Down syndrome and Alzheimer's disease: a link between development and aging

A subset of aged individuals with Down syndrome (DS) exhibits the clinical features of Alzheimer's disease (AD) but our ability to detect dementia in this population is hampered by developmental differences as well as the sensitivity of existing test tools. Despite the apparent clinical heterogeneity in aged individuals with DS, age-associated neuropathology is a consistent feature. This is due to the fact that trisomy 21 leads to a dose-dependent increase in the production of the amyloid precursor protein and subsequently the production of the amyloidogenic fragments leading to early and predominant senile plaque formation. A review of the existing literature indicates that oxidative damage and neuroinflammation may interact to accelerate the disease process particularly in individuals with DS over the age of 40 years. By combining clinical information with measures of brain-region specific neuropathology we can "work backwards" and identify the earliest and most sensitive clinical change that may signal the onset of AD. For the past 50 years, investigators in the fields of mental retardation, developmental disabilities, and aging have been interested in the curious link between AD and DS. The morphologic and biochemical origins of AD are seen in the early years of the lifespan for individuals with DS. Study of the process by which AD evolves in DS affords an opportunity to understand an important link between development and aging. This review will focus on advances in the molecular and clinical basis of this association.     

Visual Imagery Processing and Knowledge of Famous Names in Alzheimer's Disease and MCI

ABSTRACT

The study of memory for famous people and visual imagery retrieval was investigated in patients in the early stages of Alzheimer's disease (AD) and in the prodromal stage of AD, so-called Mild Cognitive Impairment (MCI). Fifteen patients with AD (MMSE ≥23), 15 patients with amnestic MCI (a-MCI) and 15 normal controls (NC) performed a famous names test designed to evaluate the semantic and distinctive physical features knowledge of famous persons. Results indicated that patients with AD and a-MCI generated significantly less physical features and semantic biographical knowledge about famous persons than did normal control participants. Additionally, significant differences were observed between a-MCI and AD patients in all tasks. The present findings confirm recent studies reporting semantic memory impairment in MCI. Moreover, the current findings show that mental imagery is lowered in a-MCI and AD and is likely related to the early semantic impairment.     

The free and cued selective reminding test for predicting progression to Alzheimer's disease in patients with mild cognitive impairment: A prospective longitudinal study

Amnestic mild cognitive impairment (aMCI) patients carry a greater risk of conversion to Alzheimer's disease (AD). Therefore, the International Working Group (IWG) on AD aims to consider some cases of aMCI as symptomatic prodromal AD. The core diagnostic marker of AD is a significant and progressive memory deficit, and the Free and Cued Selective Reminding Test (FCSRT) was recommended by the IWG to test memory in cases of possible prodromal AD. This study aims to investigate whether the performance on the FCSRT would enhance the ability to predict conversion to AD in an aMCI group. A longitudinal study was conducted on 88 aMCI patients, and neuropsychological tests were analysed on the relative risk of conversion to AD. During follow‐up (23.82 months), 33% of the aMCI population converted to AD. An impaired FCSRT TR was significantly associated with the risk of conversion to dementia, with a mean time to conversion of 25 months. The FCSRT demonstrates utility for detecting AD at its prodromal stage, thus supporting its use as a valid clinical marker.     

Alzheimer's disease in Down syndrome: neurobiology and risk

Down syndrome (DS) is characterized by increased mortality rates, both during early and later stages of life, and age-specific mortality risk remains higher in adults with DS compared with the overall population of people with mental retardation and with typically developing populations. Causes of increased mortality rates early in life are primarily due to the increased incidence of congenital heart disease and leukemia, while causes of higher mortality rates later in life may be due to a number of factors, two of which are an increased risk for Alzheimer's disease (AD) and an apparent tendency toward premature aging. In this article, we describe the increase in lifespan for people with DS that has occurred over the past 100 years, as well as advances in the understanding of the occurrence of AD in adults with DS. Aspects of the neurobiology of AD, including the role of amyloid, oxidative stress, Cu/ZN dismutase (SOD-1), as well as advances in neuroimaging are presented. The function of risk factors in the observed heterogeneity in the expression of AD dementia in adults with DS, as well as the need for sensitive and specific biomarkers of the clinical and pathological progressing of AD in adults with DS is considered.     

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.     

A Meta-Analysis of Structural and Functional Brain Imaging in Dementia of the Alzheimer's Type: A Neuroimaging Profile

We conducted a quantitative review of the imaging literature using meta-analytic methodology to characterize further the magnitude of hippocampal deficit in probable Alzheimer's disease (AD) and to determine whether other neuroanatomic structures in AD can better discriminate the disease from normal aging. Additionally, we parceled the discriminability of neuroanatomic structures by duration of disease to determine those structures most sensitive to AD in its early and late stages. One hundred twenty-one studies published between 1984 and 2000 met criteria for inclusion in the present analysis. In total, structural (i.e., CT and MRI) and functional (i.e., SPECT and PET) neuroimaging results from 3511 patients with AD, and 1632 normal healthy controls were recorded across meta-analyses. Our results include neuroimaging profiles for both early onset and longer duration patients with AD. In sum, these profiles yield a signature of diagnostic markers in both cortical and subcortical neuroanatomic areas. This signature is consistent with the clinical phenomenology of Alzheimer's dementia and should aid in the positive identification of AD.     

The cholinergic lesion of Alzheimer's disease: pivotal factor or side show?

A profound loss of cortical cholinergic innervation is a nearly invariant feature of advanced Alzheimer's disease (AD). The temporal course of this lesion and its relationship to other aspects of the disease have not yet been fully clarified. Despite assertions to the contrary, a review of the evidence suggests that a perturbation of cholinergic innervation is likely to be present even in the very early stages of AD. This cholinergic lesion is unlikely to be a major determinant of the clinical symptoms or of the neuropathological lesions. Nonetheless, it almost certainly contributes to the severity of the cognitive and behavioral deficits, especially in the areas of memory and attention. The cholinergic lesion may also influence the progression of the neuropathological process through complex interactions with amyloidogenesis, tau phosphorylation and neuroplasticity.     

Detectable Neuropsychological Differences in Early Preclinical Alzheimer’s Disease: A Meta-Analysis

The development of methods for in vivo detection of cerebral beta amyloid retention and tau accumulation have been increasingly useful in characterizing preclinical Alzheimer’s disease (AD). While the association between these biomarkers and eventual AD has been demonstrated among cognitively intact older adults, the link between biomarkers and neurocognitive ability remains unclear. We conducted a meta-analysis to test the hypothesis that cognitively intact older adults would show statistically discernable differences in neuropsychological performance by amyloid status (amyloid negative = A-, amyloid positive = A+). We secondarily hypothesized a third group characterized by either CSF tau pathology or neurodegeneration, in addition to amyloidosis (A+/N+ or Stage 2), would show lower neuropsychology scores than the amyloid positive group (A+/N- or Stage 1) when compared to the amyloid negative group. Pubmed, PsychINFO, and other sources were searched for relevant articles, yielding 775 total sources. After review for inclusion/exclusion criteria, duplicates, and risk of bias, 61 studies were utilized in the final meta-analysis. Results showed A+ was associated with poorer performance in the domains of global cognitive function, memory, language, visuospatial ability, processing speed, and attention/working memory/executive functions when compared to A-. A+/N+ showed lower performances on memory measures when compared to A+/N- in secondary analyses based on a smaller subset of studies. Results support the notion that neuropsychological measures are sensitive to different stages of preclinical AD among cognitively intact older adults. Further research is needed to determine what constitutes meaningful differences in neuropsychological performance among cognitively intact older adults.     

Episodic and semantic memory in early versus late onset Alzheimer's disease.

The aim of this study was to replicate and extend previous work demonstrating selective impairment of semantic, but not episodic, memory in late versus early onset Alzheimer's disease (AD). Measures of episodic and semantic memory were administered to 12 pairs of patients; early (less than or equal to 62) and late (greater than or equal to 68) onset pairs were matched on dementia severity and education. As hypothesized, the groups did not differ on the three episodic memory measures but did on two of three semantic memory measures. In conjunction with prior research, these findings indicate that late onset AD is characterized by more profound impairment on measures of semantic processing.     

Diagnostic Accuracy of Memory Measures in Alzheimer’s Dementia and Mild Cognitive Impairment: a Systematic Review and Meta-Analysis

With an increasing focus on biomarkers in dementia research, illustrating the role of neuropsychological assessment in detecting mild cognitive impairment (MCI) and Alzheimer’s dementia (AD) is important. This systematic review and meta-analysis, conducted in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) standards, summarizes the sensitivity and specificity of memory measures in individuals with MCI and AD. Both meta-analytic and qualitative examination of AD versus healthy control (HC) studies (n = 47) revealed generally high sensitivity and specificity (≥ 80% for AD comparisons) for measures of immediate (sensitivity = 87%, specificity = 88%) and delayed memory (sensitivity = 89%, specificity = 89%), especially those involving word-list recall. Examination of MCI versus HC studies (n = 38) revealed generally lower diagnostic accuracy for both immediate (sensitivity = 72%, specificity = 81%) and delayed memory (sensitivity = 75%, specificity = 81%). Measures that differentiated AD from other conditions (n = 10 studies) yielded mixed results, with generally high sensitivity in the context of low or variable specificity. Results confirm that memory measures have high diagnostic accuracy for identification of AD, are promising but require further refinement for identification of MCI, and provide support for ongoing investigation of neuropsychological assessment as a cognitive biomarker of preclinical AD. Emphasizing diagnostic test accuracy statistics over null hypothesis testing in future studies will promote the ongoing use of neuropsychological tests as Alzheimer’s disease research and clinical criteria increasingly rely upon cerebrospinal fluid (CSF) and neuroimaging biomarkers.     

Neuropsychological Contributions to the Early Identification of Alzheimer’s Disease

A wealth of evidence demonstrates that a prodromal period of Alzheimer’s disease (AD) exists for some years prior to the appearance of significant cognitive and functional declines required for the clinical diagnosis. This prodromal period of decline is characterized by a number of different neuropsychological and brain changes, and reliable identification of individuals prior to the development of significant clinical symptoms remains a top priority of research. In this review we provide an overview of those neuropsychological changes. In particular, we examine specific domains of cognition that appear to be negatively affected during the prodromal period of AD, and we review newer analytic strategies designed to examine cognitive asymmetries or discrepancies between higher-order cognitive functions versus fundamental skills. Finally, we provide a critical examination of the clinical concept of Mild Cognitive Impairment and offer suggestions for an increased focus on the impact of cerebrovascular disease (CVD) and CVD risk during the prodromal period of AD.     

Differential Memory Test Sensitivity for Diagnosing Amnestic Mild Cognitive Impairment and Predicting Conversion to Alzheimer's Disease

ABSTRACT

Episodic memory is the first and most severely affected cognitive domain in Alzheimer's disease (AD), and it is also the key early marker in prodromal stages including amnestic mild cognitive impairment (MCI). The relative ability of memory tests to discriminate between MCI and normal aging has not been well characterized. We compared the classification value of widely used verbal memory tests in distinguishing healthy older adults (n = 51) from those with MCI (n = 38). Univariate logistic regression indicated that the total learning score from the California Verbal Learning Test-II (CVLT-II) ranked highest in terms of distinguishing MCI from normal aging (sensitivity = 90.2; specificity = 84.2). Inclusion of the delayed recall condition of a story memory task (i.e., WMS-III Logical Memory, Story A) enhanced the overall accuracy of classification (sensitivity = 92.2; specificity = 94.7). Combining Logical Memory recognition and CVLT-II long delay best predicted progression from MCI to AD over a 4-year period (accurate classification = 87.5%). Learning across multiple trials may provide the most sensitive index for initial diagnosis of MCI, but inclusion of additional variables may enhance overall accuracy and may represent the optimal strategy for identifying individuals most likely to progress to dementia.     

Evidence for a shrinking span of personal and present existence in dementia of the Alzheimer's type

Severely impaired episodic memory deprives patients with Alzheimer's disease (AD) of a sense of personal continuity in their daily lives, yet there are no tests that accurately measure this impairment. Recently, Zakzanis, Leach, and Moscovitch (1999) examined the integrity of memory function in terms of temporal continuity in a way that would engage the patient in everyday behavior, such as informal conversation, but still allow memory function to be quantified. The task allowed the measurement of the duration of continuous, conscious experience of the present and was therefore termed "span of temporal continuity (STC)." Given that we were able to document static and growing STCs, we wanted to know whether our measure could track progressive memory loss. Accordingly, we followed a patient we believed was in the very early stages of AD to measure the change of his STC longitudinally. Along with his STC, we present our neuropsychological and brain imaging findings over the course of the investigation.     

Neuropsychological Differences Between Frontotemporal Dementia and Alzheimer's Disease: A Review

This paper surveys the similarities and differences between frontotemporal dementia (FTD) and Alzheimer's disease (AD). The review covers findings primarily from neuropsychological studies on memory, language, attention/executive function, and visuospatial abilities. However, neuropsychiatric and neuroimaging data are also briefly discussed. Distinguishing features of both FTD and AD are described in order to present a comprehensive clinical picture of these dementing diseases, which is essential for the process of differential diagnosis. The cause of specific cognitive deficits is also considered. Our comprehensive review of the empirical literature reveals that AD is characterized by early memory loss and visuospatial problems, while among the main features of FTD are behavioral abnormalities and executive dysfunctions.     

Differences in performance in CAMCOG-R domains between old and oldest old patients with Alzheimer’s disease

The purpose of this study is to evaluate the neuropsychological performance in a ≥90-year-old population with Alzheimer disease (AD) in comparison with younger elderly patients. We retrospectively studied all patients with AD attended in a specialized clinic between 1999 and 2011. Age, sex, educational level, and sensory loss data were collected. Neuropsychological evaluation included Mini-Mental State Examination and Global Deterioration Scale. We used the eight Cambridge Cognitive Assessment (CAMCOG-R) domains to evaluate and compare the neuropsychological performance in the younger than 90 years old (<90) and older than 90 years old (≥90) groups. We selected 2931 patients, 2897 <90 (98.83%) and 34 ≥90 years old (1.17%). The ≥90 group had significant lower punctuations in memory, praxis, and abstract thinking CAMOCG-R domains with 1.49, 0.75, and 0.58 less points, respectively, (p < 0.05). Neuropsychological characteristics of cognitive decline seem to be different in ≥90 compared to <90 years old patients. According to age, the biggest differences in the CAMCOG-R performance are in the memory, praxis, and abstract thinking domains.     

Is Clinical Anxiety a Risk or a Protective Factor for Executive Functioning in Youth with ADHD? A Meta-regression Analysis

Comorbidity rates between ADHD and anxiety disorders (AD) are high, but little is known about the nature of this co-occurrence. A dominant idea is that AD may intensify some (i.e., attention and working memory) and attenuate other (i.e., inhibition) ADHD symptoms. Results are mixed, potentially because of between-study differences. To investigate this further we performed a meta-regression analysis on 11 studies (n ‘ADHD-only’ = 695; n ‘ADHD + AD’ = 608), containing 35 effect sizes on attention, inhibition and working memory. Main results were: (1) no evidence of a negative effect of AD on attention and working memory; (2) better response inhibition in children with ADHD with AD than those with only ADHD (medium ES g = ? .40); (3) medication moderated this association: the effect seemed limited to studies that included medication-naïve participants; (4) the difference between the two groups increased with age for attention and with proportion of boys for working memory ability. There was no effect of comorbid disruptive behavior disorder. In conclusion, AD seems to be a protective factor for inhibition problems as assessed with laboratory tasks in ADHD, especially in children who are medication naïve. Further, AD may have a protective function for attention in older children, and for working memory in boys with ADHD. It is therefore important to screen for AD when diagnosing ADHD, and to educate those with comorbid AD about the possible positive function of feeling anxious. Potential negative effects of ADHD medication on inhibition in children with comorbid AD should be considered.     

Memory deficits in Alzheimer's patients: A comprehensive review

Despite considerable experimental work on Alzheimer's disease (AD), the underlying cognitive mechanisms as well as the precise localization of neuropathological changes critical for memory loss remains undefined. A review of the neuropsychological literature on long-term memory deficits in AD patients suggests that AD patients display (a) a pervasive deficit of explicit memory, (b) a partial deficiency of implicit memory for verbal and visuoperceptual material (as measured by repetition priming procedures), and (c) a substantial sparing of implicit memory for visuomotor skills. The explicit memory loss is likely a result of encoding as well as consolidation difficulties. A faulty lexical-semantic knowledge structure appears responsible for deficient repetition priming effects. Since neuropathological changes diffusely affect the brain of AD patients, establishing a clear relationship between localization of cerebral lesions and memory deficits is particularly difficult. Nevertheless, data suggest that extensive involvement of the hippocampal-amygdala complex plays a major role in explicit memory loss. Damage to associative cortical areas likely is involved in repetition priming deficits. The relative integrity of primary motor and sensory cortical areas and of the basal ganglia likely subsume, by contrast, the normal learning of visuomotor skills.     

The usefulness of the story recall test in patients with mild cognitive impairment and Alzheimer's disease

ABSTRACT

Background: The story recall test (SRT) is one of the most reliable neuropsychological assessments for evaluating verbal memory function in order to distinguish between individuals with normal aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD). The SRT is analogous to the logical memory test in Wechsler Memory Scale-III, which has recently been developed and standardized to apply to older adults in Korea. The purpose of this study was to examine the usefulness of the SRT and its ability to discriminate between normal cognitive aging and patients with MCI or AD. Methods: One hundred and twelve patients with MCI, 97 patients with AD, and 53 healthy elderly adults participated in this study. The SRT was compared with the Clinical Dementia Rating (CDR), Global Deterioration Scale (GDS), Korean version of the Mini Mental State Examination (K-MMSE), and the Korean version of the Hopkins Verbal Learning Test (K-HVLT). Results: The SRT was well-correlated with the dementia rating scales and the K-HVLT. However, the sensitivity and specificity of the SRT was greatly influenced by the level of education of the subjects. Conclusions: The SRT is a sensitive measurement of verbal memory function that can be used in clinical settings to discriminate between normal memory functioning and the very early and moderate stages of AD in a Korean population. Moreover, it is important to recognize that the SRT is more appropriate for subjects with a high level of education rather than a low level of education to differentiate normal cognitive aging from MCI or AD.