Conversion of amnestic Mild Cognitive Impairment to dementia of Alzheimer type is independent to memory deterioration

BACKGROUND: Mild Cognitive Impairment defines a transitional stage between normal ageing and dementia, and reflects the clinical situation where a person has memory complaints and objective evidence of cognitive impairment but no evidence of dementia. To plan the care of patients with MCI, it is important to predict as accurately as possible potential risk factors modulating the conversion to AD. AIM: To investigate the risk factors associated of conversion to dementia of Alzheimer type (AD) for subjects with amnestic Mild Cognitive Impairment (aMCI). METHODS AND MATERIALS: One hundred nineteen subjects consecutively recruited who met the operational criteria for aMCI (with or without deficits in other cognitive domains). They underwent multidimensional assessment and a neuropsychological battery at baseline and at follow-up, after 1 year. Diagnosis for dementia was based on a deficit in two or more cognitive domains severe enough to affect the participant functional abilities. Subjects converted to AD over time were classified as Demented; subjects that remained unchanged, or became cognitively normal during follow-up, were defined as Stable. RESULTS: Demented MCI (N = 40; 33.6%) were older (mean age 73.5 +/- 8.5 vs. 69.2 +/- 7.0; p = 0.006) when compared to Stable (N = 79; 66.4) and their global cognitive performances, at baseline, were more compromised when assessed by ADAS-Cog (mean score 10.7 +/- 3.9 vs 6.7 +/- 3.4; p = .000) and by MMSE (mean score 26.1 +/- 1.9 vs. 27.3 +/- 1.8; p = 0.002). Demented were similarly compromised in basic activities of daily living (BADL mean 0.2 +/- 0.4 vs 0.1 +/- 0.3 functions lost; p = NS) but more compromised on instrumental daily functions (IADL mean 0.7 +/- 0.8 vs. 0.1 +/- 0.5 functions lost; p = 0.001). The presence of white matter lesions (WML) on CT or MRI was more pronounced in Demented group (p = 0.02). After 1 year; Demented worsened on phonemic verbal fluency (PFL) (p = 0.009), Raven's coloured matrices (p = 0.003), Trail Making test A and B (p = 0.008 and p = 0.007 respectively) and in Instrumental Activities of Daily Living (IADL) (p =0 .000) respect to Stable. Logistic regression analysis revealed that ADAS-Cog basal score, Trail Making B, IADL but not memory deterioration were significantly associated to the conversion to AD. CONCLUSIONS: In subjects with aMCI poor global cognitive performance at baseline, the worsening on executive functions and on functional status but not the worsening on memory functions are independently associated with the conversion to dementia of Alzheimer type at 1 year, follow-up.     

Cognitive and functional neuroimaging correlate for anosognosia in mild cognitive impairment and Alzheimer's disease

OBJECTIVES: To investigate the correlation between anosognosia and behavioural symptoms, performance on executive tests, and frontal cortex regional cerebral blood flow (rCBF) in patients with 'amnestic mild cognitive impairment' (MCI) and mild Alzheimer's disease (AD). METHODS: From a prospective Memory Clinic cohort including consecutively referred patients, age 60 years or above, and with MMSE score 20 or above, 36 patients with AD and 30 with MCI were included in this study. Anosognosia was assessed using a categorical scale and discrepancy scores between patients' and relatives' reports on a 20-item Memory Questionnaire (MQ). Behavioural symptoms were assessed with Frontal Behavioural Inventory (FBI). Executive functions were examined with a range of neuropsychological tests. Tc99m-HMPAO SPECT was obtained in an unselected sample of 55 of the 66 patients, and rCBF was analysed in six cortical frontal regions. RESULTS: Insight was equally impaired in the two patient groups. A significant correlation was found between impaired awareness and dementia severity (MMSE). Discrepancy-scores on the MQ were significantly correlated to scores on FBI and to rCBF in the right inferior frontal gyrus, but not to executive tests. The groups classified by the categorical ratings 'full', 'shallow' and 'no' awareness were not characterized by differences in behavioural symptoms, executive performance or frontal rCBF. CONCLUSIONS: Impaired awareness is associated with behavioural symptoms and may reflect functional impairment in the right inferior frontal cortex.     

Subjective rating of executive functions in mild Alzheimer's disease

Objectives: Subjective cognitive decline is considered to be a core feature of pre-Alzheimer's disease (AD) conditions, the vast majority of literature having focused on memory concerns. Neuropsychological studies have implicated executive dysfunction on objective performance measures in AD, but no research has evaluated whether individuals with AD have concerns about their executive functions and whether it differs from their caregiver's concerns. In the present study, we sought to evaluate self- and informant ratings of executive functioning in patients with mild AD.

Method: Participants were 23 patients with mild AD and 32 healthy elderly controls (HC) and their informants who completed the Behavior Rating Inventory of Executive Function – Adult version.

Results: Patients with AD and their informants reported greater executive dysfunction than the HC group and their informants, respectively, and patients reported greater difficulty than their informants. The largest effect size for both self- and informant ratings was obtained for the Working Memory scale.

Conclusions: These findings indicate that subjective cognitive concerns in mild AD extend beyond the memory domain to executive functions. That greater difficulty was endorsed by patients than their informants suggests that at least in the mild stage of AD some awareness of executive dysfunction may be maintained in some patients. Implications for clinical care are discussed.     

A comparison of clinical,psychometric and behavioural memory tests: Findings from a community study of the early detection of dementia

Diagnostic criteria for dementia require assessment of the ability to learn new information. Ideally, this assessment should be brief and sensitive to early impairment. We present comparative data on a variety of memory tests administered to a population sample of elderly community residents who are being studied longitudinally. Of the three classes of memory tests, clinical, psychometric and everyday tests, discriminant function analysis indicated that, overall, the best discrimination between demented and non-demented individuals was achieved by some everyday tests: recalling a news item, retracing a route, and recalling a name after learning a name-photograph association. However, of the 11 tests examined in total, two were identified which together discriminated almost as efficiently as all 11 measures combined. These were recalling a name and recalling six objects. By comparison, the principal memory item in the Mini Mental State Examination, the recall of three words, produced poor discrimination. The two simple measures which provided good discrimination in this population sample may therefore be recommended to assess the ability to learn new information, where the aim of the assessment is the diagnosis of dementia.     

Nonlinear biomarker interactions in conversion from mild cognitive impairment to Alzheimer's disease

Multiple biomarkers can capture different facets of Alzheimer's disease. However, statistical models of biomarkers to predict outcomes in Alzheimer's rarely model nonlinear interactions between these measures. Here, we used Gaussian Processes to address this, modelling nonlinear interactions to predict progression from mild cognitive impairment (MCI) to Alzheimer's over 3 years, using Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Measures included: demographics, APOE4 genotype, CSF (amyloid‐β42, total tau, phosphorylated tau), [18^F]florbetapir, hippocampal volume and brain‐age. We examined: (a) the independent value of each biomarker; and (b) whether modelling nonlinear interactions between biomarkers improved predictions. Each measured added complementary information when predicting conversion to Alzheimer's. A linear model classifying stable from progressive MCI explained over half the variance (R² = 0.51, p < .001); the strongest independently contributing biomarker was hippocampal volume (R² = 0.13). When comparing sensitivity of different models to progressive MCI (independent biomarker models, additive models, nonlinear interaction models), we observed a significant improvement (p < .001) for various two‐way interaction models. The best performing model included an interaction between amyloid‐β‐PET and P‐tau, while accounting for hippocampal volume (sensitivity = 0.77, AUC = 0.826). Closely related biomarkers contributed uniquely to predict conversion to Alzheimer's. Nonlinear biomarker interactions were also implicated, and results showed that although for some patients adding additional biomarkers may add little value (i.e., when hippocampal volume is high), for others (i.e., with low hippocampal volume) further invasive and expensive examination may be warranted. Our framework enables visualisation of these interactions, in individual patient biomarker ‘space', providing information for personalised or stratified healthcare or clinical trial design.     

Mild cognitive impairment in a population-based epidemiological study

Background: It would be of considerable importance to be able to estimate the rate at which subjects with mild cognitive impairment (MCI) progress to dementia in a cohort of a population‐based epidemiological study and to establish simple diagnostic methods for the identification of people at high‐risk of dementia. Subjects in a community based elderly cohort of MCI were followed longitudinally. Methods: Subjects were selected from participants in the first epidemiological study conducted on all persons aged 65 years and older residing at home in Nakayama, Japan, using the Mini‐Mental State Examination (MMSE). Mild cognitive impairment was defined as memory deficit with objective memory assessment, without dementia, impairment of general cognitive function or disability in activities of daily living. The conversion rate was calculated using the person–year method. Results: At baseline, the sample consisted of 104 subjects selected from 1162 community dwellers aged over 65 years of age. During the 5‐year follow up, 11 subjects (10.6%) were diagnosed with Alzheimer's disease (AD), five (4.8%) were diagnosed with vascular dementia (VaD) and six (5.8%) were diagnosed with dementia of other etiology. In this survey, the annual conversion rate of MCI to AD was calculated as 8.5% per 100 person–years and shifted to dementia at a rate of 16.1% per 100 person–years. The proportion of subjects with MCI who progressed to develop dementia was the same as in previous reports. However, nearly 40% of subjects returned to normal. Conclusion: The MCI concept, as currently defined, is an unstable and heterogeneous group.     

Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content

Introduction

We investigated brain demyelination in aging, mild cognitive impairment (MCI), and dementia using a direct magnetic resonance imaging marker of myelin.

Prediction of transition from cognitive impairment to senile dementia: a prospective,longitudinal study

OBJECTIVE: The purpose of this investigation was to replicate the statistical approach used in a previous investigation (Toronto study) within a French population to determine the best predictive model for Alzheimer's disease (AD). METHOD: Data from neuropsychological tests from two prospective studies were entered into a regression model. RESULTS: Replication of the statistical approach in the Montpellier sample produced a three-test model with a specificity of 99% and sensitivity of 73%. This model consisted of a delayed auditory verbal recall test, a construction test, a category fluency test and provides probability estimates for the transition to dementia in individual cases. CONCLUSION: The models derived from these two longitudinal studies provide an empirical basis for the selection of tests for the definition of mild cognitive impairment of the Alzheimer type (MCI-A). The small set of tests derived are suitable for use in general practice.     

Behavioral regulation: factor analysis and application of the Behavioral Dyscontrol Scale in dementia and mild cognitive impairment

BACKGROUND: Executive dysfunction is a hallmark of both Dementia of the Alzheimer's Type (AD) and Vascular Dementia (VaD). A complete neuropsychological battery contains measures of executive function, but the focus tends to be on cognitive processes with verbal or written output. The Behavioral Dyscontrol Scale (BDS) is purported to be a measure of executive function that addresses control over voluntary motor behavior. Previous factor analyses revealed three-factor solutions using a variety of patient populations. Our goals were to examine the factor structure in a sample of geriatric outpatients and to apply that factor structure to detect possible differences between AD, VaD, amnestic Mild Cognitive Impairment (MCI), non-amnestic MCI, and normal controls. METHODS: An exploratory factor analysis was performed on 260 outpatient evaluations from 2002-2006. Only the seven items requiring motor responses were included. RESULTS: A two-factor solution emerged. We named the factors Motor Problem-Solving and Simple Motor Repetitive Behaviors. For the first factor, the AD and VaD groups differed from the MCI groups and normal controls, but did not differ from each other. There were no differences between the control, amnestic MCI, and non-amnestic MCI groups. There were no differences between the groups for the second factor. CONCLUSION: It was concluded that voluntary control of behavior that requires problem-solving for complex tasks may help differentiate dementia from mild cognitive impairment and normal aging.     

Clock drawing test in mild and moderate dementia of the Alzheimer's type: a comparative and correlation study

OBJECTIVES: (a) To compare two different clock drawing tests (CDTs) in mild and moderate dementia of the Alzheimer's type (DAT); (b) To examine presumed correlation between these CDTs and some demographic, cognitive and activities of daily living (ADL) variables in mild and moderate DAT. METHODS: Cross-sectional study. Psychogeriatric outpatient clinic. 49 DAT patients, total; 26-mild, 23-moderate, mean age 77.8 and 80.6, respectively.Evaluations included the Mini-Mental State Examination (MMSE), the Cambridge Cognitive Examination (CAMCOG), the Instrumental Activities of Daily Living Scale (IADL), and a Basic Activities of Daily Living (BADL)-dressing subscale. Severity of dementia was determined with the Clinical Dementia Rating (CDR). Each clock was blindly scored by the same investigator, according to Shulman's and Freedman's methods. RESULTS: Mild and moderate DAT groups were similar in age, gender and education. Performance on Shulman's clock was similar between groups while moderate DAT subjects performed significantly worse on Freedman's clock compared to mild DAT patients. Both clocks correlated highly in mild and moderate DAT. CDT scores correlated significantly with age and education only in mild DAT. Neither clock correlated with ADLs in either stage of dementia severity. CDTs correlated with the MMSE score, and the CAMCOG score in mild DAT, and only with the CAMCOG score in moderate DAT. These correlations were still significant after controlling for age and education. CONCLUSIONS: Different aspects of cognition and dementia severity are reflected depending on how a clock drawing is scored. Some scoring systems may have greater sensitivity than others in monitoring progression of cognitive deterioration. Correlation between different CDTs and the variables studied (demographic, cognitive, ADLs), when present, is not ubiqitous and changes with the dementia severity.     

Progression from normal cognition to mild cognitive impairment in a diverse clinic-based and community-based elderly cohort

Introduction

Investigation of the conversion rates from normal cognition (NC) to mild cognitive impairment (MCI) is important, as effective early intervention could potentially prevent or substantially delay the onset of dementia. However, reported conversion rates differ across studies and recruitment source. Our study examined predictors of conversion from NC to MCI in a racially and ethnically diverse sample drawn both from community and clinic recruitment sources.

Subjective memory complaints in Chinese subjects with mild cognitive impairment and early Alzheimer's disease

BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia. However, there is inconsistent opinion as to the validity of subjective memory complaints as a criterion for diagnosis. OBJECTIVE: This study aimed to examine the potential significance of applying a short memory questionnaire in the assessment of Chinese subjects with MCI and early dementia. METHODS: Three hundred and six ambulatory Chinese subjects were recruited. Each participant completed a short memory questionnaire. They were also assessed with the Chinese versions of the mini-mental state examination (CMMSE), Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), category verbal fluency test (CVFT) and span tests. Severity of cognitive impairment was evaluated using the Clinical Dementia Rating (CDR); subjects with CDR 0.5 were further classified into MCI not demented (MCIND) and MCI possible incipient dementia (MCIID) depending on the subscale scores of CDR. RESULTS: An increasing frequency of memory complaints with increasing CDR was observed (Kruskal Wallis test, chi square = 21.29, df 3, p < 0.001). With a cutoff of 3 or more memory complaints, the memory questionnaire demonstrated a sensitivity of 65.3% and 70.4% in identifying subjects with incipient and early dementia respectively. Significant associations between memory complaints and most cognitive test performance were found (Spearman's correlations, p < 0.01). Logistic regression analysis revealed that educational level, the memory questionnaire, ADAS-Cog total and delayed recall scores were significant predictors of MCIID status. CONCLUSIONS: The findings suggested that a short memory questionnaire is useful in the screening of MCI, particularly in subjects who already present with subtle functioning disturbances. Subjective memory complaints were significant correlated with objective performance of memory functions, reflecting the usefulness of memory complaints in the assessment of MCI.     

Neuropsychiatric symptoms of dementia: cross-sectional analysis from a prospective, longitudinal Belgian study

OBJECTIVE: Given the rather limited knowledge on profiles of neuropsychiatric symptoms (behavioural and psychological signs and symptoms of dementia, BPSD) in several degenerative dementias, we designed a prospective study of which we here present the baseline data. METHODS: Diagnosed according to strictly applied clinical diagnostic criteria, patients with probable Alzheimer's disease (AD) (n = 205), frontotemporal dementia (FTD) (n = 29), mixed dementia (MXD) (n = 39) and dementia with Lewy bodies (DLB) (n = 23) were included. All patients underwent a neuropsychological examination and behavioural assessment by means of a battery of scales (Middelheim Frontality Score (MFS), Behave-AD, Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia). RESULTS: In AD and MXD, activity disturbances and aggressiveness occurred in more than 80% of the patients. With a prevalence of 70%, apathy was very common whereas delusions and hallucinations were rare in FTD patients. Frequently used behavioural assessment scales like the Behave-AD systematically underestimated BPSD in FTD whereas the MFS displayed high sensitivity for frontal lobe symptoms. Hallucinations discriminated DLB patients from other dementias. A high prevalence of disinhibition (65%) in DLB pointed to frontal lobe involvement. CONCLUSIONS: Behavioural assessment may help differentiating between different forms of dementia, further stressing the need for the development of new and more sensitive behavioural assessment scales. By means of the MFS, frontal lobe involvement was frequently observed in DLB. As 70% of FTD patients displayed apathy, prevalence was about two times higher compared to the other disease groups, meanwhile indicating that apathy is frequently observed in dementia, irrespective of its etiology.