Executive functions in clinical and preclinical Alzheimer's disease

Executive functions is an umbrella term describing a wide range of higher order processes that allow the flexible modification of thought and behaviour in response to changing cognitive or environmental contexts. Impairment of executive functions is common in neurodegenerative disorders such as Alzheimer's disease. These deficits negatively affect everyday activities and hamper the ability to cope with other cognitive or behavioural disorders. In this paper, we propose a synthesis of the knowledge on executive impairments in clinical and preclinical Alzheimer's disease, mostly leaning on the current studies made in this domain. We made some propositions for neuropsychological assessment of executive functions in preclinical and clinical phases of Alzheimer's disease. We hope that this overview will provide a useful insight into an area that is still insufficiently explored in the field of the neuropsychology of Alzheimer's disease.     

Neuropathology of preclinical and clinical lateonset Alzheimer's disease

We report on the neuropathological examinations of a 74-year-old woman with Alzheimer's disease (AD) and of her 47-year-old nondementd daughter. The brain of the mother showed fully developed pathological changes of AD. By contrast, the brain of the daughter revealed only perineuronal deposition of diffuse amyloid in cerebral cortex and striking abnormalities of the endosomallysosomal system, without neurofibrillary, glial, or microglial changes. These observations suggest that amyloid deposition and endosomal-lysosomal changes are early events in late-onset AD and that they may precede the onset of dementia of several decades.     

Cognitive deficits in preclinical Alzheimer's disease

We review the literature on cognitive functioning during the transition from normal aging to clinical Alzheimer's disease (AD). There is ample empirical evidence that deficits across multiple cognitive domains are apparent years to decades before the AD diagnosis, with impairments in episodic memory representing a common cognitive manifestation of the preclinical phase of the disease. Interestingly, the magnitude of the preclinical cognitive deficits appears to be relatively stable until a few years before clinical diagnosis. The behavioural deficits associated with preclinical AD are consistent with the neural changes that appear many years before eventual diagnosis. In addition to increasing our theoretical understanding of AD development, research on cognition in preclinical AD contributes to the identification of persons at risk of developing AD for purposes of intervention.     

阿尔茨海默病症状出现前阶段研究的战略意义

阿尔茨海默病(Alzheimer's Disease,AD)是一种神经退行性疾病,临床上以进行性记忆丢失和随之而来的痴呆为特点,而神经病理上则以老年斑、神经纤维缠结和突触丢失为特点.临床前期AD(preclinical AD,PCAD)定义为能够在患者的脑和血液、脑脊液等检测到AD特定的生物标记物,但AD的临床症状并没有出现,因此也被称为“症状出现前AD(presymptomatic AD)”.PCAD和对照组比较、发现氧化应激指标和高度不溶性Aβ42有显著性升高.AD研究应该着眼于PCAD和MCI时间窗及始动因素(initiator),紧密围绕导致神经元死亡的核心机制,研究PCAD的始动因素(基因、表观遗传、代谢关键酶、微量元素)、PCAD相关蛋白代谢的结构与功能基础以及PCAD相关蛋白相互作用与神经元功能紊乱之间的关系,阐明PCAD相关始动因素的特定改变导致AD相关蛋白结构与功能异常进而导致神经元功能紊乱、神经细胞死亡的机制,并在此基础上,寻找早期PCAD发病过程中新的可用于临床早期诊断的生物标记物、药物靶点.这可以推动相关认知科学及神经科学研究的发展,减轻家庭和国家的经济负担,契合国家十二五战略方针,具有重要的科学、经济和社会意义.     

Loss of motor function in preclinical Alzheimer's disease

Accumulating evidence suggests that Alzheimer's disease (AD) has a long preclinical phase, during which time its characteristic pathology accumulates and patient function declines, but symptoms are insufficient to warrant a clinical diagnosis of dementia. There have been increasing reports of noncognitive symptoms, including loss of motor function, reported to be associated with incident AD. To understand the link between motor function and preclinical AD, this article examines: our understanding of motor function and its clinical assessment in cohort studies; the relationship of motor function and loss of cognition in older persons; risk factors for cognitive and motor decline; and the relation of post-mortem indices of AD and motor function prior to death. Together, these data suggest that age-related cognitive and motor decline may share a common causation. Furthermore, individuals with a clinical diagnosis of AD may represent the 'tip of the iceberg', since AD pathology may also account for a substantial proportion of cognitive and motor dysfunction currently considered 'normal aging' in older persons without dementia. Thus, AD may have a much larger impact on the health and wellbeing of our aging population.     

Cost of Alzheimer's disease in a developing country setting

PURPOSE: To evaluate the economic impact of AD in Denizli, Turkey. DESIGN AND METHODS: This observational study was conducted with 42 AD patients and their primary caregivers. During the initial interview, demographic data and medical histories were collected with questionnaires. For an observational period of 15 days, data on time spent for patient care were collected using standard forms. Calculations on direct cost (e.g. per day medication, outpatient physician visits during the last 3 months), indirect cost (e.g. time spent for care by caregiver for daily living (ADL) and instrumental activity of daily living (IADL)) were made by summing up and taking averages of the appropriate items. ANOVA, and linear regressions were the methods for comparisons. RESULTS: The primary caregivers of the patients mainly were their children and/or spouses. The maximum mean time spent (h/week) was 21.0 (17.5) for severely damaged cognition. The average annual cost per case was between $1,766 [95% Confidence Intervals (CI); 1.300-2.231] and $4,930 (95% CI; 3.3714-6.147). The amount of caregiver cost was the most significant item in the overall cost and it showed an increase with the declining cognitive function of patients. Daily medication cost reflected the same pattern. In contrast, cost of outpatient physician was the lowest among the patients with the worst cognition. CONCLUSIONS: These results suggest that recently AD has become a significant cost for developing countries. This pilot study gives an idea of the cost of AD in developing countries where determining the actual cost can be difficult.     

Neuropsychological and neuroimaging changes in preclinical Alzheimer's disease.

Alzheimer's disease (AD) is a common, devastating form of dementia. With the advent of promising symptomatic treatment, the importance of recognizing AD at its very earliest stages has increased. We review the extant neuropsychological and neuroimaging literature on preclinical AD, focusing on longitudinal studies of initially nondemented individuals and cross-sectional investigations comparing at-risk with normal individuals. We systematically reviewed 91 studies of neuropsychological functioning, structural neuroimaging, or functional neuroimaging in preclinical AD. The neuropsychological studies indicated that preclinical AD might be characterized by subtle deficits in a broad range of neuropsychological domains, particularly in attention, learning and memory, executive functioning, processing speed, and language. Recent findings from neuroimaging research suggest that volume loss and cerebral blood flow or metabolic changes, particularly in the temporal lobe, may be detected before the onset of dementia. There exist several markers of a preclinical period of AD, in which specific cognitive and biochemical changes precede the clinical manifestations. The preclinical indicators of AD reflect early compromise of generalized brain integrity and temporal lobe functioning in particular.     

Cerebral glucose metabolism in preclinical and prodromal Alzheimer's disease

Assessment of regional cerebral glucose metabolism by (18)F-2-fluoro-2-deoxy-D-glucose (FDG)-PET at resting state is a standard functional technique to assess cerebral function. Group studies identified significant regional metabolic impairment in asymptomatic individuals at increased risk for dementia. Substantial impairment of FDG uptake in temporoparietal association cortices emerges as a reliable predictor of rapid progression to dementia in mild cognitive impairment patients and could, therefore, serve as a biomarker for the diagnosis of prodromal Alzheimer's disease. Frontal and temporoparietal metabolic impairment is closely related to progression of disease in longitudinal studies, and multicenter studies suggest its utility as an outcome parameter to increase the efficiency of therapeutic trials.     

Elevated CNS inflammation in patients with preclinical Alzheimer's disease

Alzheimer''s disease (AD) is a progressive, neurodegenerative disease that may involve inflammatory responses in the central nervous system (CNS). Our objective was to determine whether patients with amnestic mild cognitive impairment (aMCI), a preclinical stage of AD, have inflammatory characteristics similar to patients with multiple sclerosis (MS), a known CNS inflammatory disease. The frequency of lymphocytes and levels of pro-inflammatory cytokines in the cerebrospinal fluid of aMCI patients was comparable to MS patients or patients at high risk to develop MS. Thus, brain inflammation occurs early at the preclinical stage of AD and may have an important role in pathology.     

Linguistic changes in verbal expression: a preclinical marker of Alzheimer's disease.

Despite the many studies examining linguistic deterioration in Alzheimer's disease (AD), very little is known about changes in verbal expression during the preclinical phase of this disease. The objective of this study was to determine whether changes in verbal expression occur in the preclinical phase of AD. The sample consisted of 40 healthy Spanish speakers from Antioquia, Colombia. A total of 19 were carriers of the E280A mutation in the Presenilin 1 gene, and 21 were noncarrier family members. The two groups were similar in age and education. All the participants were shown the Cookie Theft Picture Card from the Boston Diagnostic Aphasia Examination and were asked to describe the scene. Specific grammatical and semantic variables were evaluated. The performance of each group was compared using multivariate analyses of the variance for semantic and grammatical variables, and errors. Carriers of the mutation produced fewer semantic categories than noncarriers. In the preclinical phase of AD, changes in verbal expression are apparent and early detection of these differences may assist the early diagnosis of and intervention in this disease.     

Neuronal localization of C1q in preclinical Alzheimer's disease

Complement has been postulated to contribute to inflammatory reactions associated with the neuropathology of Alzheimer's disease (AD). C1q, an initial component of the complement cascade, is associated with neuritic plaques and with neurons in the hippocampus of AD brain. Here, we report the presence of C1q in a cognitively intact subject, previously identified as preclinical AD. We compared in detail brain tissue of this preclinical case with a genetically related late-onset AD case. In the AD brain, C1q was typically associated with fibrillar Abeta plaques in frontal cortex and with plaques and neurons in the hippocampus. In the preclinical subject, C1q was abundantly present but it was cell-associated only, being primarily colocalized with neurons in both frontal cortex and hippocampus. However, no predominant cortical neuronal C1q localization was found in other preclinical cases or in Down's cases of different ages. Thus, it is possible that this neuronal-associated C1q reflects an early, but transient, response to injury that may modulate the progression of neurological dysfunction in AD.     

Brain imaging evidence of preclinical Alzheimer's disease in normal aging

OBJECTIVE: This study was designed to test the hypothesis that baseline glucose metabolism and medial temporal lobe brain volumes are predictive of cognitive decline in normal older people. METHODS: We performed positron emission tomography using [18F]fluorodeoxyglucose and structural magnetic resonance imaging at baseline in 60 cognitively normal community-dwelling older subjects who were part of a longitudinal cohort study. Subjects were followed for a mean of 3.8 years, with approximately annual evaluation of global cognition (the Modified Mini-Mental State Examination) and episodic memory (delayed recall). Baseline brain volumes and glucose metabolism were evaluated in relation to the rate of change in cognitive test scores. RESULTS: Six subjects developed incident dementia or cognitive impairment (converters). Baseline positron emission tomography scans showed regions in left and right angular gyrus, left mid-temporal gyrus, and left middle frontal gyrus that predicted the rate of change on the Modified Mini-Mental State Examination (p < 0.001). The left hemisphere temporal and parietal regions remained significant when converters were excluded. Both hippocampal (p = 0.03) and entorhinal cortical volumes (p = 0.01) predicted decline on delayed recall over time, and entorhinal cortical volumes remained significant when converters were excluded (p = 0.02). These brain volumes did not predict Modified Mini-Mental State Examination decline. INTERPRETATION: These results indicate that temporal and parietal glucose metabolism predict decline in global cognitive function, and medial temporal brain volumes predict memory decline in normal older people. The anatomical location of these findings suggests detection of preclinical Alzheimer's disease pathology.     

Quantitation of cerebral atrophy in preclinical and end-stage Alzheimer's disease

Morphometric analysis of standardized gross cerebral slices from 16 patients with end-stage Alzheimer's disease (AD), 14 controls without neuropathological lesions or neurological disease, and 4 neurologically intact nondemented patients with histopathological lesions of AD was used to measure cross-sectional areas of cerebral cortex, white matter, subcortical nuclei, and the ventricular system. In AD, there was global cerebral atrophy of both cortex and white matter, selective atrophy of the amygdala and hippocampus, and ex vacuo hydrocephalus. In addition, in half the cases of AD, white matter atrophy was associated with overt histopathological evidence of patchy rarefaction of fibers and gliosis. Patients with preclinical AD had prominent and selective shrinkage of white matter comparable to that observed in AD, yet their cortical areas were normal. These observations suggest that white matter degeneration is an intrinsic component of AD. Moreover, its presence in preclinical AD where cortical atrophy is not evident indicates that cytoskeletal abnormalities associated with axonal degeneration may precede and perhaps cause the cortical atrophy observed in clinically manifested AD.     

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.     

Cognitive changes in the preclinical phase of familial Alzheimer's disease

Few studies have examined the presence of linguistic deficits in the preclinical phase of Alzheimer's disease (AD). A total of 19 healthy carriers of the E280A presenilin-1 gene mutation in chromosome 14 and 21 noncarrier family members from Antioquia, Colombia, were administered a neurolinguistic evaluation of lexical-semantic processes. Both groups were similar in age, educational level, and gender. Carriers scored significantly lower than noncarriers on naming of famous faces. Cognitive changes in lexical-semantic tasks can be detected before the clinical diagnosis of probable familial AD, and a neurolinguistic evaluation may be a useful tool in the early clinical diagnosis of sporadic AD as well.     

The neuropsychology of normal aging and preclinical Alzheimer's disease

ObjectiveA National Institute on Aging–sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.MethodsSeventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups.ResultsThere was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups.ConclusionsAlthough cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design.