Cerebral correlates of the progression rate of the cognitive decline in probable Alzheimer's disease

OBJECTIVE: To evaluate the possible relation between the rate of cognitive deterioration in patients with probable Alzheimer's disease (AD) and the distribution pattern of neural dysfunction. METHODS: The regional cerebral blood flow (rCBF) was measured in rapidly and slowly progressing groups of AD patients using single-photon emission computed tomography and was compared between the groups. While controlling for demographic and clinical factors that could be associated with the stage and prognosis of the illness, the deterioration rate of the Mini Mental State Examination (MMSE) score was significantly greater in the rapidly progressing group than that in the slowly progressing group. RESULTS: The rCBF in the right posterodorsal, anterior and superior prefrontal cortices and the inferior parietal cortex was significantly lower in the rapidly progressing patients. Moreover, lower perfusion in these regions correlated significantly with rapid deterioration in the MMSE. CONCLUSIONS: These findings suggest that the rCBF values in these cortical regions could be useful in predicting which AD patients will show a relatively rapid cognitive decline.     

Predictors of decline in Alzheimer's disease

Age of onset and aphasia are frequently proposed as predictors of decline in Alzheimer's disease (AD). We compared longitudinally the neuropsychological test performance of AD patients classified as Fast Decliners (FD, N = 18) based on the rate of change of their scores on the Mini-Mental State Examination (MMS) and a group classified as Slow Decliners (SD, N = 15). There was no statistical difference in the age of onset of AD or in severity of dementia at first visit. Performance on verbal tests was the best predictor of rapid cognitive decline, even after the influence of the overall degree of dementia had been accounted for. Among the language tasks, performance on a naming test was the best predictor. The results of this study do not support age of onset as a predictor of the course of AD. On the other hand, poor performance on language tests does predict a more rapid rate of decline in AD.     

Predictors of cognitive and functional progression in patients with probable Alzheimer's disease.

We followed 65 patients with probable Alzheimer's disease, who were initially mildly to moderately impaired, with semiannual assessments of cognitive and functional performance for up to 4 years. Scores on the Mini Mental State Examination and a combination of instrumental and self-maintenance scale of activities of daily living were regressed on time of examination (measured in 6-month increments) to estimate cognitive and functional progression rates in individual patients. Lower scores on the verbal neuropsychological tests at the time of study entry, more aggressive behavior, and sleep disturbance during the first year of observation predicted faster cognitive progression. Faster functional progression was predicted by paranoid behavior, hallucinations and activity disturbances during the first year and the presence of extrapyramidal signs and lower scores on nonverbal neuropsychological tests at the time of entry into the study. Hallucinations occurred independently of cognitive severity and may identify a distinct subgroup of patients with rapid functional progression. Because of the greater significance of functional progression for caregivers' ability to manage patients, the presence of specific behavior problems early in the disease course may help to identify individuals who will experience greater functional decline and be at risk for earlier institutionalization.     

Predictors of disease course in patients with probable Alzheimer's disease

The presence of extrapyramidal signs or psychosis may indicate greater disability in patients with probable Alzheimer's disease. We evaluated the ability of these signs, noted at a patient's first visit, to predict one of two specific clinical endpoints: (1) a preselected score on the modified Mini-Mental State examination (cognitive endpoint), and (2) a preselected score on the Blessed Dementia Rating Scale (functional endpoint). Sixty-five patients were followed either until they reached the endpoints or to the end of the study period. Survivorship curves were drawn to predict the distribution of time to onset of an endpoint in patients with and without the clinical signs. Time to reach the cognitive endpoint was shorter for patients with extrapyramidal signs or psychosis compared with those without these signs and symptoms. These clinical signs did not predict the functional endpoint. We conclude that extrapyramidal signs and psychosis may be useful predictors of intellectual decline in Alzheimer's disease.     

Predictors of cognitive impairment in an early stage Parkinson's disease cohort

The impact of Parkinson's disease (PD) dementia is substantial and has major functional and socioeconomic consequences. Early prediction of future cognitive impairment would help target future interventions. The Montreal Cognitive Assessment (MoCA), the Mini‐Mental State Examination (MMSE), and fluency tests were administered to 486 patients with PD within 3.5 years of diagnosis, and the results were compared with those from 141 controls correcting for age, sex, and educational years. Eighteen‐month longitudinal assessments were performed in 155 patients with PD. The proportion of patients classified with normal cognition, mild cognitive impairment (MCI), and dementia varied considerably, depending on the MoCA and MMSE thresholds used. With the MoCA total score at screening threshold, 47.7%, 40.5%, and 11.7% of patients with PD were classified with normal cognition, MCI, and dementia, respectively; by comparison, 78.7% and 21.3% of controls had normal cognition and MCI, respectively. Cognitive impairment was predicted by lower education, increased age, male sex, and quantitative motor and non‐motor (smell, depression, and anxiety) measures. Longitudinal data from 155 patients with PD over 18 months showed significant reductions in MoCA scores, but not in MMSE scores, with 21.3% of patients moving from normal cognition to MCI and 4.5% moving from MCI to dementia, although 13.5% moved from MCI to normal; however, none of the patients with dementia changed their classification. The MoCA may be more sensitive than the MMSE in detecting early baseline and longitudinal cognitive impairment in PD, because it identified 25.8% of those who experienced significant cognitive decline over 18 months. Cognitive decline was associated with worse motor and non‐motor features, suggesting that this reflects a faster progressive phenotype. © 2014 International Parkinson and Movement Disorder Society     

Longitudinal cognitive decline in patients with Alzheimer's disease

Progressive cognitive impairment is a defining feature of the dementia of Alzheimer's disease (AD), yet disagreement exists over which abilities decline most precipitously and which cognitive tests are more sensitive. In this study, 51 AD patients in the early to middle stages of illness and 22 age-matched normal controls were administered a battery of neuropsychological tests at 6-month intervals over a 2-year period. While the performance of the normal controls remained stable over the 2 years, the AD patients displayed progressive decline on all tests. The greatest declines occurred on tests requiring lexical/semantic processing (Boston Naming Test) and comprehension of syntactic relationships (Token Test). Performance on visuospatial tests (Wechsler Adult Intelligence Scale-Revised Block Design, Benton Visual Retention Test, Spatial Delayed Recognition Span Test) declined less rapidly. The findings support previous reports that language impairment may be central to the dementia of AD, and that confrontation naming is particularly sensitive to decline in this illness.     

Postmortem serotoninergic correlates of cognitive decline in Alzheimer's disease

Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6 years till death. In the frontal cortex, serotonin levels correlated negatively with the annual rate of MMSE decline, while serotonin1A receptor density was positively correlated with the rate of MMSE decline. Our study suggests that reduced serotonin levels and increased serotonin1A receptor density are markers for accelerated cognitive decline in AD, and provides support for the use of serotonin1A antagonists in the treatment of AD.     

Slowing the progression of cognitive decline in Alzheimer's disease using mifepristone

High circulating levels of glucocorticoid hormones adversely affect cognition. Previous studies exploring the hypothalamic-pituitary-adrenal (HPA) axis and basal cortisol levels in the elderly reported that subjects with mid-range cortisol levels outperformed subjects with high cortisol levels on assessments of memory and attention. This study examines the efficacy of mifepristone, a glucocorticoid-antagonist, in decelerating the rate of cortisol-related cognitive decline in subjects with mile-to-moderate Alzheimer's disease (AD). Rate of cognitve decline is compared in AD subjects randomized to receive 200 mg of mifepristone daily for 6 mo or placebo. The Alzheimer's Disease Assessment Scale (ADAS) and the Folstein Mini Mental Status Exam (MMSE) will be the primary measures used to assess change in cognitve function over the 6 mo period, supplemented by a neuropsychological battery testing memory and language and reasoning skills. During each visit, subjects will have samples collected for determination of plasma adrenocorticotropin (ACTH), serum cortisol and salivary cortisol levels to assess HPA axis activity. The placebo arm of this study also investigate whether subjects with high baseline cortisol levels experience greater declines in cognitive impairment over time relative to subjects with Ad who have low baseline cortisol levels. Additionally, this study test the hypothesis that AD subjects with elevated cortisol at baseline will perform more poorly on neuropsychological exams that do subjects with low cortisol.     

Education and rates of cognitive decline in incident Alzheimer's disease

BACKGROUND: Some (but not all) epidemiological studies have noted faster rates of progression in high education patients with Alzheimer's disease (AD), which has been attributed to harbouring/tolerating a higher pathological burden at the time of clinical dementia for subjects with higher education. We wanted to assess the relationship between education and rates of decline in AD. METHODS: During the course of a community based multiethnic prospective cohort study of individuals aged > or = 65 years living in New York, 312 patients were diagnosed with incident AD and were followed overall for 5.6 (up to 13.3) years. The subjects received an average of 3.7 (up to 9) neuropsychological assessments consisting of 12 individual tests. With the aid of a normative sample, a standardised composite cognitive score as well as individual cognitive domain scores were calculated. Generalised estimating equation models were used to examine the association between education and rates of cognitive decline. RESULTS: Composite cognitive performance declined by 9% of a standard deviation per year. Rates of decline before and after AD incidence were similar. For each additional year of education there was 0.3% standard deviation lower composite cognitive performance for each year of follow up. The association between higher education and faster decline was noted primarily in the executive speed (0.6%) and memory (0.5%) cognitive domains and was present over and above age, gender, ethnicity, differential baseline cognitive performance, depression, and vascular comorbidity. CONCLUSIONS: We conclude that higher education AD patients experience faster cognitive decline.     

Absence of cognitive impairment or decline in preclinical Alzheimer's disease

OBJECTIVE: To determine whether clinically nondemented elderly individuals with pathologically confirmed preclinical AD are characterized by cognitive decline as measured by psychometric tests before death. METHODS: Psychometric performance was examined retrospectively in 14 individuals who were nondemented at time of death and grouped in accordance with their neuropathologic findings: 1) Healthy brain (n = 9) was characterized by the absence of senile plaques or by only patchy neocortical deposits of plaques; 2) preclinical AD (n = 5) was characterized by neuritic and diffuse plaques distributed throughout the neocortex. All individuals showed neurofibrillary pathologic change in medial temporal lobe structures. For comparison, we also evaluated 10 individuals who died in the earliest symptomatic stage of dementia of the Alzheimer type (DAT). All individuals had been assessed by clinical and psychometric measures during life. The psychometric measures yielded a standardized factor score that represented global cognitive performance. RESULTS: At the last assessment before death, individuals with very mild DAT were impaired on the factor score and on individual psychometric measures with respect to the nondemented individuals. Those nondemented individuals with preclinical AD did not differ in performance from those with healthy brains. For individuals with at least three psychometric assessments during life, there was no decline in performance for either those with healthy brains (n = 5) or preclinical AD (n = 3), although decline was evident for very mild DAT individuals (n = 5). CONCLUSIONS: Pathologically confirmed preclinical AD is not associated with cognitive impairment or decline, even on measures shown to be sensitive to very mild DAT.     

Hallucinations, delusions, and cognitive decline in Alzheimer's disease

OBJECTIVES: To examine the occurrence of hallucinations and delusions in Alzheimer's disease over a 4 year period and their association with rate of cognitive decline. METHODS: A cohort of 410 persons with clinically diagnosed Alzheimer's disease underwent annual clinical evaluations over a 4 year period. Participation in follow up exceeded 90% in survivors. Evaluations included structured informant interview, from which the presence or absence of hallucinations and delusions was ascertained, and detailed testing of cognitive function. The primary cognitive outcome measure was a composite cognitive score based on 17 individual performance tests. The mini mental state examination (MMSE) and summary measures of memory, visuoconstruction, repetition, and naming were used in secondary analyses. RESULTS: At baseline, hallucinations (present in 41%) and delusions (present in 55%) were common and associated with lower cognitive function. In analyses that controlled for baseline level of cognitive function, demographic variables, parkinsonism, and use of antipsychotic medications, hallucinations, but not delusions, were associated with more rapid cognitive decline on each cognitive measure. In the primary model, there was a 47% increase in the average annual rate of decline on a composite cognitive measure in those with baseline hallucinations compared with those without them. This effect was mainly due to a subgroup with both auditory and visual hallucinations. CONCLUSION: These findings suggest that the presence of hallucinations is selectively associated with more rapid cognitive decline in Alzheimer's disease.     

Rapid cognitive decline in Alzheimer's disease: a literature review

Abstract

Background: The rate of cognitive decline in Alzheimer's disease (AD) varies considerably between individuals. Predicting rapid cognitive decline might help clinicians provide prognostic information, select subjects for trial intervention and/or reduce costs. Methods: PubMed and PsycINFO were searched for all the English written studies published until the end of 2010 on rapid cognitive decline in AD and factors associated with it. Results: More than 300 individual articles were retrieved. We selected 82 relevant studies. The main findings of these papers are that younger, more educated and more impaired patients are more likely to show rapid cognitive decline. ApoE alleles seem not to modify the velocity of clinical progression of dementia, or at most could have a very small effect. No inference can be made for all the other variables analysed. Conclusions: There are many studies on rapid cognitive decline. Results are heterogeneous and often contradictory. No reliable conclusions about factors that may be associated with rapid cognitive decline can yet be drawn.     

Hallucinations, cognitive decline, and death in Alzheimer's disease

The relation of psychotic symptoms to cognitive decline and mortality in Alzheimer's disease (AD) was examined during a mean of 2.2 years in 478 persons selected from clinical settings. Psychotic symptoms were ascertained at baseline and cognition was assessed semiannually with nine tests from which a global measure was formed. In analyses that controlled for age, sex, race, and education, hallucinations (29.6%), especially visual ones, were associated with more rapid global cognitive decline and increased mortality, even after controlling for baseline level of cognition and use of antipsychotic medication, and the association with mortality increased with higher level of education. Delusions and misperceptions were not strongly related to cognitive decline or mortality. The results suggest that hallucinations in Alzheimer's disease, particularly visual ones, are associated with more rapid progression.     

Language-enriched exercise plus socialization slows cognitive decline in Alzheimer's disease

This article reports the effects of language-enriched physical fitness interventions provided by University of Arizona undergraduate students to 24 mild- to moderate-stage Alzheimer's disease patients (AD Rehab group). Socialization experiences consisted of supervised volunteer work and cultural/recreational activities. Changes in global functioning and neuropsychological test performance were tracked and compared to those of a similar group of untreated patients from the Consortium for the Establishment of a Registry for Alzheimer's Disease (CERAD). Cohorts completing 4 semesters or longer showed no significant between-year changes after their first year on the Clinical Dementia Rating, a measure of global functioning, and on 5 or 6 of the cognitive and language measures. Comparisons with the CERAD sample suggested a slower rate of decline for the AD Rehab group. The stabilization of global and cognitive performance was not apparent among participants who completed only 2 semesters. Significant physical fitness and mood outcomes were previously reported in this journal.