Alzheimer's disease in the NAS-NRC Registry of aging twin veterans, IV. Performance characteristics of a two-stage telephone screening procedure for Alzheimer's dementia

In the course of a large twin study of Alzheimer's disease we used a two-stage telephone screening procedure. The modified Telephone Interview for Cognitive Status (TICS-m) served as an initial screen for dementia in 12709 individuals. The telephone Dementia Questionnaire (DQ) was then asked of collateral informants for subjects with TICS-m scores below 28, as well as for samples of persons with higher TICS-m scores. Based upon DQ responses, individuals with cognitive impairment not attributable to focal causes underwent assessment for the clinical diagnosis of Alzheimer's disease ('Alzheimer's dementia'), as did their twins. Well-defined Alzheimer's dementia was apparent in 39 subjects. Employing a cut-off of 27 or lower as indicative of cognitive impairment, the sensitivity of the TICS-m in the detection of Alzheimer's dementia was estimated at > 99% and specificity at 86%. Inclusion of the DQ increased the specificity at the 27/28 cut-point to 99%. The TICS-m score was associated with an area under the receiver operating characteristic (ROC) curve of 0.88 (95% confidence interval 0.81 to 0.94). The maximum number of cases of Alzheimer's dementia remaining undetected in the sample was estimated to be 34.     

Does sub-lethal exposure to organophosphate pesticide affect capture rates in free-living rodents?

Patients with clinical diagnoses of Alzheimer's disease, vascular dementia, or undifferentiated dementia were rated on standardized measures of depression, cognitive impairment, and functional impairment. Logistic regression was used to evaluate the relationship between functional or cognitive impairment, as well as their interaction, and depressive features in each group. This analysis revealed notable differences by type of dementia. The results imply that the mechanisms underlying depression in Alzheimer's disease may be different from those in vascular and other types of dementia. These results also provide indicators to the clinician for further evaluation of depression in different dementia subtypes.     

Standardization of the diagnosis of dementia in the Canadian Study of Health and Aging

Standardization of diagnostic procedures for cognitive impairment in large epidemiologic surveys remains difficult. This paper reports results of diagnostic standardization in a subsample of 2,914 elderly (age 65 years+) Canadians from the Canadian Study of Health and Aging (CSHA; n = 10,263). The objectives were to measure the consistency of the CSHA diagnosis as a test of validity; to assess inter-rater reliability, and to assess the impact of neuropsychological data on the diagnosis of dementia. The CSHA clinical assessment included a nurse's examination, Modified Mini-Mental Status (3MS) exam and Cambridge Mental Disorders Examination, neuropsychological tests, medical history and examination, and laboratory investigations. A final diagnosis was reached in a consensus conference which incorporated preliminary diagnoses from both physicians and neuropsychologists. Computer algorithms, which were developed to check consistency between the clinical observations and the final diagnosis, demonstrated 98% concordance with DSM-III-R criteria for dementia and 92% with NINCDS-ADRADA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) criteria for probable Alzheimer's disease. Inter-rater agreement was high: kappa = 0.81 for dementia/no dementia; kappa = 0.74 for normal/cognitive impairment, not dementia/ dementia. Comparisons of diagnoses between raters by clinical specialty revealed few systematic differences. The impact of neuropsychological input on the physician's diagnosis was most marked in the borderline cases between diagnostic categories.     

Cognitive impairment in preclinical Alzheimer's disease: A meta-analysis.

To determine the size of the impairment across different cognitive domains in preclinical Alzheimer's disease (AD), a meta-analysis based on 47 studies involving 9,097 controls and 1,207 preclinical AD cases was conducted. There were marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; somewhat smaller deficits in verbal ability, visuospatial skill, and attention; and no preclinical impairment in primary memory. Younger age (     

Visuospatial deficits predict rate of cognitive decline in autopsy-verified dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is often characterized by pronounced impairment in visuospatial skills, attention, and executive functions. However, the strength of the phenotypic expression of DLB varies and may be weaker in patients with extensive concomitant Alzheimer's disease (AD). To determine whether strength of the DLB clinical phenotype impacts cognitive decline, visuospatial and language tests were retrospectively used to predict 2-year rate of global cognitive decline in 22 autopsy-confirmed DLB patients (21 with concomitant AD) and 44 autopsy-confirmed "pure" AD patients. Generalized estimating equations (GEE) revealed a significant interaction such that poor baseline performances on tests of visuospatial skills were strongly associated with a rapid rate of cognitive decline in DLB but not AD (p     

Predictors of perceived memory impairment: do they differ in Alzheimer's disease versus normal aging?

Predictors of perceived memory impairment were investigated in 40 elderly normal adults and 28 individuals with Alzheimer's disease. Measures of perceived memory impairment, global cognitive functioning, memory, use of memory strategies, memory strategy efficacy, and depressive symptomatology were obtained for all participants. The elderly normal and Alzheimer's disease groups did not differ in the extent to which they reported perceived memory impairment. For both participant groups, more frequent use of memory strategies and lower perceived memory strategy efficacy were significant predictors of perceived memory impairment. Depressive symptomatology was an additional, significant determinant of perceived memory impairment for the elderly normal group.     

Cognitive decline from estimated premorbid status predicts neurodegeneration in Alzheimer's disease.

This study investigated the relationship between premorbid and current cognitive function with respect to the clinical features of patients with various types of neurodegeneration in the form of Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive impairment (SCI), as compared with a healthy control group (C). Clinical features (MMSE, cognitive and depressive symptoms), genetics (apolipoprotein E; APOE) and measures of neurodegeneration (Aβ42, t-tau, and p-tau) were examined, as well as present cognitive function. Various methods of assessing premorbid cognitive function were compared, including a Swedish NART-analogous test (Irregularly Spelled Words; ISW), a Swedish lexical decision test (SLDT), a Hold test (Information in WAIS-R), Best current performance test, and combined demographic characteristics. Results showed that cognitive decline (premorbid minus current cognitive function) based on SLDT and ISW was a significant predictor for MMSE and Aβ42, whereas corresponding associations for present cognitive function and decline measures based on other methods were less powerful. Results also showed that specific verbal abilities (e.g., SLDT and ISW) were insensitive to AD and that these abilities indicated premorbid cognitive function in retrospect. In conclusion, cognitive decline from premorbid status reflects the disease processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alzheimer's disease and its Lewy body variant: a clinical analysis of postmortem verified cases

OBJECTIVE: The authors compared clinical findings of Alzheimer's disease and the so-called Lewy body variant of Alzheimer's disease. METHOD: Available data were analyzed on the clinical features of 58 patients with Alzheimer's disease and 24 patients with the Lewy body variant of Alzheimer's disease who underwent postmortem examination. RESULTS: The proportion of men was significantly larger in the Lewy body variant group than in the Alzheimer's disease group (66.7% versus 34.5%), and, concordantly, the Lewy body variant group was slightly taller. The prevalence of hallucinations and delusions was significantly higher in Lewy body variant subjects than the Alzheimer's disease subjects, but there were no significant differences between the two groups in educational attainment, family history of dementia, age at onset, duration of illness, cognitive impairment, overall severity of illness, or neuropsychological findings. Patients with the Lewy body variant of Alzheimer's disease tended to experience more frequent extrapyramidal side effects of neuroleptics than did the patients with Alzheimer's disease, but for patients in the two groups who were not exposed to neuroleptics, there was little difference in frequency of extrapyramidal side effects. CSF concentration of homovanillic acid (HVA) was significantly lower in the Lewy body variant patients, even when correction was made for height. CONCLUSIONS: The Lewy body variant of Alzheimer's disease may be suspected in elderly male dementia patients who otherwise meet criteria for Alzheimer's disease but who manifest significant psychiatric symptoms and neuroleptic-induced extrapy-ramidal side effects and have low levels of CSF HVA.     

Within-Occasion Intraindividual Variability and Preclinical Diagnostic Status: Is Intraindividual Variability an Indicator of Mild Cognitive Impairment?

Intraindividual variability in cognitive test performance has the potential to be a good marker of preclinical Alzheimer's disease status (S. C. Li & U. Lindenberger, 1999). Using cross-sectional community data from 2,317 individuals aged 60-64 years, the authors of this study found that variability was greater in individuals who met criteria for mild cognitive impairment or aging-associated cognitive decline but not for age-associated memory impairment. Higher variability was associated with lower education and a non-English-speaking background. In contrast to previous findings, variability in this study did not contribute uniquely to meeting criteria for mild cognitive impairment. The reasons for the differences may reside in the authors' method of estimating mean independent variability, the use of an occasion-specific measure, or the relatively younger age of the participants. Follow-up of the cohort in 4 years will yield data on the prospective validity of variability as a risk factor for impairment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Progressive impairment on neuropsychological tasks in a longitudinal study of preclinical Alzheimer's disease.

Previous research suggests that patients with Alzheimer's disease exhibit cognitive impairment in the years preceding a clinical diagnosis. Memory impairments are particularly pronounced, but the relative degree to which other cognitive functions are impaired and the speed with which they decline during the preclinical years remains unclear. The authors report a detailed neuropsychological evaluation of 11 patients over the course of 3 years up to and including the 1st year of nonnormal diagnosis. The results suggest that performance falls off rapidly in all areas of cognitive functioning but that abilities thought to be subserved by the medial and lateral temporal lobes (episodic and semantic memory, respectively) appear to be substantially more impaired than those abilities thought to be subserved by the frontal lobes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Quantitative analysis of neuropathologic changes in the cerebral cortex of centenarians

1. The quantitative distribution of neurofibrillary tangles and senile plaques was studied in the brains of 65 elderly patients aged from 96 to 104 years by immunohistochemistry. 2. According to the clinical and neuropathological diagnoses, three groups of cases were considered: 19 patients with Alzheimer's disease, 22 patients with mixed dementia (vascular and degenerative) and 24 patients with no or very mild cognitive impairment. 3. Moderate to high neurofibrillary tangle densities were always present in the hippocampus and entorhinal cortex. The inferior temporal cortex was very frequently affected in demented and non-demented cases whereas the superior frontal cortex was spared in the majority of cases independently of the clinical diagnosis. Quantitatively, Alzheimer's disease cases showed significantly higher NFT densities than cases with no clinical findings of dementia only in the CA1 field of the hippocampus. 4. The hippocampus and entorhinal cortex were often devoid of senile plaques in non-demented cases while the vast majority of Alzheimer's disease cases had few SP in these regions. The frontal and temporal cortex were more frequently involved than the limbic structures in both non-demented and Alzheimer's disease cases. The SP densities in layers II and III of the inferior temporal and superior frontal cortex were significantly higher in Alzheimer's disease than in non-demented cases. 5. These observations suggest that the dementing process in nonagenarians and centenarians may differ to that described in younger demented individuals in that neurofibrillary tangles involve principally the hippocampal formation with relative sparing of the neocortex. Furthermore, they indicate that both the neurofibrillary tangle densities in the CA1 field and senile plaque densities in the superficial layers of the neocortex must be considered for the neuropathological diagnosis of Alzheimer's disease in this age group.     

Viewpoint on the methodology of drug trials affecting cognition of elderly patients

Clinical trials for cognitive disorders in the elderly require specific methodological guidelines. They must take into account the psychosocial dimension of the patient and his family and must be based on serious neurobiologic knowledge. In degenerative dementias the progress of research concern genetics, molecular intercellular recognition and astrocytic cells. Biology of cognition like hippocampal long term potentiation provides good pharmacologic basis for trials. In normal brain aging several ways must be developed: aminergic systems, free radicals, excitotoxic amino-acid, nerves growth factors. Clinical trials bring informations for pharmacology and epidemiology. Cholinergic neurons are the main pharmacologic target but there are many other ones: GABA-ergic system, Tau protein, amyloid. A rigourous selection of patients allows to precise the nosology of illness responsible of cognitive disorders and to point-out early clinical signs that represent a more sensitive target. Diagnostic criteria are useful in Alzheimer's disease, memory impairment, vascular dementias and other dementias. Evaluation of stage and evolution of dementia, comorbidity, limits of age and caregiver are practical problems. The effects of drugs used to treat cognitive functions are subtle so it is necessary to detect them to choose the best tests in function of each trial. Laboratory investigations can be used to evaluate the response to drug administration. Ethical point of view is represented by the fact that old people with cognitive impairment must not be away from therapeutic progress. In this field we must consider carefully the consequences of cognitive impairment on patient judgment and consent to clinical trial. Legal problems are regulated by supranational rules and French directives of Huriet law.     

Identification of body parts in Alzheimer's disease: evidence for a body schema hypothesis

This study examined the ability of patients with Alzheimer's Disease (AD) to perform a Body Part Identification (BPI) task, and also explored the relationship between BPI, intellectual level, severity of cognitive impairment and the general insight of patients into their disorder. The results showed that although AD patients are not always impaired on BPI, the degree of impairment correlates with the level of cognitive impairment measured using the Mini-Mental State Examination. The study also showed that BPI is not, however, associated with level of insight into their illness. Taken together these results provide support for the existence of a body schema that can be disrupted by AD, but is independent of the degree of insight into the illness.     

Extraskeletal osteosarcomas: a clinicopathologic study of 25 cases

OBJECTIVE: To describe a clock drawing task (CLOX) designed to elicit executive impairment and discriminate it from non-executive constructional failure. SUBJECTS: 90 elderly subjects were studied (45 elderly and well persons from the independent living apartments of a continuing care retirement community and 45 patients with probable Alzheimer's disease). The clock drawing performance of elderly patients was compared with that of 62 young adult controls. METHODS: Subjects received the CLOX, an executive test (EXIT25), and the mini mental state examination (MMSE). The CLOX is divided into an unprompted task that is sensitive to executive control (CLOX1) and a copied version that is not (CLOX2). Between rater reliability (27 subjects) was high for both subtests. RESULTS: In elderly subjects, CLOX subscores correlated strongly with cognitive severity (CLOX1: r=-0.83 v the EXIT25; CLOX2: r=0.85 v the MMSE). EXIT25 and MMSE scores predicted CLOX1 scores independently of age or education (F(4,82)=50.7, p<0.001; R2=0.71). The EXIT25 accounted for 68% of CLOX1 variance. Only the MMSE significantly contributed to CLOX2 scores (F(4,72)= 57.2, p<0.001; R2=0.74). CLOX subscales discriminated between patients with Alzheimer's disease and elderly controls (83.1% of cases correctly classified; Wilkes' lambda=0.48, p<0.001), and between Alzheimer's disease subgroups with and without constructional impairment (91.9% of cases correctly classified; Wilkes' lambda=0.31, p<0.001). CONCLUSIONS: The CLOX is an internally consistent measure that is easy to administer and displays good inter-rater reliability. It is strongly associated with cognitive test scores. The pattern of CLOX failures may discriminate clinical dementia subgroups.     

Attention and brain function in Alzheimer's disease: A review.

Cognitive and neuroscience studies point to a selective impairment of attentional functions in Alzheimer's disease (AD). Prominent deficits occur in the shifting and division of attention, whereas phasic arousal and focused attention to stimulus features are only minimally affected in the early stages of AD. Macroscopic processing interpretations of these results—global cognitive impairment, generalized cognitive slowing, processing resource deficit, and failure of central executive control ("dysexecutive" syndrome)—are discussed. An alternative approach is based on the identification of component attentional operations and their mediation by corticocortical and subcortical networks. This analysis suggests that attention represents the first cognitive indicator of neocortical dysfunction in early AD. Disconnection between frontal and posterior parietal areas may mediate the selective disruption of attentional functions in AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Postmortem studies in schizophrenia

The past decade has seen renewed interest in the neuropathology of schizophrenia. The advent of new postmortem techniques and functional imaging, along with a greater understanding of the neuropsychology of schizophrenia, have provided many new clues to the nature of the underlying brain dysfunction in this disorder. There has also been a greater understanding of the presence of severe cognitive dysfunction among many elderly persons with schizophrenia. In this article, a series of investigations are described that seek to answer basic questions about the neuropathology of schizophrenia, in particular as it pertains to cognitive impairment. The first study describes neuropathological findings in 100 consecutively autopsied persons with schizophrenia, the majority of whom had had detailed antemortem assessments. Results from this first study prompted the conclusion that schizophrenia is not characterized by classical, histologically identifiable neuropathology. Moreover, most cases of dementia in schizophrenia are probably not the result of neuropathologically identifiable dementing illnesses. The next four studies examined chemical markers that are altered in Alzheimer's disease and some other dementing conditions and have also been suggested to be abnormal in schizophrenia: choline acetyltransferase, catecholamines and indolamines, neuropeptides, and synaptic proteins. Schizophrenia cases as a group did not show a cholinergic deficit; nor did they differ from elderly comparison cases with respect to cortical catecholamines and indolamines. Among the schizophrenia cases, however, cognitive impairment was negatively correlated with choline acetyltransferase activity. Those with cognitive impairment showed evidence of cortical noradrenergic and serotonergic deficits. Neuropeptide deficits were also present in schizophrenia, but their pattern differed from that seen in Alzheimer's disease. Increased synaptic protein activity was found in the cingulate cortex of persons with schizophrenia, and this activity was correlated with schizophrenia symptoms. From this second series of studies, it was concluded that some biological measures in schizophrenia may be related to cognitive impairment (e.g., cortical amines), whereas others may be related to diagnosis (e.g., neuropeptide deficits). In addition, synaptic organization may correlate with schizophrenia symptoms.     

Association of elevated alpha 1-antichymotrypsin with cognitive impairment in a prospective study of the very old

OBJECTIVE: The authors investigated the relationships between concentrations of two acute-phase proteins, alpha 1-antichymotrypsin (ACT) and alpha 2-macroglobulin (MAC), and cognitive impairment in the very old. METHOD: Concentrations of ACT and MAC were determined in a prospective study using sera from medically stable elderly nursing home residents. Cognitive impairment was assessed with the Mini-Mental State. RESULTS: Concentrations of ACT were associated with greater cognitive impairment, as reflected by lower Mini-Mental State scores. This relationship did not exist for MAC. CONCLUSIONS: These data extend previous reports that patients with Alzheimer's disease have greater concentrations of ACT in their blood by demonstrating in a diagnostically diverse nursing home population a relationship between serum ACT and mental status. Elevated serum ACT in patients with compromised mental status may reflect a cerebral acute-phase response.     

A four year prospective study of age-related cognitive change in adults with Down's syndrome

BACKGROUND: While neuropathological studies indicate a high risk for Alzheimer's disease in adults with Down's syndrome, neuropsychological studies suggest a lower prevalence of dementia. In this study, cognitive deterioration in adults with Down's syndrome was examined prospectively over 4 years to establish rates and profiles of cognitive deterioration. METHODS: Fifty-seven people with Down's syndrome aged 30 years or older were assessed using a battery of neuropsychological tests on five occasions across 50 months. Assessments of domains of cognitive function known to change with the onset of Alzheimer related dementia were employed. These included tests of learning, memory, orientation, agnosia, apraxia and aphasia. The individual growth trajectory methodology was used to analyse change over time. RESULTS: Severe cognitive deterioration, such as acquired, apraxia and agnosia, was evident in 28.3% of those aged over 30 and a higher prevalence of these impairments was associated with older age. The rate of cognitive deterioration also increased with age and degree of pre-existing cognitive impairment. Additionally, deterioration in memory, learning and orientation preceded the acquisition of aphasia, agnosia and apraxia. CONCLUSIONS: The prevalence of cognitive impairments consistent with the presence of Alzheimer's disease is lower than that suggested by neuropathological studies. The pattern of the acquisition of cognitive impairments in adults with Down's syndrome is similar to that seen in individuals with Alzheimer's disease who do not have Down's syndrome.     

Heterogeneity of cognitive profiles in dementias of the Alzheimer type: theoretical aspects and clinical consequences

Presently, Alzheimer's disease can only be diagnosed with the coexistence of clinical symptoms and the presence of neuropathological alterations. Thus, in the absence of pre mortem biological markers, cognitive deficits form the starting point and the basis of inclusion criteria on which the clinician relies in order to make a putative diagnose of dementia of the Alzheimer type (DTA). Cognitive deficits should thus be accurately described through neuropsychological testing since it is essential to identify the cognitive deterioration patterns of the patients--in terms of selective impairment of cognitive functions--as well as the evolution of these patterns. Regarding this issue, the classical teaching of the Geneva school has proposed a homogeneous deterioration of the aphasic-apraxicagnosic syndrome into four stages. However, recent work does not support this hypothesis. On the contrary, these studies tend to show the presence of heterogeneity in neuropsychological manifestations of the disease. The aim of the present paper is to provide a critical review of this topic through a brief survey of the classical work and research that have recently been conducted. An analysis of the possible candidates responsible for the existence of this heterogeneity of cognitive profiles is presented. Finally, theoretical implications and clinical repercussions are discussed.