Executive dysfunction in Alzheimer disease

BACKGROUND: Executive dysfunction (EDF) is common in Alzheimer disease (AD); however, its relationship to other symptoms is difficult to assess in patients with AD. OBJECTIVES: To determine the prevalence of EDF and study its relationship to cognitive, functional, and neuropsychiatric symptoms in patients with AD. DESIGN, SETTING, AND PATIENTS: A retrospective analysis of data from participants in the English Instruments Protocol of the Alzheimer's Disease Cooperative Study. Subjects were drawn from a sample of patients evaluated at tertiary referral centers. RESULTS: A total of 64% of AD patients were classified as having EDF. Patients with EDF performed worse on tests of cognition (P <.001), dementia severity (P <.001), and activities of daily living (P =.01) and had more frequent symptoms of psychosis (P =.03) with greater emergence during the 12-month interval (P =.03) compared with patients with normal executive function. Less than 30% of the variance in executive function performance was explained by cognitive measures. CONCLUSION: These findings support the assessment of executive function in persons with AD and the importance of frontal lobe dysfunction in AD.     

Daytime sleepiness and functional impairment in Alzheimer disease.

OBJECTIVE: Daytime sleep has been noted to accompany dementing illness and is more pronounced as dementia severity increases. Although acknowledged by caregivers, sleepiness during the daytime is among the least troublesome of sleep behaviors described in Alzheimer Disease (AD) patients. The purpose of this study was to examine whether patient and spouse/caregiver reports of daytime sleepiness in AD were associated with lower functional status in those patients. METHODS: The authors utilized the Epworth Sleepiness Scale to assess reported daytime sleepiness and a modification of the Lawton and Brody scale to assess functional status in a group of 137 AD patients. The authors also examined typical bedtimes and wakeup times via questionnaire. RESULTS: Higher levels of daytime sleepiness were associated with greater impairments in functional status. These results were independent of level of cognitive impairment, as assessed with Mini-Mental State Exam, and they were also detectable when the authors limited analyses to data reported only by spouse/caregiver. Findings were not associated with medication use. AD patients also had earlier bedtimes and later wake-up times than a comparison group. CONCLUSION: Even apart from its association with impaired cognition, daytime sleepiness was associated with functional impairment in AD patients. Although daytime sleep may represent a welcome relief for caregivers, its presence may be associated with greater impairment in instrumental activities and may warrant intervention.     

Apathy and executive dysfunction in mild cognitive impairment and Alzheimer disease.

OBJECTIVE: The authors assessed and contrasted frontally mediated behavior changes in patients diagnosed with Mild Cognitive Impairment (MCI) and Alzheimer disease (AD). Apathy, executive dysfunction, and disinhibition are common in AD, but these behaviors have not been studied in MCI. METHODS: Participants were patients diagnosed with AD (n=25) or MCI (n=20). Current behavior and behavior before the onset of cognitive impairment was rated by knowledgeable informants on the Frontal Systems Behavior Scale (FrSBe). RESULTS: Apathy and executive dysfunction exhibited the greatest increase in both MCI and AD, and both increased significantly over baseline scores. No significant differences in behavior change were found between the two groups. Behavior change was moderately correlated with a measure of dementia severity, indicating that greater disease severity was associated with more abnormal behavior. CONCLUSION: Changes in frontally-mediated behaviors are common in very early and mild stages of cognitive impairment, even before functional decline in daily living is evident. These behaviors deserve more study in MCI because they may have implications for prognosis, treatment adherence, family distress, and patient quality of life.     

More severe functional impairment in dementia with lewy bodies than Alzheimer disease is related to extrapyramidal motor dysfunction.

OBJECTIVE: The objective of this study was to compare functional impairments in dementia with Lewy bodies (DLB) and Alzheimer disease (AD) and their relationship with motor and neuropsychiatric symptoms. METHODS: The authors conducted a cross-sectional study of 84 patients with DLB or AD in a secondary care setting. Patients were diagnosed according to published criteria for DLB and AD. The Bristol Activities of Daily Living Scale (BADLS) was used to assess functional impairments. Participants were also assessed using the Unified Parkinson's Disease Rating Scale (motor section), the Neuropsychiatric Inventory, and the Mini-Mental Status Examination. RESULTS: Patients with DLB were more functionally impaired and had more motor and neuropsychiatric difficulties than patients with AD with similar cognitive scores. In both AD and DLB, there were correlations between total BADLS scores and motor and neuropsychiatric deficits. There was more impairment in the mobility and self-care components of the BADLS in DLB than in AD, and in DLB, these were highly correlated with UPDRS score. In AD, orientation and instrumental BADLS components were most affected. CONCLUSION: The nature of functional disability differs between AD and DLB with additional impairments in mobility and self-care in DLB being mainly attributable to extrapyramidal motor symptoms. Consideration of these is important in assessment and management. Activities of daily living scales for use in this population should attribute the extent to which functional disabilities are related to cognitive, psychiatric, or motor dysfunction.     

Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease.

BACKGROUND: There is conflicting evidence as to whether Alzheimer disease (AD) is accompanied by loss of retinal ganglion cells. To evaluate this issue, we have used optical coherence tomography (OCT) to assess the thickness and volume of the retina. We have also sought to correlate our findings with visual function and cognitive impairment. METHODS: We evaluated 28 eyes of 14 patients with AD and 30 eyes of 15 age-matched control subjects. In these two groups, we measured retinal nerve fiber layer (RNFL) thickness, macular thickness, and macular volume with OCT, visual function through latency of the pattern visual evoked potential (VEP) signal, and cognitive impairment through the Mini-Mental State Examination (MMSE). RESULTS: The parapapillary and macular RNFL thickness in all quadrants and positions of AD patients were thinner than in control subjects. The mean total macular volume of AD patients was significantly reduced as compared with control subjects (P < 0.05). Total macular volume and MMSE scores were significantly correlated. No significant difference was found in the latency of the VEP P100 of AD patients and control subjects. CONCLUSIONS: Our study confirms some other studies in showing that in AD patients there is a reduction of parapapillary and macular RNFL thickness and macular volume as measured by OCT. The reduction in macular volume was related to the severity of cognitive impairment.     

Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease

BACKGROUND: Little is known about motor function in mild cognitive impairment (MCI) and its relation to the risk of Alzheimer disease (AD). OBJECTIVE: To examine motor function in persons with MCI and its relation to risk of AD. DESIGN: Longitudinal cohort study. SETTING: More than 40 Catholic religious orders across the United States. PARTICIPANTS: We studied 816 older Catholic clergy members from the Religious Orders Study. At the baseline evaluation, they were classified as having no cognitive impairment (n = 558), MCI (n = 198), or dementia (n = 60). MAIN OUTCOME MEASURES: Motor function was assessed at baseline using performance-based measures of upper and lower extremity function and a modified version of the motor section of the Unified Parkinson's Disease Rating Scale, from which previously established measures of parkinsonian signs were derived. Clinical evaluations for dementia and AD were repeated annually for up to 10 years. All analyses controlled for age, sex, educational level, and possession of at least 1 apolipoprotein E epsilon4 allele. RESULTS: At baseline, individuals with MCI had impaired motor function relative to those without cognitive impairment and superior motor function vs those with dementia. Among those with MCI, baseline levels of lower extremity motor performance, parkinsonian gait, and bradykinesia were inversely related to risk of AD, even after controlling for clinical stroke. Thus, a person with impaired lower limb performance or parkinsonian gait (10th percentile) was 2 to 3 times more likely to develop AD than a person with good lower limb function (90th percentile). CONCLUSIONS: Persons with MCI also have impaired motor function, and the degree of impairment in lower extremity function is related to the risk of AD.     

Midlife motivational abilities predict apathy and depression in Alzheimer disease: the aging, demographics, and memory study

Apathy and depression are the most common neuropsychiatric symptoms in mild cognitive impairment (MCI) and Alzheimer disease (AD). This study was the first to explore midlife motivational abilities as a predictor of the progression of apathy and depression in MCI and AD. It used a subsample of the Aging, Demographics, and Memory Study (N = 137). Participants, aged over 70, were categorized according to baseline clinical diagnosis (normal cognition, MCI, or AD). Assessments were conducted at an 18-month interval. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. Midlife motivational abilities were estimated on the basis of the main occupation using the Occupational Information Network (O*NET) database, which provides detailed information on worker abilities. Repeated measures analysis of covariance was used. Apathy and depression were found to be particularly high in participants with AD and high motivational abilities. Apathy, but not depression, increased over time in those with AD and high motivational abilities. It would appear that holding on to unattainable goals with strong motivational efforts when faced with severe cognitive loss might lead to unproductive persistence, depressive reaction, and more apathetic behavior.     

Executive dysfunction in early Alzheimer's disease.

Twenty five patients with probable mild Alzheimer''s disease were assessed for deficits in executive functioning and the impact of these deficits on performance in other neuropsychological domains. The Wisconsin card sorting test, the release from proactive interference paradigm, the verbal fluency test, and the Stroop test were adopted to classify patients with (AD+) and without (AD-) executive deficits. Seven of the patients showed an impairment in executive function (AD+), defined as a performance below the cut off score in at least two of these tests. There were no significant differences in clinical assessments, demographic features, or other cognitive functions between patients. Executive dysfunction may be an early additional feature in a subgroup of patients with mild Alzheimer''s disease. Impairment on frontal lobe tests does not seem to be related to the severity or duration of disease, or to a different pattern of impairment in other cognitive domains.     

Executive and emotional dysfunction in Machado-Joseph disease.

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia. Few studies have examined the neuropsychological and neurobehavioral profiles of patients with MJD. In this study, six individuals with MJD were given a battery of neuropsychological tests. Relative impairments on timed verbal attention tasks and verbal fluency (Stroop, Oral Symbol Digit Modalities, and Controlled Oral Word Association Test) were found. Other executive impairments also were seen on the Wisconsin Card Sorting Test, independent of motor dysfunction severity. Moderate- to severe levels of depressive symptoms were endorsed by four of the six patients, and caregivers observed increased apathy in the patients. Impaired executive and emotional functioning in MJD does not appear to be related to ataxia severity. These patients did not meet the criteria for dementia. General cognitive abilities, language, list learning, story recall, and untimed tasks of attention were within normal limits. Impaired executive abilities and emotional functioning in MJD patients is consistent with disruption of frontal-subcortical systems.     

Positron emission tomography metabolic correlates of apathy in Alzheimer disease

BACKGROUND: Apathy is the most common neuropsychiatric manifestation in Alzheimer disease (AD). Clinical, single-photon emission computed tomography, magnetic resonance imaging, and pathologic studies of apathy in AD have suggested an association with frontal dysfunction, most supportive of anterior cingulate abnormalities, but without a definitive localization. OBJECTIVE: To examine the association between apathy and cortical metabolic rate on positron emission tomography in AD. DESIGN: Forty-one subjects with probable AD underwent [(18)F] fluorodeoxyglucose positron emission tomography imaging and neuropsychiatric and cognitive assessments. Global subscale scores from the Scale for the Assessment of Negative Symptoms in Alzheimer Disease were used to designate the absence or presence of clinically meaningful apathy. Whole-brain voxel-based analyses were performed using statistical parametric mapping (SPM2; Wellcome Department of Imaging Neuroscience, London, England), which yielded significance maps comparing the 2 groups. RESULTS: Twenty-seven (66%) subjects did not have apathy, whereas 14 (34%) had apathy. Statistical parametric mapping analysis revealed significant reduced activity in the bilateral anterior cingulate region extending inferiorly to the medial orbitofrontal region (P < .001) and the bilateral medial thalamus (P = .04) in subjects with apathy. The results of the statistical parametric mapping analysis remained the same after individually covarying for the effects of global cognitive impairment, depressed mood, and education. CONCLUSIONS: Apathy in AD is associated with reduced metabolic activity in the bilateral anterior cingulate gyrus and medial orbitofrontal cortex and may be associated with reduced activity in the medial thalamus. These results reinforce the confluence of evidence from other investigational modalities in implicating medial frontal dysfunction and related neuronal circuits in the neurobiology of apathy in AD and other neuropsychiatric diseases.     

The apathy inventory: assessment of apathy and awareness in Alzheimer's disease,Parkinson's disease and mild cognitive impairment

OBJECTIVE: This study was designed to establish the validity and reliability of the apathy inventory (IA), a rating scale for global assessment of apathy and separate assessment of emotional blunting, lack of initiative, and lack of interest. METHOD: Information for the IA can be obtained from the patient or from a caregiver. We evaluated 115 subjects using the IA, consisting of 19 healthy elderly subjects, 24 patients with Mild Cognitive Impairment (MCI), 12 subjects with Parkinson's disease (PD) and 60 subjects with Alzheimer's disease (AD). RESULTS: Internal consistency, item reliability, and between-rater reliability were high. A test-retest reliability study demonstrated that caregiver responses to IA questions were stable over short intervals. A concurrent validity study showed that the IA assesses apathy as effectively as the Neuro Psychiatric Inventory apathy domain. In the caregiver-based evaluation, AD subjects had significantly higher scores than controls, both for global apathy score and for the lack of interest dimension. When the AD patients were subdivided according to diagnostic criteria for apathy, apathetic patients had significantly higher scores than non apathetic patients. With the patient-based evaluations, no differences were found among the AD, MCI and control groups. The scores in the patient-based evaluations were only higher for the PD group versus the control subjects. The results also indicated that AD patients had poor awareness of their emotional blunting and lack of initiative. CONCLUSIONS: The IA is a reliable method for assessing in demented and non-demented elderly subjects several dimensions of the apathetic syndrome, and also the subject's awareness of these symptoms.     

Cognitive impairment related to apathy in early Huntington's disease

OBJECTIVE: To investigate the relationships between cognitive impairment and apathy in patients with early Huntington's disease (HD) and to further explore the influence of depression on the outcome of cognitive changes associated with apathy. METHODS: We included 36 early HD patients, among them 20 were apathetic (HDA) and 16 were not (HDnA). The two groups were matched by age, education and severity of disease. Cognitive functions were evaluated by a comprehensive neuropsychological battery that measures memory, attention, executive function, language and visuospatial abilities. RESULTS: The HDA patients had significantly lower scores on memory, attention and executive function tests when compared with the HDnA patients (p values <0.05). We compared the performance of patients with (50%) and without depression on cognitive tasks and showed that depression per se did not influence performance. Finally, the results demonstrate that interactions between apathy and motor disturbance have a significant effect on cognitive impairment in HD. DISCUSSION: The presence of apathy is associated with more severe deficits of attention, executive function and episodic memory in early HD patients. Furthermore, the findings suggest that depression has little or no effect on cognitive deficits. Finally, apathy increased in parallel with both motor and cognitive dysfunction.     

Executive dysfunction in Alzheimer's disease

Executive functioning was examined in 20 patients with Alzheimer's disease (AD) and 20 normal elderly subjects. The results showed that AD patients present lower performance compared to control subjects in all executive tasks, confirming that some executive deficits may be present in the first stages of the disease. A factorial analysis suggested that these deficits can be related to two domains of the executive functions: the inhibition abilities and the capacity to co-ordinate simultaneously storage and processing of information. Moreover, the performance on these factors is correlated to different anterior and posterior cortical areas.     

阿尔茨海默病患者的执行功能障碍

目的了解阿尔茨海默病(A lzhe im er d isease,AD)患者执行功能损害状况及对于生活能力的影响,探讨执行功能障碍与记忆等AD常见认知功能损害的相关性。方法运用神经心理学测验的方法对40例AD患者及30例轻度认知功能损害(m ild cogn itive impairm ent,MC I)患者进行执行功能、记忆及其他认知功能检查,同时进行生活能力评定。另外选择40名健康老人作对照。结果AD组的执行功能测验成绩均显著低于健康对照组(P<0.01),其中额叶功能评定量表(FAB)(5.29±2.47)分,执行性画钟作业(CLOX1)(4.63±3.56)分,Stroop测验错误次数(Stroop1)(14.17±8.99)分,词语流畅性测验(RVR)(17.56±10.51)分。除Stroop测验反应时间(Stroop2)外,MC I组的其他执行功能测验成绩显著低于健康对照组(P<0.05),其中FAB为(7.67±2.44)分,CLOX1为(7.86±3.78)分,Stroop1为(7.21±8.07)分,RVR为(30.86±8.38)分。用多元逐步回归方法分析不同认知功能对生活能力的影响,结果为反映执行功能的FAB测验成绩处于第一位,独立与操作性日常生活能力(IADL)相关(β=-0.778,t=-7.079,P<0.01)。各项执行功能测验与年龄相关性不明显(r=0.026~0.250,P>0.05),与简易精神状态量表(MMSE)、记忆测验成绩相关性好(r=0.438~0.786,P<0.01)。结论AD患者具有明显的执行功能障碍;在尚未到达痴呆水平的MC I阶段也可发现执行功能损害。执行功能和整体认知功能及记忆等认知域功能具有良好的相关性。AD患者的执行功能障碍是导致生活能力下降的重要因素。     

Astrocyte dysfunction in Alzheimer disease

Astrocytes are glial cells that are distributed throughout the central nervous system in an arrangement optimal for chemical and physical interaction with neuronal synapses and brain blood supply vessels. Neurotransmission modulates astrocytic excitability by activating an array of cell surface receptors and transporter proteins, resulting in dynamic changes in intracellular Ca²⁺ or Na⁺. Ionic and electrogenic astrocytic changes, in turn, drive vital cell nonautonomous effects supporting brain function, including regulation of synaptic activity, neuronal metabolism, and regional blood supply. Alzheimer disease (AD) is associated with aberrant oligomeric amyloid β generation, which leads to extensive proliferation of astrocytes with a reactive phenotype and abnormal regulation of these processes. Astrocytic morphology, Ca²⁺ responses, extracellular K⁺ removal, glutamate transport, amyloid clearance, and energy metabolism are all affected in AD, resulting in a deleterious set of effects that includes glutamate excitotoxicity, impaired synaptic plasticity, reduced carbon delivery to neurons for oxidative phosphorylation, and dysregulated linkages between neuronal energy demand and regional blood supply. This review summarizes how astrocytes are affected in AD and describes how these changes are likely to influence brain function. © 2017 Wiley Periodicals, Inc.     

Executive impairments predict functional declines in vascular dementia

The purpose of this study was to examine the course and predictors of functional decline among patients with vascular dementia (VaD). Twenty-eight VaD patients completed three tests of executive functions and underwent MRI scanning to generate quantitative ratings of subcortical neuropathology at a baseline evaluation. The caregiver-rated Lawton and Brody Activities of Daily Living Questionnaire was used to estimate instrumental activities of daily living (IADLs) at the baseline evaluation and at a 1 year follow-up. We hypothesized that: (a) IADLs would decline significantly over the course of 1 year, and (b) baseline performance on executive tasks and subcortical neuropathology would predict IADL impairment at 1 year follow-up, even after accounting for global cognitive dysfunction. A paired samples t-test demonstrated that IADLs declined significantly over the course of 1 year, and regression analyses revealed that baseline performance on executive tasks was a significant predictor of IADLs at the 1 year follow-up, even after accounting for global cognitive dysfunction. Contrary to our expectation, subcortical neuropathology did not explain unique variance in IADLs after accounting for executive dysfunction. These findings demonstrate that baseline executive dysfunction is a significant and powerful predictor of future functional decline in individuals with VaD.     

不同类型的血管性认知损害的执行功能障碍

目的 分析不同类型的血管性认知功能损害(VCI)患者的执行功能损害特征.方法 经头颅MRI证实为皮质下缺血性小血管病(SIVD)患者64例,其中16例单一的执行功能损害(s-VCI-ND)、26例多个认知领域损害(m-VCI-ND)和22例血管性痴呆(VaD)患者,完成一系列神经心理测验,包括总体认知水平、记忆、语言、注意/执行功能、空间结构能力等各个认知领域.其中执行功能检查包括定势转移、优势抑制、工作记忆、概念形成和流畅性5个分因子,共15种独立的分测验.结果 汉诺塔测验、示踪排序测验、同步听觉连续加法测验等在非痴呆VCI(VCI-ND)患者中的完成率低于50%,不适合VCI-ND的检测;s-VCI-ND组与健康对照组比较,分别反映4种执行功能成分的连线测验B耗时数(216.5±69.3、137.4±37.9)、Stroop色词测验卡片C耗时数(115.4±30.1、72.9±17.5)、卡片分类测验(1.9±1.4、2.7±1.2)和范畴流畅性测验(列举动物14.2±2.3、17.7±4.4)差异具有统计学意义(t=4.73、5.72、2.04、3.53,均P<0.05);VCI-ND的认知表现介于健康老人组和VaD组之间,其中m-VCI-ND有比较严重的执行功能损害和情景与语义记忆障碍,其认知缺损模式接近VaD,很可能是VaD的前期状态.结论 SIVD所致VCI的执行功能损害缺乏选择性,部分执行功能测验可以作为早期检测VCI-ND的敏感工具.