Rate of forgetting in mild Alzheimer's-type dementia

Patients with mild dementia of the Alzheimer's type (DAT) and matched controls were examined for rate of forgetting line drawings of common objects. DAT patients demonstrated rapid forgetting in the first 10 min after learning to criterion. This finding is discussed with respect to memory consolidation and neuropathologic changes in dementia of the Alzheimer's type.     

Selective reminding procedure in depression and dementia

Patients with mild dementia of the Alzheimer's type (DAT), patients with major depression, and normal elderly control subjects were administered a verbal learning task using the selective reminding procedure. Depressed patients were impaired on total recall and the proportion of items retained from one trial to the next without reminding and did not benefit from imagery in retaining items over consecutive trials. The DAT patients were impaired on all measures derived from the test, including storage and recognition memory. With the exception of the ability to benefit from imagery, all of the measures distinguished depressed and mild DAT patients. These findings are consistent with deficient encoding in DAT and performance deficits as a function of effortful cognitive processing in depression.     

Mild cognitive impairment: a neuropsychological perspective

Mild cognitive impairment (MCI) is a clinical diagnosis in which deficits in cognitive function are evident but not of sufficient severity to warrant a diagnosis of dementia. For the majority of patients, MCI represents a transitional state between normal aging and mild dementia, usually Alzheimer's disease. Multiple subtypes of MCI are now recognized. In addition to presentations featuring memory impairment, symptoms in other cognitive domains (eg, executive function, language, visuospatial) have been identified. Neuropsychological testing can be extremely useful in making the MCI diagnosis and tracking the evolution of cognitive symptoms over time. A comprehensive test battery includes measures of baseline intellectual ability, attention, executive function, memory, language, visuospatial skills, and mood. Informant-based measures of neuropsychiatric symptoms, behaviors, and competency in instrumental activity are also included. Careful assessment can identify subtle deficits that may otherwise elude detection, particularly in individuals of superior baseline intellectual ability. As we move closer to disease-modifying therapy for Alzheimer's disease, early identification becomes critical for identifying patients who have an opportunity to benefit from treatment.     

Pantomime and imitation of limb gestures in relation to the severity of Alzheimer's disease

The present study was designed to investigate the relationship between performance of limb gestures and the severity of Alzheimer's disease (A.D.). Apraxia tends to occur at later stages of A.D., and the severity of apraxia has been shown to vary with the severity of A.D. dementia. Participants were 19 mild (including 9 with no cognitive impairment and 10 with mild impairment) and 18 moderate A.D. patients as well as 25 controls and they were asked to pantomime (P) or imitate (both concurrent (CI) and delayed (DI)), eight transitive gestures to assess praxis performance. Results indicated that the moderate patients performed less accurately than mild and non-impaired patients, and that across all groups, the imitation conditions were performed less accurately than pantomime, relative to controls. Correlational analyses revealed that MMSE scores were correlated with all three performance conditions suggesting that impaired praxis performance may relate to more global impairment. Finally, a frequency analysis was conducted to examine whether A.D. patients showed patterns of apraxia as described in Roy's model (1996). Results indicated that A.D. patients showed greatest impairment on pattern 7 (deficits in P, DI, and CI), reflecting late-stage gesture production, with a greater frequency of moderate patients exhibiting each apraxic pattern.     

Very Early Decline in Recognition Memory for Odors in Alzheimer’s Disease

When in the progression of Alzheimer’s disease (AD) a decline in detection sensitivity and recognition memory for odors begins, and whether a fast progression in dementia is related to a fast loss in odor sensitivity, was determined by studying 78 patients with probable AD, categorized as very mild, mild, or moderate in degree of dementia, and 78 controls. Taste and vision were studied for comparison. Whereas the earliest decline in odor sensitivity and visual memory was found in mild patients, a decline in odor memory was found in the very mild patients. Similar taste thresholds in the four groups suggest that the poor odor detectability in AD was not related to task demands in threshold testing. A fast progression in dementia was also found to be related to a fast loss in odor sensitivity. The findings imply that memory-based olfactory tests may contribute to early diagnosis of AD.     

Assessing working memory and language comprehension in Alzheimer's disease.

Studies of language impairments in patients with Alzheimer's disease have often assumed that impairments in linguistic working memory underlie comprehension deficits. Assessment of this hypothesis has been hindered both by vagueness of key terms such as "working memory" and by limitations of available working memory tasks, in that many such tasks either seem to have little relationship to language comprehension or are too confusing or difficult for Alzheimer's patients. Four experiments investigated the usefulness of digit ordering, a new task assessing linguistic working memory and/or language processing skill, in normal adults and patients with probable Alzheimer's disease. The digit ordering task was shown to be strongly correlated with the degree of dementia in Alzheimer's patients. The task correlated with measures of language processing on which patients and normal controls performed differently. The results are interpreted as indicating that linguistic representations, linguistic processing, and linguistic working memory are intertwined, such that a deficit of one (e.g., working memory) cannot be said to "cause" a deficit in the other. The implications of this approach are explored in terms of task demands in comprehension and memory measures, and interpretation of previous results in the literature.     

轻度阿尔茨海默症患者的前瞻记忆

轻度阿尔茨海默症往往伴随着不同程度的前瞻记忆衰退。已有研究以轻度阿尔茨海默症与前瞻记忆衰退的关联程度为主线, 对比了这一关联与“其他认知缺陷疾病-前瞻记忆衰退”、“轻度阿尔茨海默症-回溯记忆衰退”以及“轻度阿尔茨海默症-遗传表达”这三种关联的类似程度。此外, 也有研究涉及到了如何促进轻度阿尔茨海默症患者的前瞻记忆。将来的研究应引入病情程度、前瞻记忆任务类型等变量, 深入探讨轻度阿尔茨海默症与前瞻记忆衰退的关联, 并使用ERP、fMRI等神经生理技术确定轻度阿尔茨海默症患者前瞻记忆衰退的机制。     

Event understanding and memory in healthy aging and dementia of the Alzheimer type

Segmenting ongoing activity into events is important for later memory of those activities. In the experiments reported in this article, older adults' segmentation of activity into events was less consistent with group norms than younger adults' segmentation, particularly for older adults diagnosed with mild dementia of the Alzheimer type. Among older adults, poor agreement with others' event segmentation was associated with deficits in recognition memory for pictures taken from the activity and memory for the temporal order of events. Impaired semantic knowledge about events also was associated with memory deficits. The data suggest that semantic knowledge about events guides encoding, facilitating later memory. To the extent that such knowledge or the ability to use it is impaired in aging and dementia, memory suffers.     

Cognitive deficits following coronary artery bypass grafting: prevalence, prognosis, and therapeutic strategies

There is increasing recognition that coronary artery bypass grafting (CABG) may be a risk factor for subtle cognitive decline although the presence and pattern of such decline has varied across studies. Cognitive deficits may present as short-term memory loss, executive dysfunction and psychomotor slowing. Although they are usually are not severe enough to meet criteria for mild cognitive impairment or vascular dementia, they lower quality of life and add to hospitalization and out-of-hospital costs. Proposed mechanisms include surgical-related trauma, genetic susceptibility (eg, apolipoprotein E4 allele), microembolization, other vascular or ischemic changes, and temperature during surgery. Depression and anxiety levels predict subjective perception of these deficits more than objective cognitive performance. Both nonpharmacologic (eg, emboli reduction, temperature, or glucose management) and pharmacologic (eg, dexanabinol, glypromate, nootropics) strategies to prevent post-CABG cognitive deficits are under investigation. Given the large numbers of subjects who may already have CABG associated cognitive deficits, clinical trials of agents being tested for Alzheimer's disease (eg, donepezil, rivastigmine, memantine, neramexane, ginkgo) may also be informative. The results of multicenter long-term outcome studies (with matched control groups) as well as ongoing treatment trials will more conclusively address some of these issues. These data emphasize the need for clinicians to monitor cognitive function before and after coronary bypass surgery, and to educate patients.     

Spatial and visual learning deficits in Alzheimer's and Parkinson's disease

Experimental paradigms adopted from animal models were used to compare the neuropsychological mechanisms underlying the dementias of Alzheimer's and Parkinson's diseases. Two tasks were selected because characteristic profiles of impairment in nonhuman primates are seen following selective lesions of frontal cortex, temporal cortex, and fornix. The tasks consisted of a spatial and a visual learning problem, each with two components: (1) original learning and (2) reversal of the original learning. The Alzheimer's patients were significantly impaired on original learning and reversal learning in the visual modality compared with demented Parkinson's patients, even though both groups were equated for severity of dementia. On the spatial tasks, both the Alzheimer's and the demented Parkinson's patients were impaired on reversal learning but not on original learning. The profile of deficits on the visual tasks may serve to differentiate Alzheimer's from Parkinson's dementia and may reflect selective orbitofrontal system lesions in the former.     

Strategic sequence planning and prospective memory impairments in frontally lesioned head trauma patients performing activities of daily living

The aim of this research was to study strategic sequence planning and prospective memory in activities of daily living (ADL) in 10 patients with frontal lobe lesions after a mild to moderate closed head injury (CHI). The lesions were documented radiologically. The CHI patients were compared to 12 normal controls with a neuropsychological test battery and a realistic simulation of complex multitask ADL (planning and preparing a meal). Though the CHI patients were significantly slow on one test and subject to interference on an attention test, they manifested no basic executive or memory deficit on the paper-pencil tests. However, the CHI patients manifested marked anomalies in the organization of behavior in the meal preparation task. While small sequences of actions were easily produced, large action sets could not be correctly executed. An outstanding difficulty in strategic planning and prospective memory, particularly time-based more than event-based, appears to be an important underpinning of the impairment of ADL observed in the CHI patients with frontal lobe lesions.     

Cholinergic lesions produce task-selective effects on delayed matching to position and configural association learning related to response pattern and strategy

192IgG-saporin (SAP) was used to selectively destroy cholinergic neurons in the rostral basal forebrain (e.g., medial septum (MS) and vertical limb of the diagonal band of Broca (VDB)) and/or the caudal basal forebrain (e.g., nucleus basalis magnocellularis (NBM)) of ovariectomized Sprague-Dawley rats. The effects of these lesions on two different cognitive tasks, a delayed matching to position (DMP) T-maze task, and a configural association (CA) operant conditioning task, were evaluated and compared. Injecting SAP into either the MS or NBM significantly impaired acquisition of the DMP task. Analysis showed that the effects were due largely to an affect on response patterns adopted by the rats during training, as opposed to an effect on working memory performance. Notably, the impairment in DMP acquisition did not correlate with the degree of cholinergic denervation of the hippocampus. Despite the deficit, most animals eventually learned the task and reached criterion; however by the end of training, controls and animals that received SAP into either the MS or NBM appeared more likely to use an allocentric place strategy to solve the task, whereas animals that received SAP into both the MS and NBM were more likely to use an egocentric response strategy. Cholinergic lesions also produced a small but significant affect on acquisition of the CA task, but only with respect to response time, and only in the SAP-NBM-treated animals. SAP-NBM lesions also produced small but significant impairments in both the number of responses and response time during the acquisition of simple associations, possibly reflecting an effect on alertness or attention. Notably, the effects on CA acquisition were small, and like the effects on DMP acquisition did not correlate with the degree of cholinergic denervation of the hippocampus. We conclude that selective basal forebrain cholinergic lesions produce learning deficits that are task specific, and that cholinergic denervation of either the frontal cortex or hippocampus can affect response patterns and strategy in ways that affect learning, without necessarily reflecting deficits in working memory performance.     

Cognitive impairment in the early phase of multiple sclerosis and its relationship with mood, demographic and clinical variables

Our aim was to study cognitive performance in the early phase of MS. In addition, we studied whether depression, demographic and clinical variables differentiate cognitively impaired patients from non-impaired patients. A group of 52 MS-RR patients with mild level of neurological disability and 51 healthy controls were administered a comprehensive neuropsychological battery. The MS group performed significantly worse on several measures of attention and processing speed and visuoperceptive/visuoconstructive tasks. Verbal memory is characterized by working memory deficits, whereas the visual memory impairment is attributable to deficits in acquisition and consolidation/recuperation. Results shows that cognitive impairment is evident even in MS patients in the early course of their disease. Depression scores were higher in cognitively impaired patients as compared with unimpaired patients. The effect of educational level suggests that higher education delays the onset of cognitive decline.     

An experimental approach to detecting dementia in Down syndrome: a paradigm for Alzheimer's disease

Measures developed from animal models of aging may detect dementia of the Alzheimer's type in a population at-risk for Alzheimer's disease (AD). Although, by middle age, individuals with Down syndrome (DS) show an extraordinarily high prevalence of AD-type pathology, their severe idiopathic cognitive deficits tend to confound the clinical diagnosis of AD. The current study was designed to improve detection of AD in DS by using measures of learning and memory derived from animal models of aging. Adults with DS (N=34) were assessed and reassessed (n=19) approximately one year later using stimulus-response (S-R) test methods derived from experimental literature, as well as standardized informant-based tests. Results demonstrated high validity and reliability of select tests. The implication of early symptom detection in a population at-risk for AD-type dementia was discussed in terms of potential brain regions of interest.     

前临床期痴呆的认知特征：当前研究进展和未来研究展望

在这篇文章中, 我将讨论从正常老化到痴呆, 这一通常被称为痴呆前临床阶段的认知功能的转变。研究表明, 阿尔茨海默症和血管性痴呆病人在临床确诊之前的几年中, 会出现明显的认知损伤。早期最突出的损伤存在于情节记忆、加工速度以及执行功能。这些功能性损伤与神经生物学研究证实的边缘系统和新皮层区存在多重损伤是相一致的。虽然早在临床诊段之前, 病人组和控制组的平均成绩存在巨大差异, 但同时这两组测试成绩的分布在很大程度上是重叠的。寻求降低这种重叠度的方法是未来研究的一个重要任务。这有可能通过将认知的和其他指标(如基于脑的、基因的、临床的、社会的)相结合构建预测模型来实现。此外, 在未来研究中以下三方面也是急需考虑问题: (a) 找出在 前临床期间认知功能急速下降的时间点: (b) 评估从前临床到临床诊断变化速率中存在的个体差异; (c) 确定特定因素与随后发生的痴呆之间的关联强度是如何随时间向临床确诊推进而逐渐变化的。     

Early signs of memory impairment among multiple sclerosis patients with clinically isolated syndrome

The study investigates primary and secondary verbal memory and motor/executive functions (response inhibition and strategy shifting ability) in multiple sclerosis (MS) patients with clinically isolated syndrome (CIS). We studied 44 CIS patients and compared them to 49 patients with relapsing remitting MS (RR-MS) displaying mild disability and to a large cohort of age- and education level-matched healthy volunteers(n=230). Results showed that both CIS and RR-MS patients evidenced a disproportionate impairment in the immediate and delayed recall of the second (as compared to the first) of two short narratives of the Logical Memory WMS-III subtest, and reduced performance on the Memory for Digits-Forward. Performance of either group on the executive tasks was not impaired, showing evidence of a reversed speed-accuracy trade-off. Illness duration emerged as a significant predictor of memory and executive task performance. Clinical, psychoemotional, and brain imaging findings were also examined as potential correlates of memory deficits and disease progression among CIS patients. These findings may signify early-onset decline of specific cognitive functions in CIS, which merits regular follow-up assessments and monitoring of psychoemotional adaptation and everyday functioning.     

Effects of Unilateral Entorhinal Cortex Lesion and Ganglioside GM1 Treatment on Performance in a Novel Water Maze Task

Transient deficits have been reported after unilateral entorhinal cortex (EC) lesion. To determine whether there is a more persistent deficit, adult male Sprague–Dawley rats with electrolytic or sham lesions of the left entorhinal cortex were examined on acquisition of a modified working memory task in the Morris water maze. This delayed matching-to-sample task, with a 1-h intertrial interval, reveals a significant deficit in total distance to platform in both presentation (Trial 1) and matching (Trial 2) in the rats with entorhinal lesions. We have also found that this test can be used to assess significant deficits in perseveration (repeated nonproductive movement) in rats with entorhinal lesions. The deficits can be seen up to 16 days postinjury. Administration of ganglioside GM1 resulted in a moderate improvement in performance in both water maze measures analyzed. All groups (sham operated, lesion with saline treatment, and lesion with ganglioside GM1 treatment) were given three other tests, which were used to evaluate possible contributing factors to deficient water maze performance. A one-trial test for exploration of novel objects revealed no significant, simple working memory deficit in any group. Plus maze testing, to assess possible differences in levels of anxiety or increased activity as a component of water maze performance, also revealed no differences in the three groups. All groups were also similar in motor activity, shown by monitoring of activity levels. The worsened water maze performance observed in rats with EC lesion may be related to deficits in working memory ability within the framework of acquisition of a more complex spatial learning task.     

Functional decline in the early stages of Alzheimer's disease

At present most reports of functional decline in patients with Alzheimer's Disease (AD) are anecdotal, and few studies have objectively documented the course of the disease. This is a report of a 2-year follow-up of 15 AD patients characterized by mild functional impairment, and 22 age-, sex-, and education-matched control subjects. In a previous cross-sectional study of these 37 subjects and 16 AD patients with moderate functional impairment, we found that measures of memory and attention deficits accounted for much of the impairment observed in functional competence. The current longitudinal study found that these same initial assessments could be used to predict functional decline in the 15 mildly impaired patients. These patients were observed to decline to levels similar to those of the 16 moderate patients. In contrast, the control subjects exhibited little decline during the same period. These results both affirm that it is possible to diagnose AD in its mild form and demonstrate the validity of the initial diagnosis.     

The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage

Clozapine is an atypical antipsychotic drug that has been shown to improve spatial memory in some animal models; however its efficacy in reversing spatial memory impairment in rats with hippocampal lesions is unknown. To address this issue, we tested the effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage in three separate experiments. In each experiment, adult male rats received sham surgery or direct stereotaxic infusions of the excitotoxin, NMDA, into the hippocampus. In the first study, seven days after surgery, the sham control animals received daily saline injections while the lesioned animals were split into two groups that received daily saline or clozapine (2.0 mg/kg, sc) injections. During the fifth week of injections, all animals were tested in a food-motivated delayed spatial alternation task. Saline-treated rats with excitotoxic hippocampal damage displayed significant deficits in delayed spatial alternation. Daily clozapine injections completely reversed this deficit. In a second experiment, it was found that clozapine treatment limited to the testing days only did not improve alternation performance in lesioned rats. Finally, in a third experiment, chronic clozapine treatment did not improve alternation performance in lesioned rats that were pre-trained in the alternation task prior to surgery. These results suggest that chronic, but not acute, clozapine treatment enables rats with hippocampal damage to develop new spatial learning, but can not rescue old spatial learning established prior to damage. These results may have implications for the treatment of cognitive deficits caused by hippocampal dysfunction in disorders such as schizophrenia, Alzheimer's disease, and others.