Intellectual, mnemonic, and frontal functions in dementia with Lewy bodies: A comparison with early and advanced Parkinson's disease

Both Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share a common neuropathological marker, the presence of Lewy bodies in brain stem and basal forebrain nuclei. DLB, in addition, is associated with Lewy bodies in the neocortex, and, in it's more common form, with Alzheimer-type pathological markers, particularly amyloid plaques. Published neuropsychological studies have focused on the differential profiles of DLB and Alzheimer's disease (AD). However, it is presently unclear whether DLB should be classified as a variant of AD or PD. In the present study we compare a healthy age-matched control group with three groups of patients, one with DLB, and two with PD. One of the PD groups was early in the course (PD-E) and the second, more advanced group (PD-A), was matched on severity of cognitive impairment with the DLB group. The results show that DLB was associated with a different pattern of neuropsychological impairment than the PD-A group, particularly in tests believed to be mediated by prefrontal cortical regions.     

Intellectual, mnemonic, and frontal functions in dementia with Lewy bodies: A comparison with early and advanced Parkinson's disease

Both Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share a common neuropathological marker, the presence of Lewy bodies in brain stem and basal forebrain nuclei. DLB, in addition, is associated with Lewy bodies in the neocortex, and, in it's more common form, with Alzheimer-type pathological markers, particularly amyloid plaques. Published neuropsychological studies have focused on the differential profiles of DLB and Alzheimer's disease (AD). However, it is presently unclear whether DLB should be classified as a variant of AD or PD. In the present study we compare a healthy age-matched control group with three groups of patients, one with DLB, and two with PD. One of the PD groups was early in the course (PD-E) and the second, more advanced group (PD-A), was matched on severity of cognitive impairment with the DLB group. The results show that DLB was associated with a different pattern of neuropsychological impairment than the PD-A group, particularly in tests believed to be mediated by prefrontal cortical regions.     

Perceptions of Familial Risk in those Seeking a Genetic Risk Assessment for Alzheimer’s Disease

Perceived risk is a complex concept that influences the genetic counseling process and can affect client coping and behavior. Although the association between family history and risk perception is well recognized in the literature, no studies have explored this relationship specifically in those seeking genetic susceptibility testing for a common chronic condition. REVEAL is a randomized trial assessing the impact of APOE disclosure and genetic risk assessment for Alzheimer’s disease (AD). Using baseline REVEAL data, we hypothesized that there would be a significant association between the degree of AD family history and risk perception of AD, and that this relationship would be stronger in those who believed that genetics is a very important AD risk factor. In our sample of 293 participants, we found that a higher self-perceived risk of AD was associated with strength of family history of AD (p < 0.001), belief in genetics as an important AD risk factor (p < 0.001), being female (p < 0.001) and being Caucasian (p = 0.02). These results are the first to demonstrate the association between family history and risk perception in persons volunteering for genetic susceptibility testing for a common complex disease.     

Diffuse Lewy Body Disease: Clinical,Pathological, and Neuropsychological Review

The pathophysiological etiologies and clinical presentations of neurodegenerative dementias have been found to be complex and heterogeneous. Recently, Lewy body inclusions have been identified as an etiological factor in 20–34% of autopsied dementia cases. The term diffuse Lewy body disease (DLBD) is generally accepted as the diagnostic term representative of this currently under-reported and under-recognized disease. This article reviews the literature on the clinical, pathological, and neuropsychological features of this disorder. Differential diagnostic issues are discussed as well as current pharmacological treatment. Nine confirmed cases of DLBD are presented to demonstrate the various features of this disorder. The diagnostic implications of neuropsychological examination results are discussed in relation to other common dementing neurologic diseases.     

The Differential Effects of Alzheimer's Disease and Lewy Body Pathology on Cognitive Performance: a Meta-analysis

Differential diagnosis of Alzheimer’s disease (AD) from normal aging and other dementia etiologies is imperative for disease specific treatment options and long-term care planning. Neuropathological confirmation is the gold standard for neurodegenerative disease diagnosis, yet most published studies examining the use of neuropsychological tests in the differential diagnosis of dementia rely upon clinical diagnostic outcomes. The present study undertook a meta-analytic review of the literature to identify cognitive tests and domains that allow for the differentiation of individuals with AD pathology from individuals with dementia with Lewy Bodies (DLB) pathology and pathology-free individuals. A comprehensive literature search yielded 14 studies that met the inclusion criteria for the present meta-analysis. Six studies comprised 222 decedents with AD compared to 433 normal controls, and eight studies comprised 431 cases of AD compared to 155 decedents with DLB. Results revealed that the effect of having neuropathologically confirmed AD versus DLB lowered performance in the memory domain, and having DLB decreased performance in the visuospatial domain. No single test differed significantly across the AD and DLB groups. For the AD and pathology free comparison, results indicated that that AD was associated with poorer performance on the memory and language domains. With respect to specific cognitive tests, AD produced lower scores on list learning tests, category fluency, and the Digit Symbol substitution test. The limited number of studies meeting inclusion criteria warrants formulation of guidelines for reporting in clinico-pathological studies; suggested guidelines are provided.     

Differences Between African American and White Research Volunteers in Their Attitudes,Beliefs and Knowledge Regarding Genetic Testing for Alzheimer’s Disease

Genetic susceptibility testing for common diseases is expanding, but little is known about race group differences in test perceptions. The purpose of this study was to examine differences between African Americans and Whites in knowledge, attitudes, and motivations regarding genetic susceptibility testing for Alzheimer’s disease (AD). Before enrolling in an AD genetic testing research trial, 313 first-degree relatives of AD patients (20% African American; 71% female; mean age = 58 years) were surveyed regarding: (1) knowledge about genetics and AD risk; (2) concerns about developing AD; and (3) reasons for seeking testing. In comparison to Whites, African Americans were less knowledgeable about genetics and AD risk (p < .01) and less concerned about developing AD (p < .05), with lower levels of perceived disease risk (p = .04). The results suggest that African Americans and Whites differ notably in their knowledge, beliefs, and attitudes regarding genetic testing for AD. Additional research with more representative samples is needed to better understand these differences.     

A Property Level Analysis of Lexical Semantic Representation in Alzheimer′s Disease

In order to assess the hypotheses that Alzheimer′s disease (AD) results in a property level restructuring, loss, or degradation of lexical-semantic knowledge, Alzheimer′s patients and normal elderly subjects were presented with a property verification task in which they were asked to judge the truth value of telegraphic statements which paired objects with their properties (e.g., "Apple is red"). Objects with either high- or low-typical exemplars of categories (e.g., "oak" is a high typical exemplar of the category "tree," while "palm" is a less typical item). Properties were varied with respect to normatively determined dominance (e.g, "fins" is a high dominant property of "trout," while "slimy" is a less dominant property) and whether they were distinctive (i.e., served to distinguish between subsets of exemplars within a category) or shared among most or all category members (e.g., "stem" for the category "fruit"). Analyses of accuracy and reaction time data suggested that AD results in neither a loss per se of representation of properties, nor a reorganization of relations between objects′ properties. However, results were consistent with a property level degradation of AD patients′ object concepts. While there was no evidence for a differential degradation of distinctive vs shared properties, results suggested that AD patients have degraded representations of lower dominant properties and properties of low-typical category exemplars.     

Clinicopathological findings of suicide in the elderly: three cases

The neuropathological correlates of suicide in older persons have received little research attention. Our recent study of elderly suicide victims from an Australian forensic medicine department (n = 143), unlike a previous case-control study, did not find an increased prevalence of Alzheimer's disease (AD) in older persons who committed suicide despite a history of dementia in 6.3%. Both studies were limited to the examination of AD-related pathology by the availability of tissue. We present clinicopathological data on three cases from our study for whom autopsy findings were available. These cases included: a community-dwelling male in his early eighties with dementia who was found to have multiple cortical and striatal lacunes and glial scars, small vessel cerebrovascular disease (SVD) and AD-related pathology; a community-dwelling male in his mid-seventies with depression and loss of concentration, with brainstem predominant Lewy body disease (LBD) and AD-related pathology; and a female nursing home resident in her nineties with a history of stroke and prior suicide attempts who was found to have infarcts and SVD in frontal regions. Neuropathological findings in elderly suicide victims may include multiple neurodegenerative pathologies. The burden and distribution of neurodegenerative diseases apart from AD, including SVD and LBD, should be assessed as possible pathophysiological factors contributing to late life suicide.     

Cholinesterase-inhibitor therapy for dementia: novel clinical substrates and mechanisms for treatment response

Historically, drugs that increase central cholinergic transmission have primarily been investigated for relieving cognitive symptoms in mild-to-moderate Alzheimer's disease. These efforts have led to the somewhat unexpected findings that cholinergic therapy has a beneficial effect on selected neuropsychiatric symptoms in AD across disease stages. In Parkinson's disease with dementia and dementia with Lewy bodies, cholinergic deficits are more severe than in AD, and there is emerging evidence that cholinesterase inhibitors are efficacious in treating core symptoms of attentional disturbance and psychosis. Recent data also suggest a rational basis for cholinergic therapy in vascular dementia. The cognitive and neuropsychiatric effects of cholinergic therapy observed in AD and other dementias form the crux of an integrative model of cholinergic therapeutic efficacy that encompasses the diverse central nervous system actions of acetylcholine and its complementary interactions with central monoamine transmitters. This heuristic framework highlights the broader therapeutic potential of cholinergic therapy for symptom-based indications in other neuropsychiatric disorders.     

Talkativeness in Cognitively Normal Women at Genetic Risk for Alzheimer’s Disease

Previous research has suggested a correlation between some linguistic patterns and the risk for Alzheimer’s disease (AD). There is increasing clinical need to identify factors that can be used alone or in combination to predict the onset of AD. The purpose of the present study was to explore the association of language skills and genetic risk for Alzheimer’s disease. Oral and written language samples of cognitively normal women with a susceptibility gene for AD (ApoE e4) were compared to those of noncarriers on measures of grammatical complexity, topic relevance, and talkativeness by observers unaware of participant genotypes. Participants included 29 ApoE e4 carriers 49-73 years of age, and 29 e4 noncarriers 48-76 years of age, most of whom had a first-degree relative with AD. Carriers and noncarriers were group matched for age, educational level, and estimated IQ. Participant groups did not differ significantly in language complexity or topic relevance. However, the ApoE e4 group was significantly more talkative than the noncarrier group (p &lt; .05).     

Executive Control Functions in Degenerative Dementias: A Comparative Review

This paper reviews the literature concerning executive control impairments in degenerative dementias. The construct of executive control functioning is examined, as is the neuroanatomy of frontal–subcortical networks, believed to underlie executive function (EF) impairments. The pattern of EF impairments in Alzheimer's disease (AD) which affects temporal and parietal brain regions most severely is contrasted with observed executive dysfunctions in patients with dementias involving degeneration of primarily frontal and frontal–subcortical brain areas. EF impairments are present in each of these types of dementing illnesses. Although EF impairments are present in AD, they are less prominent than the memory disorder in the neuropsychological profile of the disease and tend to become more pronounced later in the course of the illness. In contrast, patients with frontal or frontal–subcortical dementia may demonstrate executive dysfunction, which occurs earlier in the disease progression and may be initially more severe.     

Evidence of Impaired Glucose Tolerance and Insulin Resistance in Patients With Alzheimer&rsquo;s Disease

Alzheimer’s disease (AD) and diabetes rarely occur together, a finding that provides a possible clue as to the development of AD. Abnormal glucose metabolism is not limited to diabetes, but also can include impaired glucose tolerance, insulin resistance, and hyperinsulinemia. AD patients have significantly varying insulin levels after drinking sugared sodas and thus may be classified as insulin resistant. After reviewing the literature on impaired glucose tolerance and insulin production in AD, we present several hypotheses as possible explanations for the relationship between insulin resistance and AD. Finally, we suggest future studies, including studies on use of thiazolidinediones (currently used in the treatment of diabetes) in AD.     

Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team-based Variant Classification

We sought to delineate the genetic test review and interpretation practices of clinical cardiovascular genetic counselors. A one-time anonymous online survey was taken by 46 clinical cardiovascular genetic counselors recruited through the National Society of Genetic Counselors Cardiovascular Special Interest Group. Nearly all (95.7%) gather additional information on variants reported on clinical genetic test reports and most (81.4%) assess the classification of such variants. Clinical cardiovascular genetic counselors typically (81.0%) classify variants in collaboration with cardiologist and/or geneticist colleagues, with the genetic counselor as the team member who is primarily responsible. Variant classification is a relatively recent (mean 3.2 years) addition to practice. Most genetic counselors learned classification skills on the job from clinical and laboratory colleagues. Recent graduates were more likely to have learned this in graduate school (p?<?0.001). Genetic counselors are motivated to take responsibility for the classification of variants because of prior experiences with variant reclassification, inconsistencies between laboratories, and incomplete laboratory reports. They are also driven by a sense of professional duty and their proximity to the clinical context. This practice represents a broadening of the skill set of clinical cardiovascular genetic counselors and a unique expertise that they contribute to the interdisciplinary teams in which they work.     

Investigating medical decision‐making capacity in patients with cognitive impairment using a protocol based on linguistic features

A critical question is whether cognitively impaired patients have the competence for autonomous decisions regarding participation in clinical trials. The present study aimed to investigate medical decision‐making capacity by use of a Swedish linguistic instrument for medical decision‐making (LIMD) in hypothetical clinical trials in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Three comparable groups (age, education) participated in the study: AD (n = 20; MMSE: 24.1 ± 3.3) and MCI (n = 22; MMSE: 26.7 ± 2.4) patients and healthy controls (n = 37; MMSE: 29.1 ± 1.0). Medical decision‐making capacity was operationalized as answers to questions regarding participation in three hypothetical clinical trials. Answers were scored regarding comprehension, evaluation and intelligibility of decisions, and a total LIMD score was used as the measure of medical decision‐making ability. Groups differed significantly in LIMD with AD patients performing worst and MCI poorer than the control group. A strong association was found between all LIMD scores and diagnosis which supported the assertion that LIMD as it is designed is a one‐dimensional instrument of medical decision‐making capacity (MDMC). The results indicate that a fundamental communicative ability has an impact on the competence for autonomous decisions in cognitive impairment.     

Differential memory impairment in dementia with Lewy bodies and Alzheimer's disease

This study was conducted in order to elucidate the functioning of the Central Executive System of Working Memory (WM) and to clarify the status of other cognitive functions in Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Fourteen DLB, 22 AD, and 23 control subjects were assessed with the dual task paradigm and other cognitive tests. When compared with controls, DLB subjects performed more poorly in concurrent conditions on semantic WM tasks, and AD subjects performed more poorly on the spatial WM task. The DLB subjects had an inferior verbal span and AD subjects, an inferior recall on the CVLT. These data suggest relative impairments of verbal and semantic WM in DLB and relative impairments of spatial WM and verbal episodic memory in AD.     

Genes and family environment in familial clustering of cancer

Familial clustering of a disease is defined as the occurrence of the disease within some families in excess of what would be expected from the occurrence in the population. It has been demonstrated for several cancer types, ranging from rare cancers as the adenomatosis-coli-associated colon cancer or the Li-Fraumeni syndrome to more common cancers as breast cancer and colon cancer. Familial clustering, however, is merely an epidemiological pattern, and it does not tell whether genetic or environmental causes or both in combination are responsible for the familial clustering. Familial clustering may be due to genetic predisposition to the disease, but exposure to environmental factors — shared by members of some families, but not by members of other families — may also cause familial clustering and hence mimic genetic inheritance in the study of nuclear families. Based on assumptions regarding the individual steps in the biological process starting with exposure to carcinogens and ending with death from disseminated cancer we suggest that genetic and environmental factors may both be involved in most of these steps. The present paper focuses on research methodologies necessary to discriminate between the effect of genes and family environment in the development of cancer.     

Early Detection of Memory Impairment in Alzheimer’s Disease: A Neurocognitive Perspective on Assessment

We propose that the earliest neuropsychological detection of Alzheimer’s disease (AD) can be informed by current views about the neuropathogenesis of AD and cognitive models of memory and its neurobiological substrates. The primary impairment in early AD is encoding/consolidation, resulting from medial temporal lobe (MTL) pathology. On theoretical and empirical grounds, paired associate learning (PAL) appears to be the ideal paradigm for detecting MTL dysfunction in early AD. It has not been embraced as a test of choice, however, and this critical review discusses why the paradigm may have not fulfilled its potential. We suggest that a new PAL variant, ‘associate-recognition’, may prove to be clinically efficacious.     

Processing of mass/count information in Alzheimer’s disease and mild cognitive impairment

This study examines the processing of a specific linguistic distinction, the mass/count distinction, in patients suffering from Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Fourteen AD and 10 MCI subjects were tested using a sentence grammaticality judgement task where grammaticality violations were caused by determiner–noun mismatches, as well as a sentence–picture matching task to assess their ability to access mass and count readings of dual nouns. Considerable heterogeneity was observed within each subject group, and performance across groups was almost identical. It is concluded that a combination of linguistic and attentional and/or learning factors are responsible for the range of impairments; specifically, a subset of subjects exhibit no linguistic nor attentional/learning impairment, another subset exhibit only an attentional and/or learning impairment but no linguistic impairment, and a third subset (comprising more than half of the subjects included in this study) exhibit a linguistic impairment. It is postulated that the latter group have difficulty processing sense extensions in metonymous nouns. It is further claimed that, at least within the limits of the study, language impairments can be of the same severity and nature across AD and MCI subjects.     

Analyzing feature distinctiveness in the processing of living and non-living concepts in Alzheimer’s disease

The conceptual structure account (CSA) is a model specifying the role of the living and non-living domain dichotomy in the structure of semantic memory. According to this model, feature distinctiveness and the perceptual–functional inter-correlation of concepts are assumed to play a major role in impairing the ability to discriminate between living and non-living concepts in Alzheimer’s disease (AD). The hypothesis was tested in this study by using naming and sorting tasks traditionally considered as assessing distinctiveness, and a property verification task where distinctiveness and perceptual–functional inter-correlation were objectively controlled against norms especially created for this purpose. Alzheimer’s patients (n = 59) with minimal, mild or moderate dementia and normal elderly adults (n = 31) participated in the study. Overall, the findings did not support the CSA predictions. They revealed a distinctiveness effect on response accuracy with shared features dominating distinctive features regardless of domain. They also revealed more difficulties in the tasks involving effortful processes. The results stress the need to consider both cognitive demands of tasks and structural aspects of knowledge in the evaluation of semantic memory in AD.     

Environmental enrichment eliminates the anxiety phenotypes in a triple transgenic mouse model of Alzheimer’s disease

Although the impacts of environmental enrichment (EE) in several genetic models of Alzheimer’s disease (AD) have been documented, the focus has remained predominantly on cognition. Few have investigated the expression of emotional phenotypes that mimic the notable affective features in AD. Here, we studied the interaction between EE and the coexpression of three genetic risk factors (mutations) for AD. In a longitudinal design, 3×Tg-AD mutants and wild type controls were compared at 6–7 months and subsequently at 12–13 months of age. Under standard housing, phenotypes of heightened anxiety levels were identified in the 3×Tg-AD mice in the elevated plus maze and open-field tests. Such trait differences between genotypes were substantially diminished under EE housing, which was attributable to the anxiolytic impact of EE on the mutant mice as much as the anxiogenic impact of EE on the wild type mice. In contrast, the phenotypes in learned fear were not significantly modified by EE in the tests of Pavlovian freezing and conditioned active avoidance conducted at either age. Rearing under EE thus has uncovered a novel distinction between innate and acquired expressions of fear response in the 3×Tg-AD mouse model that might be relevant to the mental health management of AD.