The relationship between diabetes and depressive symptoms in men with or at risk of HIV infection.

OBJECTIVES: The aim of the study was to compare the prevalence of comorbid diabetes and depressive symptoms in men living with HIV (MLWH) with that in men without HIV infection and to determine associations between glycaemic control and depressive symptoms. METHODS: Participants included 920 MLWH and 840 men without HIV infection from the Multicenter AIDS Cohort Study (MACS) with available data regarding glycaemic status [categorized as normal for fasting blood glucose (FBG) < 100 mg/dL, prediabetes for FBG 100-125 mg/dL, and diabetes, defined by self-report, diabetes medication use or FBG ≥ 126 mg/dL on at least two consecutive visits, with diabetes classified as controlled if Hemoglobin A1c (HbA1C) < 7.5% and uncontrolled if HbA1C ≥ 7.5%]. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) score, with CES-D ≥ 16 scores classified as elevated depressive symptoms. A modified Poisson regression model with robust variance was used and adjusted for covariates including HIV serostatus. RESULTS: Compared to men without HIV infection, MLWH had a higher mean CES-D score, but a similar prevalence of diabetes (11.3% versus 12.8%, respectively; P = 0.33). The concomitant prevalence of diabetes and elevated depressive symptoms did not differ by HIV serostatus (P = 0.215). In an adjusted analysis, men with uncontrolled diabetes had a greater prevalence of depressive symptoms compared to men with normoglycaemia (prevalence ratio = 1.43; 95% confidence interval 1.11, 1.84). The association between glycaemic status and depressive symptoms did not differ by HIV serostatus (P = 0.22 for interaction). CONCLUSIONS: Both controlled and uncontrolled diabetes were independently associated with a greater prevalence of depressive symptoms, regardless of HIV serostatus. These results highlight the importance of identifying depression in people with diabetes.

The association between physical activity and cognition in men with and without HIV infection.

OBJECTIVES: HIV-associated neurocognitive disorders are highly prevalent, and physical activity (PA) is a modifiable behaviour that may affect neurocognitive function. Our objective was to determine the association between PA and neurocognitive function and the effect of HIV on this association. METHODS: PA was assessed in the Multicenter AIDS Cohort Study with the International Physical Activity Questionnaire. A neuropsychological test battery assessed global impairment and domain-specific impairment (executive function, speed of processing, working memory, learning, memory, and motor function) every 2 years. Semiannually, the Symbol Digit Modalities Test and Trail Making Test Parts A and B were performed. Adjusted logistic regression models were used to assess the PA-neurocognitive function association. Using longitudinal data, we also assessed the PA category-decline of neurocognitive function association with multivariate simple regression. RESULTS: Of 601 men, 44% were HIV-infected. Low, moderate, and high PA was reported in 27%, 25%, and 48% of the HIV-infected men vs. 19%, 32% and 49% of the HIV-uninfected men, respectively. High PA was associated with lower odds of impairment of learning, memory, and motor function [odds ratio (OR) ranging from 0.52 to 0.57; P < 0.05 for all]. The high PA-global impairment association OR was 0.63 [95% confidence interval (CI) 0.39, 1.02]. Among HIV-infected men only, across multiple domains, the high PA-impairment association was even more pronounced (OR from 0.27 to 0.49). Baseline high/moderate PA was not associated with decline of any domain score over time. HIV infection was marginally associated with a higher speed of decline in motor function. CONCLUSIONS: A protective effect of high PA on impairment in neurocognitive domains was observed cross-sectionally. Longitudinal PA measurements are needed to elucidate the PA-neurocognitive function relationship over time.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

A physical model for dementia.

Aging associated brain decline often result in some kind of dementia. Even when this is a complex brain disorder a physical model can be used in order to describe its general behavior. A probabilistic model for the development of dementia is obtained and fitted to some experimental data obtained from the Alzheimer's Disease Neuroimaging Initiative. It is explained how dementia appears as a consequence of aging and why it is irreversible.

Plasma biosignature and brain pathology related to persistent cognitive impairment in late-life depression.

Cognitive impairment is highly prevalent among individuals with late-life depression (LLD) and tends to persist even after successful treatment. The biological mechanisms underlying cognitive impairment in LLD are complex and likely involve abnormalities in multiple pathways, or 'cascades,' reflected in specific biomarkers. Our aim was to evaluate peripheral (blood-based) evidence for biological pathways associated with cognitive impairment in older adults with LLD. To this end, we used a data-driven comprehensive proteomic analysis (multiplex immunoassay including 242 proteins), along with measures of structural brain abnormalities (gray matter atrophy and white matter hyperintensity volume via magnetic resonance imaging), and brain amyloid-ß (Aß) deposition (PiB-positron emission tomography). We analyzed data from 80 older adults with remitted major depression (36 with mild cognitive impairment (LLD+MCI) and 44 with normal cognitive (LLD+NC)) function. LLD+MCI was associated with differential expression of 24 proteins (P<0.05 and q-value <0.30) related mainly to the regulation of immune-inflammatory activity, intracellular signaling, cell survival and protein and lipid homeostasis. Individuals with LLD+MCI also showed greater white matter hyperintensity burden compared with LLD+NC (P=0.015). We observed no differences in gray matter volume or brain Aß deposition between groups. Machine learning analysis showed that a group of three proteins (Apo AI, IL-12 and stem cell factor) yielded accuracy of 81.3%, sensitivity of 75% and specificity of 86.4% in discriminating participants with MCI from those with NC function (with an averaged cross-validation accuracy of 76.3%, sensitivity of 69.4% and specificity of 81.8% with nested cross-validation considering the model selection bias). Cognitive impairment in LLD seems to be related to greater cerebrovascular disease along with abnormalities in immune-inflammatory control, cell survival, intracellular signaling, protein and lipid homeostasis, and clotting processes. These results suggest that individuals with LLD and cognitive impairment may be more vulnerable to accelerated brain aging and shed light on possible mediators of their elevated risk for progression to dementia.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

A genome-wide association meta-analysis of plasma Aß peptides concentrations in the elderly.

Amyloid beta (Aß) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aß peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aß peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aß-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aß1-40 and Aß1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aß1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aß1-42 secretion. In conclusion, our study results suggest that plasma Aß peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

Late-life depression and increased risk of dementia: a longitudinal cohort study.

Late-life depression (LLD) is associated with an increased risk of developing dementia; however, it is not known whether individuals with a history of LLD exhibit a more rapid rate of cognitive decline. We aimed to determine whether those with LLD experienced faster cognitive decline compared with never-depressed control (NDC) participants from the community and whether stratification of LLD into early-onset depression (EOD) and late-onset depression (LOD) subtypes revealed differing rates and domain-specific expression of cognitive decline. We conducted a prospective, longitudinal study where 185 participants with LLD (remitted) and 114 NDC were followed for 5 years on average. EOD was defined as having first lifetime depressive episode at <60years and LOD at ≥60years. Every year, participants underwent comprehensive neuropsychological assessment. Composite scores for each cognitive domain were calculated through averaging standardized scores across tests. LLD compared to NDC demonstrated significant baseline impairment but did not decline more rapidly. EOD were significantly impaired in attention/processing speed and global cognitive function at baseline but did not experience more rapid decline as compared to NDC. Those with LOD compared to both NDC and EOD performed worse in all domains at baseline and experienced more rapid decline in verbal skills and delayed memory ability. Our findings suggest that baseline impairment may lower the threshold for those with LLD to develop dementia. EOD and LOD may represent distinct phenotypes of cognitive impairment with differing neural substrates. LOD may represent a distinct phenotype with a more rapid decline in verbal skills and delayed memory.

Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease.

BACKGROUND: Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects of memantine in combination with ChEIs use in Alzheimer disease (AD). This study was conducted to examine the effects of ChEIs and memantine on time to death and time to NH admission. METHODS: Time to NH admission and death was examined in 943 probable AD patients who had at least a 1-year follow-up evaluation. Of these patients, 140 (14.9%) used both ChEIs and memantine, 387 (41%) [corrected] used only ChEIs, and 416 (44.1%) [corrected] used neither. The mean (SD) follow-up time was 62.3 (35.8) months. The analysis was conducted with multivariable Cox proportional hazard models controlling for critical covariates (ie, age, education level, gender, severity of the dementia, hypertension, diabetes mellitus, heart disease, psychiatric symptoms and use of psychotropic medications). RESULTS: Compared with those who never used cognitive enhancers, patients who used ChEIs had a significant delay in NH admission (HR: 0.37, 95% CI 0.27 to 0.49); this effect was significantly augmented with the addition of memantine (HR: 0.29, 95% CI 0.11 to 0.72) (memantine+ChEI vs ChEI alone). ChEIs alone, or in combination with memantine had no significant association on time to death. CONCLUSIONS: This observational study revealed that the addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission.

Generalized tensor-based morphometry of HIV/AIDS using multivariate statistics on deformation tensors.

This paper investigates the performance of a new multivariate method for tensor-based morphometry (TBM). Statistics on Riemannian manifolds are developed that exploit the full information in deformation tensor fields. In TBM, multiple brain images are warped to a common neuroanatomical template via 3-D nonlinear registration; the resulting deformation fields are analyzed statistically to identify group differences in anatomy. Rather than study the Jacobian determinant (volume expansion factor) of these deformations, as is common, we retain the full deformation tensors and apply a manifold version of Hotelling's $T(2) test to them, in a Log-Euclidean domain. In 2-D and 3-D magnetic resonance imaging (MRI) data from 26 HIV/AIDS patients and 14 matched healthy subjects, we compared multivariate tensor analysis versus univariate tests of simpler tensor-derived indices: the Jacobian determinant, the trace, geodesic anisotropy, and eigenvalues of the deformation tensor, and the angle of rotation of its eigenvectors. We detected consistent, but more extensive patterns of structural abnormalities, with multivariate tests on the full tensor manifold. Their improved power was established by analyzing cumulative p-value plots using false discovery rate (FDR) methods, appropriately controlling for false positives. This increased detection sensitivity may empower drug trials and large-scale studies of disease that use tensor-based morphometry.

A randomised pilot study to assess the efficacy of an interactive, multimedia tool of cognitive stimulation in Alzheimer's disease.

OBJECTIVE: To determine the usefulness of an interactive multimedia internet-based system (IMIS) for the cognitive stimulation of Alzheimer's disease. METHODS: This is a 24-week, single-blind, randomised pilot study conducted on 46 mildly impaired patients suspected of having Alzheimer's disease receiving stable treatment with cholinesterase inhibitors (ChEIs). The patients were divided into three groups: (1) those who received 3 weekly, 20-min sessions of IMIS in addition to 8 h/day of an integrated psychostimulation program (IPP); (2) those who received only IPP sessions; and (3) those who received only ChEI treatment. The primary outcome measure was the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Secondary outcome measures were: Mini-Mental State Examination (MMSE), Syndrom Kurztest, Boston Naming Test, Verbal Fluency, and the Rivermead Behavioral Memory Test story recall subtest. RESULTS: After 12 weeks, the patients treated with both IMIS and IPP had improved outcome scores on the ADAS-Cog and MMSE, which was maintained through 24 weeks of follow-up. The patients treated with IPP alone had better outcome than those treated with ChEIs alone, but the effects were attenuated after 24 weeks. All patients had improved scores in all of the IMIS individual tasks, attaining higher levels of difficulty in all cases. CONCLUSION: Although both the IPP and IMIS improved cognition in patients with Alzheimer's disease, the IMIS program provided an improvement above and beyond that seen with IPP alone, which lasted for 24 weeks.

Alzheimer's disease and depression: neuropsychological impairment and progression of the illness.

The authors longitudinally evaluated the cognitive functions of patients with probable Alzheimer's disease who also met criteria for major depression and compared them with matched patients with Alzheimer's disease who were not depressed. They found no significant difference in the pattern of neuropsychological deficits between the two groups; composite scores on attention, language, memory, learning, and visuospatial functions did not differentiate the two groups at baseline or at 1-year follow-up. The results of this preliminary report suggest that depression does not modify the neuropsychological features and the rate of progression of Alzheimer's disease.

Changes in cognitive functioning following treatment of late-life depression.

OBJECTIVE: Knowledge of the relationship between various clinical characteristics and cognitive functioning is advancing, but little is known about the cognitive response to treatment for geriatric depression. The purpose of this study was to examine the cognitive response to treatment for patients with late-life depression. METHOD: Subjects included 45 nondemented, elderly depressed patients who achieved remission after 12 weeks of antidepressant treatment and 20 elderly comparison subjects. All subjects were administered a battery of clinical measures, including cognitive screening instruments, before and after treatment. RESULTS: As a group, the elderly depressed patients showed a small improvement in overall cognitive functioning after treatment. Among depressed patients with concomitant cognitive impairment at baseline, performance on the Mattis Dementia Rating Scale domains of conceptualization and initiation/perseveration improved significantly relative to those of depressed patients with normal cognition. Despite the improvement following treatment, the overall level of cognitive functioning in the elderly depressed patients with cognitive impairment at baseline remained mildly impaired, especially in the memory and initiation/perseveration domains. CONCLUSIONS: Elderly depressed patients with cognitive impairment may experience improvement in specific domains following antidepressant treatment but may not necessarily reach normal levels of performance, particularly in memory and executive functions. This subgroup of late-life depression patients is likely at high risk of developing progressive dementia.

Learning deficit in Parkinson's disease. Comparison with Alzheimer's disease and normal aging.

The learning ability of 12 patients with Parkinson's disease (PD) was studied using a verbal paired-associate learning task, and was compared with that of ten patients with Alzheimer's Disease (AD) and 12 controls (NC). Overall, the PD patients performed significantly better than the AD patients but significantly worse than the NC subjects. Their performance was not related to their overall level of cognitive functioning as measured by the Mattis' Dementia Rating Scale, but was unequally distributed suggesting that the PD population actually consisted of more than one subgroup. A low error group performed like controls, while a high error group had a learning impairment comparable to that of AD patients. It is concluded that PD patients may have three patterns of neuropsychologic performance: some are unimpaired, some have "focal" abnormalities, and some have a generalized impairment of cognitive function.

Neuropsychological function in Alzheimer's disease. Pattern of impairment and rates of progression.

Although patients with Alzheimer's disease (AD) generally have impairments in multiple areas of cognitive function, there are those patients who appear to have neuropsychological deficits more prominent in one domain than in other domains. We examined the neuropsychological status of 86 patients with probable AD and 92 elderly control subjects and identified the patterns of impairments in the patients with AD. Independent deficits of visuoconstructional and lexical/semantic abilities were identified in a subset of patients by a principal components analysis. Individual patients were identified who were predominantly impaired in one, but not the other, neuropsychological domain. There were no striking relationships between the demographic characteristics of the patients and their pattern of deficits at the initial evaluation. There were no significant differences in age at onset or rate of progression of dementia among patients with different patterns of cognitive dysfunction. A review of the results of this and other studies suggests that the language impairment in AD may be associated with two distinct neuropsychological abnormalities: a lexical/semantic impairment that is unrelated to onset or progression of symptoms, and a syntactic impairment that may be associated with earlier onset and more rapid progression of dementia.

Extrapyramidal signs in patients with probable Alzheimer disease.

OBJECTIVE: To examine whether extrapyramidal signs (EPSs) were associated with more rapid progression of Alzheimer disease (AD). DESIGN: Cross-sectional with longitudinal follow-up and the likelihood of arriving at 4 end points: Mini-Mental State Examination score of less than 9, Blessed Dementia Rating Scale score for activities of daily living of 15 or more, institutionalization, and death using a proportional hazard model with 6 variables: overall EPSs, bradykinesia, tremors, abnormal gait, cogwheel rigidity, and postural instability. SETTING: Multidisciplinary behavioral neurology research clinic. PATIENTS: We examined the individual EPS characteristics of 164 patients with mild-moderately probable AD, free of neuroleptic medication, participating in a longitudinal study of dementia. RESULTS: Patients with AD with EPSs (n= 51 [31%]) were older (P>.001) and had lower Mini-Mental State Examination scores (P=.003) than those without EPSs at study entry. Bradykinesia was present in 35 (69%) of the 51 patients with EPSs, abnormal gait in 18 (35%), rigidity in 10 (20%), postural instability in 10 (20%), tremors in 7 (14%), and oral-mandibular dyskinesia in 2 (4%). Using proportional hazard analysis with time-dependent covariates for overall EPSs and individual EPSs, adjusted by age at study entry, education, Mini-Mental State Examination score, and Blessed Dementia Rating Scale score for activities of daily living, the development of EPSs was associated with time to institutionalization (P<.001) but not with cognitive (eg, Mini-Mental State Examination score <9) or functional (eg, Blessed Dementia Rating Scale score > or = 15) decline or death. However, when we examined severity of the EPSs, as measured by the New York University Parkinson's Disease Scale, the development of EPSs was associated with functional decline (P=.005). Of the individual EPSs, rigidity predicted death (P<.001) and institutionalization (P=.03), whereas tremors predicted functional decline (P=.02). CONCLUSIONS: In this cohort, the presence or absence of EPSs is related to time to institutionalization, but not to severe cognitive or functional impairment or death. However, when severity of the extrapyramidal phenomenon is taken into account, EPSs are related to functional decline. Further, it appears that a subgroup of patients with AD with EPSs, where cogwheel rigidity and tremors are the core signs, can have a worse outcome.

Psychiatric medication and abnormal behavior as predictors of progression in probable Alzheimer disease.

OBJECTIVE: To examine whether the use of psychiatric medication and the presence of abnormal behaviors affects the progression of Alzheimer disease. DESIGN: Cross-sectional with longitudinal follow-up and the likelihood of arriving at 4 end points: (1) Mini-Mental State Examination score of 9 or lower; (2) Blessed Dementia Rating Scale score of 15 or higher for activities of daily living; (3) nursing home admission; and (4) death, evaluated using a proportional hazard model with 9 variables: psychosis, insomnia, wandering, aggression, psychomotor agitation, depression, and use of antidepressants, antipsychotic agents, or sedatives/hypnotics. SETTING: Multidisciplinary dementia research clinic. PATIENTS: We examined baseline and follow-up behavioral symptoms and the use of psychiatric medication in 179 mildly to moderately impaired patients with probable Alzheimer disease participating in a longitudinal study of dementia. Patients were observed from 2.4 to 172 months (mean duration +/- SD, 49.5+/-27.4 months). RESULTS: Nine patients (5%) were taking sedatives/ hypnotics; 16 (9%), antipsychotic agents; and 22 (12%), antidepressants at study entry. Patients taking antipsychotic agents had lower Mini-Mental State Examination scores and higher Blessed Dementia Rating Scale scores for activities of daily living than patients not taking any medication. Using proportional hazard analysis with time-dependent covariates for individual psychiatric symptoms and medications, we found that the development of psychosis was associated with functional decline (time to Blessed Dementia Rating Scale score of > or =15), institutionalization, aggression, and agitation with functional decline after adjusting for age at study entry, education, Mini-Mental State Examination scores, and Blessed Dementia Rating Scale scores. Use of antipsychotic medication was associated with functional decline, and sedatives/hypnotics with death. Neither the presence of psychiatric symptoms nor use of medication was associated with rate of cognitive decline (time to Mini-Mental State Examination score of < or =9). CONCLUSIONS: These findings indicate that the use of antipsychotic agents and sedatives can affect the natural course of Alzheimer disease. Psychosis, agitation, and aggression are important predictors of outcome, even when the effects of medication to treat them is taken into account.

Dissociations between skill learning and verbal recognition in amnesia and dementia.

Patients with Huntington's disease (HD), patients with alcoholic Korsakoff's syndrome, and normal control subjects were compared on tests of skill learning (mirror reading) and verbal recognition. Like previously reported results, the patients with Korsakoff's syndrome acquired the mirror-reading skill at a normal rate but were severely impaired in their recognition of the words used on the mirror-reading task. In contrast to the amnesic patients, the demented patients with HD were retarded in their ability to acquire this skill but showed normal verbal recognition. Besides emphasizing substantial differences in the anterograde substantial differences in the anterograde memory disorders of these two patient populations, the results suggest that the memory disorder of patients with HD may appear much more severe when recall rather than recognition test paradigms are employed. This failure of recall by the patients with HD may be due to an inability to generate strategies necessary to search their short- and long-term memories.

The natural history of Alzheimer's disease. Description of study cohort and accuracy of diagnosis.

OBJECTIVE: We describe the sampling, initial evaluation, and final diagnostic classification of subjects enrolled in a natural history study of Alzheimer's disease (AD). DESIGN: Volunteer cohort study. SETTING: Multidisciplinary behavioral neurology research clinic. PATIENTS OR OTHER PARTICIPANTS: Three-hundred nineteen individuals were enrolled in the Alzheimer Research Program between March 1983 and March 1988. Of these, 204 were originally classified with AD, 102 were normal elderly control subjects, and 13 were considered special cases. MAIN OUTCOME MEASURES: Final consensus clinical diagnosis, final neuropathologic diagnosis, and death. RESULTS: Of the 204 patients enrolled in the study, re-review after as many as 5 years of follow-up resulted in a final clinical classification of 188 with probable AD. Seven patients were believed to have a significant vascular component to the dementia, three were found to have developed depression, and six were excluded on other clinical grounds. Neuropathologic examination of 50 brains indicated definite AD in 43. After removing these seven misdiagnosed patients, the final group of probable/definite AD totaled 181 individuals. Accuracy of the baseline clinical diagnosis relative to neuropathology was 86%, and when follow-up clinical data were considered, 91.4%. Detailed neuropsychological testing yielded high sensitivity (0.988) and specificity (0.983) to dementia. Analyses of survival time from study entry until death revealed that older patients were significantly more likely to die during follow-up, but neither sex, years of education, nor pattern of cognitive impairment were related to survival. CONCLUSIONS: These data provide the descriptive basis for future studies of this cohort. They indicate that longitudinal follow-up of demented cases increases accuracy of diagnosis, and that detailed cognitive testing aids in early classification.