Drug therapy strategies in Alzheimer's disease

Treatments in Alzheimer's disease include treatment of cognitive impairment and behavioral manifestations (agitation, depression, anxiety, delusions). It should be noted that many non cognitive behaviors may have some relations to underlying cognitive impairment. In the not too distant future, physicians can expect to see a variety of medications and controversies over the benefits of slowing symptoms with cholinergic therapeutics approved for clinical use and (or) preventing progression of Alzheimer's disease assessed in clinical trials will emerge.     

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.     

EEG spectral abnormalities and psychosis as predictors of cognitive and functional decline in probable Alzheimer's disease

We examined whether either psychotic features (e.g., delusions and hallucinations) or EEG abnormalities are associated with more rapid progression of Alzheimer's disease (AD). AD patients with psychosis have exhibited more EEG abnormalities than those without psychosis, and both abnormal EEG and psychosis have been noted to be predictors of functional and cognitive decline in AD. Ninety-five probable AD patients participating in a longitudinal study of dementia had an EEG and a semistructured psychiatric interview at baseline. Using EEG spectral analysis, we classified records as normal/abnormal based on the parasagittal mean frequency. Patients with abnormal EEGs were more functionally (e.g., Blessed Rating Scale for activities of daily living) and cognitively (e.g., Mini-Mental State) impaired than patients with normal EEG. AD patients with psychosis were only more functionally impaired than patients without psychosis. A two-factor analysis showed no interaction between abnormal EEG and psychosis. In addition, using a Cox proportional hazard model adjusted for age and education, the presence of an abnormal EEG or psychotic symptom at study entry was associated with higher risk of reaching severe cognitive and functional impairment during follow-up. Neither abnormal EEG nor the presence of psychosis predicted death. These results indicate that both abnormal EEG and psychosis are independent predictors of disease progression but not of physical survival.     

The cardinal features of cognitive and noncognitive dysfunction and the differential efficacy of tacrine in Alzheimer's disease patients

The Alzheimer's Disease Assessment Scale (ADAS), frequently used in clinical trials to assess overall pathology of Alzheimer's disease (AD), comprises two subscales. The cognitive subscale (ADAS-COG) consists of 11 items, and the noncognitive subscale consists of 9 items. Factor analyses were carried out on ADAS-COG and ADAS-NONCOG item scores from the most recent and largest (n = 663) placebo-controlled, multicenter, 30-week study (970-61) of tacrine in patients with AD conducted by the clinical research group at Parke-Davis Pharmaceutical Research. Through factor analyses the primary dimensions of variation in the ADAS-COG and ADAS-NONCOG were defined. Obliquely rotated three principal factors of ADAS-COG and three principal factors of ADAS-NONCOG have been interpreted as three cardinal features of cognitive function corresponding to memory, language, and praxis, and three cardinal features of noncognitive function corresponding to agitation, depression, and lack of concentration. Reliably defined factors of ADAS-COG enabled comparisons of longitudinal changes in cognitive dysfunction. Factor scores at week 30, adjusted to baseline factor scores, were used to compare the effects of tacrine with those of placebo on cognitive cardinal features. Additionally, the effect of concurrent depression on cardinal features of cognitive dysfunction was evaluated by gender.     

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)     

Relationship between cognitive status and behavioral symptoms in Alzheimer's disease and mixed dementia

OBJECTIVE: To investigate the relationship between cognitive and behavioral impairments in Alzheimer's disease (AD) and to examine whether the addition of cerebrovascular disease modifies that relationship. DESIGN: Correlational analysis. SETTING: An outpatient dementia clinic. PATIENTS: An autopsy-confirmed series of 28 patients with AD and 16 patients with mixed Alzheimer and vascular dementia (MIX). MEASUREMENTS: Neuropsychological and behavioral tests during life: Mini-Mental State (MMS), Blessed Dementia Scale (BDS), Haycox Dementia Behavior Scale (HDBS), and two non-cognitive functional scales derived from the BDS and HDBS. RESULTS: In the AD group, MMS scores correlated significantly with scores on the BDS, HDBS, and two non-cognitive functional scales. In the MIX group, however, no significant relationship was observed between MMS scores and scores on any of the behavioral measures. CONCLUSIONS: These observations suggest that in AD, cognitive and behavioral impairments progress simultaneously. However, with the addition of a vascular component to the dementing process, cognitive and behavioral impairments may progress more independently.     

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 (     

Visual attention deficits in Alzheimer's disease: Simple versus conjoined feature search.

The authors investigated selective attention in patients with Alzheimer's disease (AD), using a well-known visual search procedure. In simple feature search, the deficit observed in AD patients represented a baseline shift in the median hit reaction time (RT). On the conjoined feature search task, the median hit RT for AD patients increased disproportionately with increasing array size, indicating an additional cognitive impairment on this task. Of particular importance, the cognitive deficit observed in conjunction search was more profound than that predicted on the basis of previous reports of global cognitive slowing in AD. There was some evidence that the performance of AD patients improved more than the performance of controls over the duration of the experimental test session. Patients also had more difficulty in detecting targets on the right side of hemispace and in more peripheral locations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Risk factors of dementia Alzheimer's type

The paper presents the study of risk factors and factors-protectors of the development of dementia of Alzheimer's type (DAT). 40 patients with Alzheimer's disease (AD), 40 patients, with senile DAT and 80 healthy individuals of the same sex, age and education level were examined. The pairs were formed: the patient-normal. The main risk factor in DAT group was family predisposition to dementia. AD risk factors may be the exposure to radioactive materials or chronic psychotraumatic situations during life. Senile DAT risk factors may be traumas of head without lack of consciousness. Acute and frequent psychotraumatic situations as well as some somatic diseases (and related drug therapy) were factors-protectors in the whole DAT group. Groups of patients with AD and senile DAT differed by both risk factors and factors-protectors, confirming DAT heterogeneity. Hypothetic biologic basis of the data obtained is described.     

Learning and retention in preclinical and early Alzheimer's disease.

Accelerated forgetting has been proposed as the first sign in preclinical and early Alzheimer's disease (AD). The authors investigated learning and retention in participants who later developed AD with free and cued selective reminding (FCSR; H. Buschke, 1984; E. Grober & H. Buschke, 1987), a test that maximizes learning by inducing deep semantic processing and by controlling study and test conditions. AD patients in the preclinical stage recalled significantly fewer words than did matched control participants, indicating an impairment of learning; nonetheless, patients' retention was identical to that of control participants. A retention deficit was documented 3 years later for AD patients but not for control participants, whose retention was still perfect. Thus, a retention deficit is not present in preclinical AD when hallmark learning deficits can be documented. Detection of preclinical and very early AD may be best accomplished by using robust learning tests that control cognitive processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nerve growth factor: structure, function and therapeutic implications for Alzheimer's disease

Over the past decade, neurotrophic factors have generated much excitement for their potential as therapy for neurological disorders. In this regard, nerve growth factor (NGF), the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of Alzheimer's disease (AD). This interest is based on the observation that cholinergic basal forebrain (CBF) neurons which provide the major source of cholinergic innervation to the cerebral cortex and hippocampus undergo selective and severe degeneration in advanced AD and that these neurons are dependent upon NGF and its receptors for their survival. In fact, NGF transduces its effects by binding two classes of cell surface receptors, TrkA and p75(NTR), both of which are produced by CBF neurons. This review focuses on NGF/receptor binding, signal transduction, regulation of specific cellular endpoints, and the potential use of NGF in AD. Alterations in NGF ligand and receptor expression at different stages of AD are summarized. Recent results suggest that cognitive deficits in early AD and mild cognitive impairment (MCI) are not associated with a cholinergic deficit. Thus, the earliest cognitive deficits in AD may involve brain changes other than simply cholinergic system dysfunction. Recent findings indicate an early defect in NGF receptor expression in CBF neurons; therefore treatments aimed at facilitating NGF actions may prove highly beneficial in counteracting the cholinergic dysfunction found in end-stage AD and attenuating the rate of degeneration of these cholinergic neurons.     

Working memory and control of attention in persons with Alzheimer's disease and mild cognitive impairment.

The goal of the present study was to assess 3 attentional control processes--divided attention, manipulation capacities, and inhibition--in persons with mild cognitive impairment (MCI) and with mild Alzheimer's disease (AD). Manipulation capacities were tested by comparing immediate serial recall with alphabetical-order recall of words. Divided attention was tested with the Brown-Peterson procedure, in which participants divide their attention between simple addition tasks and consonant trigrams over delays. Inhibition was tested with the Hayling procedure, in which participants complete sentences with words irrelevant to their context. Persons with AD showed severe impairment on the 3 attentional control components. Persons with MCI exhibited impaired performance on the Brown-Peterson procedure but normal performance on the other 2 tasks. With AD and MCI participants, there was a negative correlation between general cognitive deficits and impairment on attentional control tasks, indicating that attentional control deficits increase in the MCI/AD continuum. When separating MCI with and without significant subsequent decline, those with subsequent decline showed impaired performance on both the Brown-Peterson procedure and manipulation task. These data suggest that control of attention tasks can track AD at a preclinical stage and that impairment increases gradually during the preclinical phase of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amnestic mild cognitive impairment: Difference of memory profile in subjects who converted or did not convert to Alzheimer's disease.

Episodic long-term, short-term, and implicit memory were investigated in 79 elderly subjects who fulfilled criteria for the amnestic form of mild cognitive impairment (a-MCI; i.e., by having an idiopathic amnestic disorder with absence of impairment in cognitive areas other than memory and without confounding medical or psychiatric conditions) and who developed Alzheimer's disease (AD) after 2 years as well as in 111 subjects affected by a-MCI who did not develop dementia. Results document a memory profile in a-MCI subjects characterized by preserved short-term and implicit memory and extensive impairment of episodic long-term memory. In virtually all episodic memory indexes examined (learning, forgetting, recognition abilities), a-MCI subjects who converted to AD were more severely impaired than were subjects who did not become demented. This memory profile, which closely resembles that exhibited by amnestic patients with bilateral mesial-temporal lobe lesions, confirms a precocious phase in preclinical AD characterized by selective involvement of mesial-temporal areas and worsening of the memory impairment as atrophic changes progress in hippocampal structures. In this context of pervasive episodic memory impairment, tests assessing the free recall of verbal material following a delay interval demonstrated the greater sensitivity to memory deficits of a-MCI subjects who developed AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Working memory in mild cognitive impairment and Alzheimer's disease: Contribution of forgetting and predictive value of complex span tasks.

Objective: This study examines working memory (WM) in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Method: Performances on sentence span and operation span were measured in individuals meeting criteria for MCI (n = 20) and AD (n = 16) as well as in healthy older adults (n = 20). In addition, the effect of retention interval was assessed by manipulating the length of first and last items of trials (long-short vs. short-long), as forgetting might contribute to impaired performance in AD and MCI. Results: Results show a group effect (p     

Wandering: a significant problem among community-residing individuals with Alzheimer's disease

This study evaluated the frequency, predictors, and effects of wandering in a population-based sample of 193 individuals with Alzheimer's disease (AD). Although wandering occurred in subjects at all levels of cognitive impairment, analysis of variance indicated that for the group as a whole, greater frequency of wandering was associated with significantly more impairment in cognition, day-to-day functioning, and behavior. Caregiver distress also increased significantly with increased frequency of wandering. Logistic regression modeling identified functional impairment and disruptive behavior problems as the strongest independent predictors of wandering occurring within the past week. Cluster analysis revealed four characteristic groups of wanderers that represented a continuum of wandering frequency, each having a unique pattern of other behavioral disturbances. Based on this analysis, we recommend further evaluation and the development of possible treatment strategies that address the individual differences found among AD patients who wander.     

Quantitative MRI volume changes in late onset schizophrenia and Alzheimer's disease compared to normal controls

Volumes of medial and lateral temporal lobe structures were assessed using magnetic resonance imaging (MRI) in 11 patients with late-life onset schizophrenia (LOS), 18 normal elderly controls and 12 patients with moderate cognitive impairment due to Alzheimer's disease (AD) who had no non-cognitive symptoms. While both patient groups had smaller volumes of several medial temporal regions (e.g. entorhinal cortex, left hippocampus), schizophrenics had significantly smaller anterior superior temporal gyri (STG) than normal controls, but AD patients did not. We have previously demonstrated anterior STG volume to be reduced in early life onset schizophrenia.     

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.     

Executive dysfunction and Alzheimer's disease: Performance on a test of planning ability, the Porteus Maze Test.

Planning ability, as measured by the Porteus Maze Test, was evaluated in 85 Alzheimer's disease (AD) patients and 65 controls. AD patients performed worse on Test Age and 2 of 5 qualitative error scores. Principal components analysis revealed 3 Porteus components: Test Age and First Third Errors; Cut Corner and Cross Line Errors; and Last Third Errors. Among AD patients, factor analysis of Porteus measures and other cognitive tests revealed 4 factors. A nonverbal factor included Test Age and 3 nonverbal measures. A verbal factor included no Porteus measure. The remaining factors resembled the last 2 components from the analysis of Porteus scores alone. Test Age and 4 other cognitive measures correlated with ratings on an activities of daily living scale. Porteus Maze performance was impaired in a substantial number of patients with dementia and may be a useful measure of executive function in this population. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

No increased incidence of Alzheimer's disease in elderly schizophrenics

There is currently controversy as to the morphological basis of cognitive impairment in elderly schizophrenics. In contrast to previous findings, recent studies have found no increased frequency of Alzheimer's disease (AD) pathology in elderly schizophrenics. We examined 99 consecutive autopsy cases of patients over the age of 55 years from a psychiatric hospital who met the DSM-III-R and ICD.10 criteria for schizophrenia (mean age 69.5 +/- 8.25 years; mean duration of illness 35.15 +/- 10.1 years), 56% showing moderate to severe dementia. All brains were blindly reviewed for evidence of AD using CERAD criteria and Braak staging of neuritic AD lesions. "Definite" AD (CERAD C, Braak stage V) was seen in 2 cases aged 56 and 67 years, respectively [2% of total or 1/68 (1.4%) of those over age 65]. "Probable" AD (CERAD B, Braak stages IV-V) were seen in 5 cases aged 71-89 years (mean 79 years; 5% of total or 7.3% of those over age 65), and 1 case each with multiple cerebral infarcts and with Parkinson's disease pathology. In addition, 2 females aged 82 and 89 years, respectively, revealed senile dementia with tangles (NIA, CERAD negative; Braak stage IV), 1 with hippocampal sclerosis. The total incidence of definite and probable AD in this cohort was 7.1% or 8.7% for those over age 65. This is in line with other recent studies showing that the frequency of AD in elderly schizophrenics may be equal or even less than in the general population. The reasons for this negative association and the basis of cognitive deficits in elderly schizophrenics--those with dementia usually showing significantly lower brain weight--await further elucidation.     

Severity of cognitive impairment in Alzheimer's disease affects list learning using the California Verbal Learning Test (CVLT)

Impairment in list learning is considered a primary symptom of Alzheimer's disease (AD), yet there are no published reports examining the relationship between list learning and severity of cognitive impairment. We gave nine-item and 16-item versions of the California Verbal Learning Test (CVLT; Delis et al., 1987), a standardized shopping list assessment of memory, to 24 AD patients (mean age = 76.2 +/- 8.1; mean years of education = 13.8 +/- 2.4), who were stratified into four groups based on MMSE scores (mean = 16.0 +/- 5.6). ANOVAs revealed severity effects for total list learning (p < 0.001), the first trial (p < 0.001), the last trial (p < 0.001) and short- and long-delay recall measures. Most of these differences seemed due to floor effects. For example, the modal number of words recalled after a delay was 0 by subjects with MMSE scores below 21. Severity of cognitive impairment was associated with the proportion of intrusions such that the most severely demented subjects gave almost entirely intrusion responses. Surprisingly, list length did not significantly affect any of the free recall measures. Our results suggest that list learning and recall seem to be lost relatively early in AD. Measures of list recall like the CVLT may not be useful in tracking severity of cognitive impairment over time.