presentation, an MR imaging scale that is both reproducible and easily implemented would assist in monitoring and evaluating this adverse event. MATERIALS AND METHODS: On the basis of a review of existing cases from a phase II bapineuzumab study, a scale was constructed with a 6-point score for the 6 regions on each side of the brain (range, 0-60). Scores would be obtained for both parenchymal and sulcal hyperintensities and frequently co-occurring gyral swelling. Inter-rater reliability between 2 neuroradiologists was evaluated in 20 patients, 10 with known ARIA-E and 10 without, by using the intraclass correlation coefficient. RESULTS: The 2 raters had excellent agreement in the identification of ARIA-E cases. A high inter-rater agreement was observed for scores of parenchymal hyperintensity (ICC = 0.83; 95% CI, 48-96) and sulcal hyperintensity (ICC = 0.89; 95% CI, 63-97) and for the combined scores of the 2 ARIA-E findings (ICC = 0.89; 95% CI, 62-97). Gyral swelling scores were observed to have lower inter-rater agreement (ICC = 0.54; 95% CI, -0.06-0.86). CONCLUSIONS: The proposed rating scale provides a reliable and easily implemented instrument to grade ARIA-E imaging findings. We currently do not recommend including swelling.

Cognitive effects of carisbamate in randomized, placebo-controlled, healthy-volunteer, multidose studies.

Adverse cognitive effects are an important concern for drugs that influence the central nervous system. Carisbamate is a novel drug in development for treatment of seizures and neuropathic pain. Information on its cognitive effects is limited. Three controlled, multiple-dose, crossover studies with treatment durations of 5-9 days were designed to examine the cognitive effects of carisbamate on healthy volunteers. In one study, apparent dose-dependent effects on response, vigilance, and recognition speed were observed (1000 mg and 1500 mg/day). Carisbamate did not differ from placebo for most variables in the other two studies, but increased reaction time and reduced Sternberg memory were seen at higher dosages. Carisbamate did not produce clinically significant adverse effects on cognitive performance at doses <1000 mg/day. Effects were mild to modest at the higher doses tested.

Long-term response to galantamine in relation to short-term efficacy data: pooled analysis in patients with mild to moderate Alzheimer's disease.

BACKGROUND: This analysis aimed to identify an operational, clinically relevant definition of response achieved in short-term clinical trials to support the identification of patients with Alzheimer's disease (AD) who would benefit most from long-term galantamine therapy. METHODS: Data were analyzed from 6 randomized placebo-controlled trials of up to 6 months' duration, which included patients with mild to moderate AD receiving maintenance doses of galantamine 16-24 mg/day, and from 12 open-label extensions (galantamine 24 mg/day maintenance therapy). Assessments included changes from baseline in the 11-item AD Assessment Scale-Cognitive subscale (ADAS-Cog 11). RESULTS: Pooled analysis of the 5-6 month trial data showed that at the trial endpoint (2-5 months after reaching maintenance doses), the proportions of galantamine- (n=1,173) versus placebo-treated patients (n=801) with probable AD categorized according to "improved", "stable" or "non-rapid decline" criteria, were 45.8% versus 27.2%, 59.5% versus 37.1%, and 87.6% versus 69.7%, respectively (observed cases analysis), whilst changes in ADAS-Cog 11 scores versus baseline were -4.9, -4.7 and -2.9 points, respectively, for "improved", "stable" and "non-rapid decline" galantamine-treated patients (-1.5 points for galantamine recipients overall). "Improved" or "stable" galantamine-treated patients displayed mean improvement in ADAS-Cog 11 scores over baseline until 18 months after starting treatment, and attenuated deterioration thereafter; for galantamine-treated patients exhibiting "non-rapid decline", mean ADAS-Cog 11 score returned to baseline after approximately 12 months. CONCLUSIONS: Patients who demonstrate improvement, stability, or limited cognitive decline 2-5 months after reaching maintenance doses of galantamine are more likely to experience continued benefit from long-term galantamine therapy.

Autosomal dominant subcortical gliosis presenting as frontotemporal dementia.

OBJECTIVE: To describe a multigenerational kindred with a frontotemporal dementia clinical syndrome (FTDS), extensive subcortical gliosis pathology, and autosomal dominant genetics. METHODS: Clinical, imaging, and pathologic evaluations of multiple family members. RESULTS: Symptom onset commonly occurred in the fifth or sixth decade, although some kindred members did not develop obvious symptoms until their eighth decade. White matter changes were prominent on both MRI and CT imaging. Results from six brain autopsy evaluations showed consistent but varying degrees of pathology that, while unique, share some histologic similarities with leukodystrophies. These brains were notably devoid of both tau- and ubiquitin-containing inclusions. CONCLUSIONS: Subcortical gliosis in this kindred arises from mutation of a novel gene or else represents a unique frontotemporal dementia clinical syndrome variant caused by mutation of an already known gene. Clinical relevance and research implications are discussed.

Analyses of mortality risk in patients with dementia treated with galantamine.

OBJECTIVE: To analyze mortality data from patients with Alzheimer's disease (AD), Alzheimer's plus cerebrovascular disease (AD + CVD) or vascular dementia (VaD). METHODS: (1) Meta-analysis of mortality data from double-blind, placebo-controlled, randomized trials; and (2) recontact study to collect additional longer term mortality data from previous galantamine trial participants. RESULTS (META-ANALYSIS): Across 12 trials (< or =6 months duration), there was no increased risk of mortality associated with the use of galantamine (n = 4116) compared with that of placebo (n = 2386) (OR galantamine/placebo: 0.67, 95% CI 0.41-1.10). RESULTS (RECONTACT STUDY): Median survival was 79 months for patients with AD (n = 478) and 59 months for patients with AD + CVD (n = 180) or VaD (n = 145). Prolonged galantamine treatment (> vs < or =6 months) was not associated with decreased survival time (75 vs 61 months respectively; P = 0.02). Cox regression analyses were consistent with the Kaplan-Meier analyses. CONCLUSIONS: We found no short-term or longer term evidence of increased risk of mortality associated with the use of galantamine in patients with AD, AD + CVD or VaD.

Safety and efficacy of galantamine in subjects with mild cognitive impairment.

OBJECTIVE: To assess the safety of galantamine in subjects with mild cognitive impairment (MCI), the ability of galantamine to benefit cognition and global functioning in subjects with MCI, and the ability of galantamine to delay conversion to dementia. METHODS: In two studies, 2,048 subjects, 990 in Study 1 and 1,058 in Study 2, with a Clinical Dementia Rating (CDR) = 0.5, CDR memory score > or =0.5, without dementia were randomized to double-blind galantamine (16-24 mg/day) or placebo for 24 months. Primary efficacy endpoint at month 24 was number (%) of subjects who converted from MCI to dementia (CDR > or = 1.0). RESULTS: There were no differences between galantamine and placebo in 24-month conversion rates (Study 1: 22.9% [galantamine] vs 22.6% [placebo], p = 0.146; Study 2: 25.4% [galantamine] vs 31.2% [placebo], p = 0.619). Mean CDR-sum of boxes declined less with galantamine than placebo at 12 and 24 months in Study 1 (p = 0.024 [12 months] and p = 0.028 [24 months]), but not in Study 2 (p = 0.662 [12 months] and p = 0.056 [24 months]). Digit Symbol Substitution Test scores improved with galantamine in Study 1 at 12 months and in Study 2 at 24 months (Study 1: p = 0.009 [month 12] and p = 0.079 [Month 24]; Study 2: p = 0.154 [month 12] and p = 0.020 [month 24]). The most frequently reported adverse event was nausea (galantamine, 29%; placebo, 10%). Serious AEs occurred in 19% of each group. Mortality of the cohort after retrospectively determining the status of subjects (98.3%) at 24 months was 1.4% (galantamine) and 0.3% (placebo); RR (95% CI), 1.70 (1.00, 2.90). CONCLUSIONS: Galantamine failed to significantly influence conversion to dementia. Galantamine was generally well tolerated. Whereas recorded mortality was greater in the galantamine group than in the placebo group in the original per-protocol assessment, a post hoc analysis of the cohort was consistent with no increased risk.

Galantamine treatment of vascular dementia: a randomized trial.

BACKGROUND: To evaluate efficacy and safety of galantamine for patients with vascular dementia (VaD). METHODS: In this multinational, randomized, double-blind, placebo-controlled, parallel-group clinical trial, 788 patients with probable VaD who also satisfied strict centrally read MRI criteria were randomized to receive galantamine or placebo. Efficacy was evaluated using measures of cognition, daily function, and behavior. The primary efficacy measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog/11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL) total score. Secondary outcomes included the Clinician's Interview Based on Impression of Change-Plus Caregiver Input (CIBIC-plus), Neuropsychiatric Inventory, and EXIT-25 for assessment of executive functioning. Safety and tolerability were also monitored. RESULTS: Patients treated with galantamine had a greater improvement in ADAS-cog/11 after 26 weeks compared with placebo (-1.8 vs -0.3; p < 0.001). There was no difference between galantamine and placebo at week 26 on the ADCS-ADL score (0.7 vs 1.3; p = 0.783). Improvement in global functioning measured by the CIBIC-plus associated with galantamine approached significance (p = 0.069). A difference between treatment groups for EXIT-25 favoring galantamine was detected (p = 0.041). Safety data revealed that 13% of galantamine and 6% of placebo patients discontinued treatment because of adverse events. CONCLUSIONS: Significance was not reached for both co-primary endpoints. Galantamine was effective for improving cognition, including executive function, in patients with vascular dementia, with good safety and tolerability. However, improvement in activities of daily living with galantamine was similar to that observed with placebo.

Antibody types and IgG subclasses in paraneoplastic neurological syndromes.

Three major patterns of antineuronal antibody response have been identified in patients with paraneoplastic neurological syndromes: Type I ('Anti-Yo'), associated with cerebellar degeneration in the setting of breast or gynecological cancer, Type IIa ('anti-Hu') associated with encephalomyeloneuritis in patients with small cell carcinoma of the lung, and Type IIb ('anti-Ri') associated with breast cancer. We have employed immunofluorescence methods to determine the antibody classes and the IgG subclasses which react with neurons in each of these patterns of paraneoplastic antibody response. In this study, IgG was the only antibody class identified; IgM and IgA antibodies were not found. IgG1 was the major subclass represented and was found in 9/9 patients with Type I antibody response, 26/27 patients with Type IIa antibody response, and 3/3 patients with Type IIb antibody response. Many patients also exhibited positive staining for IgG2 and IgG3. Trace amounts of IgG4 antineuronal antibodies were detected in a single patient with Type I antibody response; IgG4 antibodies were not found in other patients. Patients with paraneoplastic neurological syndromes exhibit an antibody response which is overwhelmingly IgG and is comprised predominantly of IgG subclasses capable of fixing complement. The role of these antibodies in the pathogenesis of paraneoplastic neurological disease remains uncertain.

Neuropsychological assesment of psychogeriatric patients with limited education.

Traditional published norms for neuropsychological tests that do not consider demographic effects can lead to spuriously high false positive rates among low-educated elderly individuals. This problem may be compounded when trying to identify dementia in psychogeriatric patients whose cognitive functioning is also compromised by psychiatric illness. This study investigated the clinical utility of low education neuropsychological test norms to discriminate amongst demented and nondemented psychogeriatric inpatients and healthy community elderly with limited education. Results indicated that the Mattis Dementia Rating Scale (MDRS), the Fuld Object Memory Evaluation (FOME), the Mini-Mental State Examination (MMSE), and a Clock drawing task had high discriminability in differentiating the three groups. Application of demographically corrected norms has important implications for diagnosis and treatment planning, especially when neuropsychological status is complicated by psychiatric illness.

Patients with Alzheimer's disease who cannot perform some motor skills show normal learning of other motor skills.

Previous researchers have claimed that patients with Alzheimer's disease (AD) learn new motor skills normally, although many AD patients cannot perform the tasks and must be eliminated from the analysis. Excluding them assumes that they have a deficit of motor performance (competence to perform the task), but not of motor learning (ability to improve performance). The present study administered 4 motor tasks to 20 AD patients and 20 controls. The results showed that the ability to complete 1 task (performance) did not predict the rate of improvement (learning) on another task, which indicates that AD patients do indeed have a performance deficit and not a general deficit of motor skill learning. Dementia ratings predicted the ability to perform tasks but not the ability to learn them. It is concluded that it is defensible to claim that AD patients learn a motor skill normally, even if some of the patients are unable to perform the task.

Cognitive screening of nursing home residents: factor structures of the Mini-Mental State Examination.

OBJECTIVE: To examine factor structures of the Mini-Mental State Examination, attempting first to replicate any of previously proposed 2-factor solutions; and to explore, secondly, the presence of clinically more differentiated and statistically stable factor structures representing common neurocognitive dimensions. DESIGN: Factor analytic investigation of descriptive dataset collected on nursing home residents. Two factor analyses were performed, one in which the number of factors was fixed at 2 in an effort to replicate previous studies, and one in which the number of factors to retain was determined by the scree test. Both factor analyses used established methods for judging the adequacy of the correlation matrix and the significance of factor loadings, and both applied principal components analysis for initial factor extraction and the equamax criterion for orthogonal rotation. SETTING: Seven nursing homes with a total of 894 beds. PARTICIPANTS: 922 assessments on nursing home residents were performed, of which 892 were complete and entered into the factor analyses. The observation-to-variable ratio exceeded 81:1, assuring the statistical stability of factor solutions derived. MEASUREMENT: The Mini-Mental State Examination, with standardization of words to be recalled and the inverted spelling of "world" as the mental reversal task. MAIN RESULTS: Two factor structures were derived. A 2-factor solution, explaining 36.5% of the variance and statistically and conceptually different from those obtained in previous studies, distinguished between Perceptual-Organizational and Psychomotor skills. A 4-factor solution, which explained 56.1% of the variance, included a factor named Executing Psychomotor Commands, while also further differentiating the perceptual-organizational processes into the factors of Memory, Concentration, and Language. CONCLUSION: The 2-factor solution shows that, notwithstanding previous claims to the contrary, the MMSE can make stable and independent distinctions between psychomotor and perceptual-organizational processes. However, this solution is statistically and conceptually limited and, therefore, of limited clinical and scientific relevance. The 4-factor solution of the MMSE maps well onto commonly recognized dimensions of neurocognitive ability. It offers a stable, intuitively sound, and statistically supported framework for clinical differentiation of cognitive screening data into independent clinical dimensions of neurocognitive functioning. Thus, it offers clinicians and researchers a 4-dimensional framework for interpreting data obtained by means of the MMSE. Studies with other populations of cognitively impaired and intact elderly are recommended to validate and extend the present findings.