Neuropsychological Measures that Predict Progression from Mild Cognitive Impairment to Alzheimer's type dementia in Older Adults: a Systematic Review and Meta-Analysis

This study aimed to determine the extent to which cognitive measures can predict progression from mild cognitive impairment (MCI) to Alzheimer’s type dementia (AD), assess the predictive accuracy of different cognitive domain categories, and determine whether accuracy varies as a function of age and length of follow-up. We systematically reviewed and meta-analyzed data from longitudinal studies reporting sensitivity and specificity values for neuropsychological tests to identify individuals with MCI who will develop AD. We searched articles in Medline, Cochrane, EMBASE, PsycINFO, and the Web of Science. Methodological quality was assessed using the STARDem and QUADAS standards. Twenty-eight studies met the eligibility criteria (2365 participants) and reported predictive values from 61 neuropsychological tests with a 31-month mean follow-up. Values were pooled to provide combined accuracy for 14 cognitive domains. Many domains showed very good predictive accuracy with high sensitivity and specificity values (≥ 0.7). Verbal memory measures and many language tests yielded very high predictive accuracy. Other domains (e.g., executive functions, visual memory) showed better specificity than sensitivity. Predictive accuracy was highest when combining memory measures with a small set of other domains or when relying on broad cognitive batteries. Cognitive tests are excellent at predicting MCI individuals who will progress to dementia and should be a critical component of any toolkit intended to identify AD at the pre-dementia stage. Some tasks are remarkable as early indicators, whereas others might be used to suggest imminent progression.     

Feasibility of telecognitive assessment in dementia

Videoconferencing (VC) technology has been used successfully to provide psychiatric services to patients in rural and otherwise underserved settings. VC-based diagnostic interviewing has shown good agreement with conventional face-to-face diagnosis of dementia in several investigations, but extension of this technology to neurocognitive assessment has received little attention. To this end, the authors administered a brief battery of common neuropsychological tests via VC technology (telecognitive) and traditional face-to-face methods to 14 older persons with mild cognitive impairment (MCI) and 19 persons with mild to moderate Alzheimer's disease (AD). Highly similar test scores were obtained when participants were tested in-person or via VC. Telecognitive assessment appears to be a valid means to conduct neuropsychological evaluation of older adults with cognitive impairment. Furthermore, continued development of VC technology has implications for expanding neuropsychological assessment options in under-served populations.     

A comparison of the diagnostic accuracy of the AD8 and BCAT-SF in identifying dementia and mild cognitive impairment in long-term care residents

We compared the accuracy of the Brief Cognitive Assessment Tool—Short Form (BCAT-SF) and AD8 in identifying mild cognitive impairment (MCI) and dementia among long-term care residents. Psychometric analyses of 357 long-term care residents (n = 228, nursing home; n = 129, assisted living) in Maryland referred for neuropsychological evaluation evidenced robust internal consistency reliability and construct validity for the BCAT-SF. Furthermore, hierarchical logistic regression and receiver operating characteristic curve analyses demonstrated superior predictive validity for the BCAT-SF in identifying MCI and dementia relative to the AD8. In contrast, previously reported psychometric properties or cut scores for the AD8 could not be cross-validated in this long-term care sample. Based on these findings, the BCAT-SF appears to be a more reliable and valid screening instrument than the AD8 for rapidly identifying MCI and dementia in long-term care residents.     

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.     

The impact of conventional versus robust norming on cognitive characterization and clinical classification of MCI and dementia

We examined the impact of conventional versus robust normative approaches on cognitive characterization and clinical classification of MCI versus dementia. The sample included participants from the National Alzheimer's Coordinating Center Uniform Data Set. Separate demographically adjusted z-scores for cognitive tests were derived from conventional (n = 4273) and robust (n = 602) normative groups. To assess the impact of deriving scores from a conventional versus robust normative group on cognitive characterization, we examined likelihood of having a low score on each neuropsychological test. Next, we created receiver operating characteristic (ROC) curves for the ability of normed scores derived from each normative group to differentiate between MCI (n = 3570) and dementia (n = 1564). We examined the impact of choice of normative group on classification accuracy by comparing sensitivity and specificity values and areas under the curves (AUC). Compared with using a conventional normative group, using a robust normative group resulted in a higher likelihood of low cognitive scores for individuals classified with MCI and dementia. Comparison of the classification accuracy for distinguishing MCI from dementia did not suggest a statistically significant advantage for either normative approach (Z = −0.29, p = .77; AUC = 0.86 for conventional and AUC = 0.86 for robust). In summary, these results indicate that using a robust normative group increases the likelihood of characterizing cognitive performance as low. However, there is not a clear advantage of using a robust over a conventional normative group when differentiating between MCI and dementia.     

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.     

Memory profiling in mild cognitive impairment: Can we determine risk for Alzheimer's disease?

Mild cognitive impairment (MCI) is considered a transitional stage between normal ageing and Alzheimer's disease (AD), but not all MCI cases progress to AD and there has been limited focus on how to identify who will progress. Given claims for a characteristic kind of memory impairment in AD involving deficits in encoding and consolidation of information, we propose that ‘memory profiling’ of individuals with MCI may help identify which individuals will progress. We initially set out to establish whether the same characteristic memory profile was present prior to the onset of AD (preAD). Very few studies provided data that allowed us to examine this, but results tentatively supported an encoding/consolidation profile in preAD. A single study tested the clinically important contrast of preAD versus non‐preAD MCI cases and found no difference under any condition or in memory profiles, but interpretation of the findings is limited by short duration of follow‐up, ceiling effects, and task limitations in assessing more complex and qualitative aspects of memory. Although existing data lead to equivocal conclusions, we believe that memory profiling is an endeavour worth pursuing, particularly given the increasing number of people with MCI presenting for clinical assessment. We propose that tests designed specifically to measure memory processes should be sensitive to preAD and are required in prospective longitudinal designs to identify these clinically crucial MCI cases.     

Neuropsychological Characteristics of Dementia with Lewy Bodies and Parkinson’s Disease with Dementia: Differentiation, Early Detection, and Implications for “Mild Cognitive Impairment” and Biomarkers

Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are neurodegenerative conditions sharing a disorder of α-synuclein metabolism. Temporal differences in the emergence of symptoms and clinical features warrant the continued clinical distinction between DLB and PDD. While DLB and PDD groups’ neuropsychological profiles often differ from those in Alzheimer’s disease (AD), the diagnostic sensitivity, specificity, and predictive values of these profiles remain largely unknown. PDD and DLB neuropsychological profiles share sufficient similarity to resist accurate and reliable differentiation. Although heterogeneous cognitive changes (predominantly in memory and executive function) may manifest earlier and more frequently than previously appreciated in Parkinson’s disease (PD), and executive deficits may be harbingers of dementia, the enthusiasm to uncritically extend the concept of mild cognitive impairment (MCI) to PD should be tempered. Instead, future research might strive to identify the precise neuropsychological characteristics of the prodromal stages of PD, PDD, and DLB which, in conjunction with other potential biomarkers, facilitate early and accurate diagnosis, and the definition of neuroprotective, neurorestorative, and symptomatic treatment endpoints.     

Neuropsychological tools to predict conversion from amnestic mild cognitive impairment to dementia. The TREDEM Registry

Most of the studies about conversion from Mild cognitive impairment (MCI) to dementia have focused on amnestic MCI (aMCI) which is considered a preclinical phase of Alzheimer’s disease. The aim of the present study was to identify neuropsychological tools that would best predict conversion from aMCI to dementia. Fifty-five aMCI subjects on the Treviso Dementia Registry were investigated. They underwent a neuropsychological evaluation during their first assessment and again at follow-up. Cox proportional-hazard regression models were created to measure the association between the dependent variable (dementia diagnosis or MCI status maintenance) and the neuropsychological test scores at baseline. The sample (28 women and 27 men; mean age 76.82 ± 5.88 years; education 7.62 ± 3.99 years) was observed for an average time of 2.17 ± 1.25 years. A Cox backward stepwise regression showed that the Rey Auditory Verbal Learning Test, Delayed Recall (p = .041) and Semantic Verbal Fluency tests (p = .031) appear to be useful in predicting conversion to dementia.     

Category Cued Recall Following Controlled Encoding as a Neuropsychological Tool in the Diagnosis of Alzheimer’s Disease: A Review of the Evidence

Aim of the present review paper was to evaluate the hypothesis (included in the proposal of new research criteria for Alzheimer’s disease; Dubois et al., Lancet Neurology, 6, 734–746, 2007) that a neuropsychological tool which provides support for the semantic encoding of memorandum at the time of study and supplies category cues at the time of retrieval (i.e. the Grober-Buschke paradigm) is more effective than traditional measures of free recall in 1) differentiating patients affected by the amnestic form of Mild Cognitive Impairment (MCI) or by mild to moderate forms of Alzheimer’s disease (AD) from healthy matches, 2) predicting the conversion of individuals with MCI to AD, and 3) differentiating AD patients from individuals affected by other forms of dementia. Results of the review are controversial regarding the superiority of the Grober-Buschke procedure in differentiating individuals affected by AD or MCI from healthy individuals. The only study that evaluated this issue directly found that the Grober-Buschke procedure was more sensitive and specific than more traditional memory tests in predicting the conversion of MCI patients to AD. Finally, two studies reported that patients affected by AD or other forms of dementia showed different performance patterns in the free and cued recall tasks of the Grober-Buschke procedure. In conclusion, although encouraging results are reported in the few studies that investigated the ability of this procedure to predict the evolution of individuals with amnestic MCI and to differentiate AD patients from patients with other forms of cortical and subcortical dementia, more experimental work is needed to confirm these positive findings.     

Fitness to drive following cerebral pathology: The Rookwood Driving Battery as a tool for predicting on‐road driving performance

The use of neuropsychological testing to determine fitness to drive in people with neuropathology is likely to be an increasingly attractive alternative to on‐road testing for many candidates for assessment. The Rookwood Driving Battery has been shown to have good predictive value for determining some who are likely to fail an on‐road test in early studies. This study replicated earlier research by examining the predictive value and theoretical validity of the battery on a larger sample of 391 participants, as well as extending earlier analysis by examining the effect of older age (over 70 years) and the interaction between age and pathology on battery and on‐road performance. The battery demonstrated good positive and negative predictive values for predicting on‐road performance. There were significant effects of older age on both the Rookwood Battery performance and the on‐road test, with older adults performing significantly poorer on both. There was no interaction between age and pathology on the Rookwood Battery but on‐road age interacted with some pathologies to produce significantly poorer performances. Furthermore, correlation and regression analysis indicate that the battery is a powerful instrument that encompasses tests of core neuropsychological functions needed for driving.     

Correlation between functional mobility and cognitive performance in older adults with cognitive impairment

Association between cognitive impairment and gait performance occurs in mild cognitive impairment (MCI) and Alzheimer‘s disease (AD), particularly under “divided attention” conditions, leading to a greater risk of falls. We studied 36 controls, 42 MCI, and 26 mild AD patients, using the Timed Up-and-Go test (TUG) under four conditions: TUG single – TUG1; TUG cognitive – TUG2; TUG manual –TUG3; TUG cognitive and manual – TUG4. Cognition was assessed using the MMSE, SKT, Exit25, and TMT (A and B). We found significant correlations between cognitive scores and TUG2 [r values (MMSE: –0.383, TMT-A: 0.430, TMT-B: 0.386, Exit25: 0.455, SKT: 0.563)] and TUG4 [(MMSE: –0.398, TMT-A: 0.384, TMT-B: 0.352,Exit25: 0.466, SKT: 0.525)] in the AD group, and between all TUG modalities and SKT in MCI and AD. Our results revealed that functional mobility impairment in cognitive dual tasks correlated to cognitive decline in AD patients and to attention and memory impairment in MCI.     

Dissociations in visual attention deficits among persons with mild cognitive impairment

Impairments in visual attention and visual information processing have been identified as part of the neuropsychological features of Alzheimer's disease (AD), even in its earliest stages. There is increasing recognition that these deficits may be selective rather than global, with some attentional subtypes being more vulnerable than others. The few studies that have investigated attentional deficits in mild cognitive impairment (MCI), a putatively prodromal phase of AD, have not satisfactorily addressed the possible selectivity in attentional deficits in MCI. This study examined potential dissociations in visual attention deficits in MCI using a measure that assesses simple, divided, and selective attention. The results indicated a hierarchy of attentional impairments, with divided attention being the most affected and simple attention the least. Among participants with MCI, 53% showed evidence of impairment in divided attention compared to 19% of controls (OR = 4.81, p < .001). Poorer visual attention was also associated with poorer overall cognitive status. The implications of these findings for early identification of MCI, prevention of functional decline in MCI, and delay/reversal of cognitive degradation in MCI are discussed.     

A novel technique for the quantitative assessment of apraxic deficits: Application to individuals with mild cognitive impairment

The purpose of this study was to apply two novel quantitative assessments of apraxia to issues surrounding the cognitive profile of individuals with mild cognitive impairment (MCI) who are at increased risk of Alzheimer's disease (AD). In particular, it was wished to determine whether such quantitative assessment techniques can detect minor degrees of impairment at a stage in the putative disease process before apraxia has become clinically obvious. A total of 23 individuals with MCI and 75 healthy controls were assessed on two 3‐item sequential movement tasks involving either meaningful or meaningless actions. A traditional rating scale assessment of gesture‐to‐command was also administered. MCI patients took significantly longer than control subjects to complete the sequential movement tasks despite unimpaired performance on the traditional gesture production tasks. Furthermore, retrospective analyses revealed that, at the group level, only MCI patients who subsequently proceeded to a clinical diagnosis of AD were significantly slower than controls at the initial assessment. These findings provide the first evidence that the neuropsychological deficits associated with MCI may extend to the domain of praxic functions. Consequently, this work contributes to the growing literature questioning the clinical usefulness of the concept of MCI and the appropriateness of current diagnostic criteria for distinguishing this condition from mild AD.     

Diagnosis of cognitive impairment onset in older adults based on limitations in language skills / Diagnóstico del inicio del deterioro cognitivo en mayores a partir de limitaciones en las capacidades lingüísticas

Abstract

Progressive decline in language has been described in neuropsychological studies on Alzheimer’s disease and Mild Cognitive Impairment (MCI). We investigate this decline in its early stages, as well as its manifestations and the linguistic differences between participants at risk of developing MCI and without impairment. Participants were 36 older adults, all aged over 65. They were assessed using 31 subtests grouped into eight areas: fluency, comprehension, oral expression, reading, writing, memory, perceptual organization and processing speed. Our results showed significant differences between participants at risk of developing MCI and without impairment in verbal tests but not in manipulative tests. All participants at risk of developing MCI scored lowest in these eight areas. Our findings illustrate the relevance of investigating language skills in people at risk of developing MCI. Investigating these neuropsychological changes will help design appropriate intervention programmes that affect areas with higher levels of impairment.     

A data-driven approach to neuropsychological features in isolated REM behaviour disorder: A latent class analysis

Recent evidence demonstrated that neuropsychological assessment may be considered a valid marker of neurodegeneration in idiopathic REM sleep behaviour disorder (iRBD). However, little is known about the possible neuropsychological heterogeneity within the iRBD population. This retrospective study aimed to identify and describe different neuropsychological phenotypes in iRBD patients by means of a data-driven approach using latent class analysis. A total of 289 iRBD patients underwent a neuropsychological assessment evaluating cognitive domains: global cognition, language, short- and long-term memory, executive functions and visuospatial abilities. The presence of mild cognitive impairment (MCI) was also assessed. Latent class analysis was carried out to identify iRBD subtypes according to neuropsychological scores. The most parsimonious model identified three latent classes. Groups were labelled as follows: Class 2 “severely impaired” (n = 83/289): mean pathological scores in different tests, a high percentage of MCI multiple-domain and impairment in all neuropsychological domains. Class 1 “moderately impaired” (n = 44/289): mean neuropsychological score within the normal value, a high percentage of MCI (high risk to phenoconversion) and great impairment in the visuospatial domain. Class 3 “slightly impaired” (n = 162/289): no deficit worthy of attention except for short- and long-term memory. Our results suggest three different clinical phenotypes within the iRBD population. These findings may be relevant in the future for predicting the clinical trajectories of phenoconversion in iRBD.     

Memory factors in Rey AVLT: Implications for early staging of cognitive decline

Supraspan verbal list learning is widely used to assess dementia and related cognitive disorders where declarative memory deficits are a major clinical sign. While the overall learning rate is important for diagnosis, serial position patterns may give insight into more specific memory processes in patients with cognitive impairment. This study explored these patterns in a memory clinic clientele. One hundred eighty three participants took the Rey Auditory‐Verbal Learning Test (RAVLT). The major groups were patients with Alzheimer's disease (AD), Vascular Dementia (VD), Mild Cognitive Impairment (MCI), and Subjective Cognitive Impairment (SCI) as well as healthy controls (HC). Raw scores for the five trials and five serial partitions were factor analysed. Three memory factors were found and interpreted as Primacy, Recency, and Resistance to Interference. AD and MCI patients had impaired scores in all factors. SCI patients were significantly impaired in the Resistance to Interference factor, and in the Recency factor at the first trial. The main conclusion is that serial position data from word list testing reflect specific memory capacities which vary with levels of cognitive impairment.     

Dissociations in Visual Attention Deficits among Persons with Mild Cognitive Impairment

ABSTRACT

Impairments in visual attention and visual information processing have been identified as part of the neuropsychological features of Alzheimer's disease (AD), even in its earliest stages. There is increasing recognition that these deficits may be selective rather than global, with some attentional subtypes being more vulnerable than others. The few studies that have investigated attentional deficits in mild cognitive impairment (MCI), a putatively prodromal phase of AD, have not satisfactorily addressed the possible selectivity in attentional deficits in MCI. This study examined potential dissociations in visual attention deficits in MCI using a measure that assesses simple, divided, and selective attention. The results indicated a hierarchy of attentional impairments, with divided attention being the most affected and simple attention the least. Among participants with MCI, 53% showed evidence of impairment in divided attention compared to 19% of controls (OR = 4.81, p < .001). Poorer visual attention was also associated with poorer overall cognitive status. The implications of these findings for early identification of MCI, prevention of functional decline in MCI, and delay/reversal of cognitive degradation in MCI are discussed.     

The free and cued selective reminding test: Validation for mild cognitive impairment and Alzheimer's disease

The International Working Group on Alzheimer's disease (AD) suggested the free and cued selective reminding test (FCSRT) to assess memory, as it showed high sensitivity and specificity in the differentiation of AD from healthy controls and other dementias. The FCSRT involves the use of selective reminding with semantic cueing in memory assessment. This study aims to validate the FCSRT for mild cognitive impairment (MCI) and AD through the analysis of the diagnostic accuracy and the suggestion of cut‐off scores. Patients were classified into two groups according to standard criteria: MCI (n = 100) and AD (n = 70). A matched control group (n = 101) of cognitively healthy subjects was included. The reliability and the validity of the FCSRT were analysed on the immediate (IR) and delayed (DR) recalls. The Cronbach's alpha was 0.915 for the IR and 0.879 for the DR. The total recall measures revealed good areas under the curve for MCI (IR: .818; DR: .828) and excellent for AD (IR: .987; DR: .991). Furthermore, the MCI group was subdivided with respect to a non‐similar/similar AD pattern of impairment, with almost half of the subjects showing an AD‐like decline. This analysis represents a novel contribution regarding the properties of the FCSRT in illustrating the heterogeneity of MCI at baseline. The FCSRT has proved to be a very useful tool in the characterization of the memory impairment of the AD spectrum.