Level of recall, retrieval speed, and variability on the Cued-Recall Retrieval Speed Task (CRRST) in individuals with amnestic mild cognitive impairment.

Individuals with amnestic mild cognitive impairment (aMCI) show deficits on traditional episodic memory tasks and reductions in speed of performance on reaction time tasks. We present results on a novel task, the Cued-Recall Retrieval Speed Task (CRRST), designed to simultaneously measure level and speed of retrieval. A total of 390 older adults (mean age, 80.2 years), learned 16 words based on corresponding categorical cues. In the retrieval phase, we measured accuracy (% correct) and retrieval speed/reaction time (RT; time from cue presentation to voice onset of a correct response) across 6 trials. Compared to healthy elderly adults (HEA, n = 303), those with aMCI (n = 87) exhibited poorer performance in retrieval speed (difference = -0.13; p < .0001) and accuracy on the first trial (difference = -0.19; p < .0001), and their rate of improvement in retrieval speed was slower over subsequent trials. Those with aMCI also had greater within-person variability in processing speed (variance ratio = 1.22; p = .0098) and greater between-person variability in accuracy (variance ratio = 2.08; p = .0001) relative to HEA. Results are discussed in relation to the possibility that computer-based measures of cued-learning and processing speed variability may facilitate early detection of dementia in at-risk older adults.

Now is the Time to Improve Cognitive Screening and Assessment for Clinical and Research Advancement.

Wang et al. analyze Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment accuracy as screening tests for detecting dementia associated with Alzheimer's disease (AD). Such tests are at the center of controversy regarding recognition and treatment of AD. The continued widespread use of tools such as MMSE (1975) underscores the failure of advancing cognitive screening and assessment, which has hampered the development and evaluation of AD treatments. It is time to employ readily available, efficient computerized measures for population/mass screening, clinical assessment of dementia progression, and accurate determination of approaches for prevention and treatment of AD and related conditions.

Characterization of memory profile in idiopathic REM sleep behavior disorder.

OBJECTIVE: The present study aims to examine whether declarative memory dysfunction relates to impaired core memory mechanisms or attentional and executive dysfunction in idiopathic REM Sleep Behavior Disorder (iRBD). METHOD: In this observational, cross-sectional study, were enrolled 82 individuals with the diagnosis of iRBD according to the International Classification of Sleep Disorders and 49-matched healthy controls fulfilling inclusion criteria. All participants underwent two memory tasks, namely the Rey Auditory Verbal Learning Test (RAVLT) and Memory Binding Test (MBT), which include conditions of varying degrees of dependence on executive functioning, as well as different indicators of core memory processes (e.g., learning, retention, relational binding). RESULTS: We used Bayesian multivariate generalized linear model analysis to evaluate the effect of iRBD on memory performance controlled for effects of age and sex. Individuals with iRBD displayed worse memory performance in the delayed free recall task (b = -0.37, 95% PPI [-0.69, -0.05]), but not on delayed recognition of the same material. Their performance in cued recall tasks both in immediate and delayed conditions was in comparison to controls relatively spared. Moreover, the deficit in delayed free recall was mediated by attention/processing speed. CONCLUSIONS: In iRBD, we replicated findings of reduced free recall based on inefficient retrieval (retrieval deficit), which was small in terms of effect size. Importantly, the memory profile across measures does not support the presence of core memory dysfunction, such as poor learning, retention or associative binding.

Association of crossword puzzle participation with memory decline in persons who develop dementia.

Participation in cognitively stimulating leisure activities such as crossword puzzles may delay onset of the memory decline in the preclinical stages of dementia, possibly via its effect on improving cognitive reserve. We followed 488 initially cognitively intact community residing individuals with clinical and cognitive assessments every 12-18 months in the Bronx Aging Study. We assessed the influence of crossword puzzle participation on the onset of accelerated memory decline as measured by the Buschke Selective Reminding Test in 101 individuals who developed incident dementia using a change point model. Crossword puzzle participation at baseline delayed onset of accelerated memory decline by 2.54 years. Inclusion of education or participation in other cognitively stimulating activities did not significantly add to the fit of the model beyond the effect of puzzles. Our findings show that late life crossword puzzle participation, independent of education, was associated with delayed onset of memory decline in persons who developed dementia. Given the wide availability and accessibility of crossword puzzles, their role in preventing cognitive decline should be validated in future clinical trials.

Medial temporal lobe correlates of memory screening measures in normal aging, MCI, and AD.

UNLABELLED: This article aimed to study the correlations for both the Memory Impairment Screen (MIS) and the Free and Cued Selective Reminding Test (FCSRT) with regard to the volumetric measures of hippocampal formation and entorhinal cortex and to explore the effect size of these measures. METHODS: A total of 34 healthy controls, 24 participants with mild cognitive impairment (MCI), and 20 mild-to-moderate-staged Alzheimer disease (AD) participants underwent neuropsychological testing and magnetic resonance imaging (MRI). Global volumetric measures were obtained and hippocampal and entorhinal volumes were calculated. Spearman correlations were calculated between memory scores and brain volumes and an effect size analysis was performed. RESULTS: No significant correlations with global brain volumes were found. There were dissimilar correlations among groups regarding memory and hippocampal and entorhinal volumes. No significant relationships were observed in healthy controls. The MCI group reached the higher correlation indexes, up to r = .55. In AD, only one significant correlation was observed between the delayed score of the FCSRT and the left hippocampus. Effect size values were higher for memory tests than for MRI measures, reaching d = 4.3 for the delayed score of the FCSRT. CONCLUSIONS: Although the MIS did not reach the strong results of the FCSRT, it demonstrated a similar pattern to the FCSRT in correlational analysis. These results support the validity and usefulness of the MIS despite its brevity of application. Memory testing showed better discrimination among healthy controls, MCI, and AD participants than MRI measures by means of effect size analysis.

Memory impairment in Parkinson's disease: The retrieval versus associative deficit hypothesis revisited and reconciled.

OBJECTIVE: Our study explored the retrieval deficit and the associative deficit hypotheses of memory impairments in Parkinson's disease (PD). The former supports a memory deficit mediated by attention/executive dysfunctions, whereas the latter hypothesizes a hippocampal memory impairment in PD. METHOD: We studied 31 controls and 34 PD patients classified as PD with normal cognition (PD-NC; n = 18) and PD with mild cognitive impairment (PD-MCI; n= 16). To test the retrieval deficit hypothesis, we measured the performance in encoding, retention, and recognition in verbal and visual domains; to test the associative deficit hypothesis, we used a specific associative binding measure. Using resting-state functional-MRI, we compared the functional connectivity of different hippocampal subfields between PD patients and controls, and we related it to memory performance. RESULTS: Consistently with the retrieval deficit hypothesis, PD-MCI, and PD-NC, were impaired in free recall encoding and retention in comparison to controls, especially in the visual domain. However, as predicted by the associative deficit hypothesis, PD-MCI and, to a lesser extent, PD-NC, showed also significant associative and binding deficits in cued recall. Notably, PD patients compared to controls did not show structural differences, although they had lower connectivity between the anterior hippocampi and the precuneus/superior parietal cortex. Worse performance in memory was associated with a more severe disruption of the hippocampal connectivity. CONCLUSIONS: The pervasive pattern of memory impairment in PD supports both hypotheses. The interplay between the hippocampus, related to associative memory deficits, and the precuneus, related to attentional control, provides a neural signature that reconciles them. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Mild cognitive impairment: believe it or not?

Mild cognitive impairment (MCI) was previously defined as a transitional state that can precede dementia, but the condition and the rates of conversion remain controversial. MCI is now the focus of natural history studies, along with Alzheimer's disease (AD) prevention. The objective of our review will be to consider the question of whether MCI is a well enough established entity that it can be a diagnosis in medical practice and a valid target of Alzheimer's prevention therapy. MCI was originally defined by Petersen et al. (1999) as progressive memory loss, prodrome of Alzheimer's disease. More recently MCI has been expanded to other cognitive domains with other potential causes like normal aging, fronto-temporal dementia, and vascular dementia. Despite many consensus conferences, experts cannot agree on critical aspects of the MCI, particularly with respect to its clinical utility. Based on neuropsychological studies, a hippocampal memory profile has been proposed for MCI as prodromal AD. Further research is needed to advance these criteria. We have no doubt, however, that in the future, the diagnosis of AD as disease (not only a dementia syndrome) will be made in the early pre-dementia stage and will be drawn from a combination of neuropsychological, neuro-imaging and CSF biomarkers.

Novel Cognitive Paradigms for the Detection of Memory Impairment in Preclinical Alzheimer's Disease.

In spite of advances in neuroimaging and other brain biomarkers to assess preclinical Alzheimer's disease (AD), cognitive assessment has relied on traditional memory paradigms developed well over six decades ago. This has led to a growing concern about their effectiveness in the early diagnosis of AD which is essential to develop preventive and early targeted interventions before the occurrence of multisystem brain degeneration. We describe the development of novel tests that are more cognitively challenging, minimize variability in learning strategies, enhance initial acquisition and retrieval using cues, and exploit vulnerabilities in persons with incipient AD such as the susceptibility to proactive semantic interference, and failure to recover from proactive semantic interference. The advantages of various novel memory assessment paradigms are examined as well as how they compare with traditional neuropsychological assessments of memory. Finally, future directions for the development of more effective assessment paradigms are suggested.

Memory Binding Test Predicts Incident Dementia: Results from the Einstein Aging Study.

BACKGROUND: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI. OBJECTIVE: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study. METHODS: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12). RESULTS: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p = 0.006). MBT TIP remained a significant predictor of dementia (p = 0.0002) when adjusting for FCSRT-FR or CR-L1. CONCLUSIONS: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis.

Genetic Risk of Alzheimer's Disease: Three Wishes Now That the Genie is Out of the Bottle.

The availability and increasing popularity of direct-to-consumer genetic testing for the presence of an APOE4 allelle led the Alzheimer's Foundation of America Medical, Scientific and Memory Screening Advisory Board to identify three critical areas for attention: 1) ensure consumer understanding of test results; 2) address and limit potential negative consequences of acquiring this information; and 3) support linking results with positive health behaviors, including potential clinical trial participation. Improving access to appropriate sources of genetic counseling as part of the testing process is critical and requires action from clinicians and the genetic testing industry. Standardizing information and resources across the industry should start now, with the input of consumers and experts in genetic risk and health information disclosure. Direct-to-consumer testing companies and clinicians should assist consumers by facilitating consultation with genetic counselors and facilitating pursuit of accurate information about testing.

Abnormality of gait as a predictor of non-Alzheimer's dementia.

BACKGROUND: Neurologic abnormalities affecting gait occur early in several types of non-Alzheimer's dementias, but their value in predicting the development of dementia is uncertain. METHODS: We analyzed the relation between neurologic gait status at base line and the development of dementia in a prospective study involving 422 subjects older than 75 years of age who lived in the community and did not have dementia at base line. Cox proportional-hazards regression analysis was used to calculate hazard ratios with adjustment for potential confounding demographic, medical, and cognitive variables. RESULTS: At enrollment, 85 subjects had neurologic gait abnormalities of the following types: unsteady gait (in 31 subjects), frontal gait (in 12 subjects), hemiparetic gait (in 11 subjects), neuropathic gait (in 11 subjects), ataxic gait (in 10 subjects), parkinsonian gait (in 8 subjects), and spastic gait (in 2 subjects). During follow-up (median duration, 6.6 years), there were 125 newly diagnosed cases of dementia, 70 of them cases of Alzheimer's disease and 55 cases of non-Alzheimer's dementia (47 of which involved vascular dementia and 8 of which involved other types of dementia). Subjects with neurologic gait abnormalities had a greater risk of development of dementia (hazard ratio, 1.96 [95 percent confidence interval, 1.30 to 2.96]). These subjects had an increased risk of non-Alzheimer's dementia (hazard ratio, 3.51 [95 percent confidence interval, 1.98 to 6.24]), but not of Alzheimer's dementia (hazard ratio, 1.07 [95 percent confidence interval, 0.57 to 2.02]). Of non-Alzheimer's dementias, abnormal gait predicted the development of vascular dementia (hazard ratio, 3.46 [95 percent confidence interval, 1.86 to 6.42]). Among the types of abnormal gait, unsteady gait predicted vascular dementia (hazard ratio, 2.61), as did frontal gait (hazard ratio, 4.32) and hemiparetic gait (hazard ratio, 13.13). CONCLUSIONS: The presence of neurologic gait abnormalities in elderly persons without dementia at base line is a significant predictor of the risk of development of dementia, especially non-Alzheimer's dementia.

Leisure activities and the risk of dementia in the elderly.

BACKGROUND: Participation in leisure activities has been associated with a lower risk of dementia. It is unclear whether increased participation in leisure activities lowers the risk of dementia or participation in leisure activities declines during the preclinical phase of dementia. METHODS: We examined the relation between leisure activities and the risk of dementia in a prospective cohort of 469 subjects older than 75 years of age who resided in the community and did not have dementia at base line. We examined the frequency of participation in leisure activities at enrollment and derived cognitive-activity and physical-activity scales in which the units of measure were activity-days per week. Cox proportional-hazards analysis was used to evaluate the risk of dementia according to the base-line level of participation in leisure activities, with adjustment for age, sex, educational level, presence or absence of chronic medical illnesses, and base-line cognitive status. RESULTS: Over a median follow-up period of 5.1 years, dementia developed in 124 subjects (Alzheimer's disease in 61 subjects, vascular dementia in 30, mixed dementia in 25, and other types of dementia in 8). Among leisure activities, reading, playing board games, playing musical instruments, and dancing were associated with a reduced risk of dementia. A one-point increment in the cognitive-activity score was significantly associated with a reduced risk of dementia (hazard ratio, 0.93 [95 percent confidence interval, 0.90 to 0.97]), but a one-point increment in the physical-activity score was not (hazard ratio, 1.00). The association with the cognitive-activity score persisted after the exclusion of the subjects with possible preclinical dementia at base line. Results were similar for Alzheimer's disease and vascular dementia. In linear mixed models, increased participation in cognitive activities at base line was associated with reduced rates of decline in memory. CONCLUSIONS: Participation in leisure activities is associated with a reduced risk of dementia, even after adjustment for base-line cognitive status and after the exclusion of subjects with possible preclinical dementia. Controlled trials are needed to assess the protective effect of cognitive leisure activities on the risk of dementia.

Should older adults be screened for dementia? It is important to screen for evidence of dementia!

Multiple arguments for considering routine dementia screening have been presented. Furthermore, dementia diagnoses are widely unrecognized. As a result, persons with dementia are missing important clinical care and treatment interventions. By distinction, the problems of defining, diagnosing, and treating mild cognitive impairment (MCI) are not yet resolved, and MCI is not ready for a screening recommendation. Dementia screening approaches, including cognitive testing and functional assessment, must be evaluated on their scientific merits, including sensitivity and specificity for recognizing affected individuals in at-risk populations. Screening tests must be "cost-worthy", with the benefits of true-positive test results justifying the costs of testing and resolving false-positive cases, with due consideration for proper diagnostic evaluation and potential harms. With the tremendous number of new cases projected in the near future and the expected emergence of beneficial therapies, considerably more research is needed to develop more efficient screening systems.

Memory Binding Test Distinguishes Amnestic Mild Cognitive Impairment and Dementia from Cognitively Normal Elderly.

OBJECTIVE: We aimed to assess reliability and cross-sectional discriminative validity of the Memory Binding Test (MBT) to distinguish persons with amnestic cognitive impairment (aMCI) and dementia from cognitively normal elderly controls. METHOD: The MBT was administered to 20 participants with dementia, 31 with aMCI and 246 controls, who received the first administration of the MBT from May 2003 to December 2007, as a substudy of the community-based Einstein Aging Study (age range: 70+). The optimal index resulted from comparing the partial area under the receiver operating characteristic curves (ROC AUC) of four major MBT indices for specificities ≥0.70. Optimal cut-score of the optimal index was selected by maximizing the sum of sensitivity and specificity. Age and education effects were assessed using stratified cut-scores and adjusted logistic regression. Reliability was computed as intraclass correlation between scores at baseline and 1-year follow-up for participants who remained cognitively normal. RESULTS: Total number of Items recalled in the Paired condition (TIP) was elected the optimal index. TIP cut-score was ≤22 for differentiating aMCI alone (sensitivity = 0.74, specificity = 0.73) and aMCI and dementia combined (sensitivity = 0.84, specificity = 0.73) from controls. It was ≤17 for differentiating dementia from aMCI and controls (sensitivity = 0.95, specificity = 0.87). Age and education adjustments did not materially improve discriminative validity. The reliability of TIP was 0.77. CONCLUSIONS: MBT achieved moderate to good reliability. TIP had superior cross-sectional discriminative validity than the other MBT indices. We recommend using the empirical cut-score of TIP ≤22 for discriminating aMCI and dementia and ≤17 for discriminating dementia alone.

Should older adults be screened for dementia?

The question of whether to screen for dementia and Alzheimer's disease (AD) has been discussed in many forums throughout the world. Generally, medical advisory groups and policy-making groups have recognized the importance of early diagnosis but have uniformly avoided making recommendations to screen at-risk populations. This presentation reflects the support for reconsidering the importance of screening individuals at risk or above a certain age. In this statement, the majority of the authors support the consideration of dementia risk factors in individuals at age 50, with routine yearly screening after 75. Other authors remain concerned that the benefits of treatments of early disease do not yet support a general screening recommendation. These statements are made to encourage progress toward the development of a consensus regarding the widespread institution of screening policy. Accordingly, members of the worldwide scientific community are invited to add their perspective by contributing short commentaries (1500 words) on this subject.

Validation of the Argentine version of the Memory Binding Test (MBT) for Early Detection of Mild Cognitive Impairment.

BACKGROUND: "Forgetfulness" is frequent in normal aging and characteristic of the early stages of dementia syndromes. The episodic memory test is central for detecting amnestic mild cognitive impairment (MCI). The Memory Binding Test (MBT) is a simple, easy and brief memory test to detect the early stage of episodic memory impairment. OBJECTIVE: To validate the Argentine version of the MBT in a Latin American population and to estimate the diagnostic accuracy as a tool for early detection of MCI. METHODS: 88 subjects (46 healthy controls and 42 patients with amnestic MCI) matched for age and educational level were evaluated by an extensive neuropsychological battery and the memory binding test. RESULTS: A significantly better performance was detected in the control group; all MBT scales were predictive of MCI diagnosis (p<.01). The MBT showed high sensitivity (69%) and high specificity (88%), with a PPV of 93% and a NPV of 55% for associative paired recall. A statistically significant difference (c2=14,164, p<.001) was obtained when comparing the area under the curve (AUC) of the MBT (0.88) and the MMSE (0.70). CONCLUSION: The Argentine version of the MBT correlated significantly with the MMSE and the memory battery and is a useful tool in the detection of MCI. The operating characteristics of the MBT are well suited, surpassing other tests commonly used for detecting MCI.

"Esquecimento" é queixa frequente no envelhecimento normal e também ocorre nos primeiros estágios de síndromes demenciais. Testes de memória episódica são fundamentais para detectar comprometimento cognitivo amnéstico (CCL). O teste de Memória Associativa (Memory Binding Test-MBT) é um teste fácil e breve para detectar a fase inicial de perda de memória episódica. OBJETIVO: Validar a versão argentina do MBT e estimar a sua acurácia como instrumento diagnóstico para a detecção precoce do CCL. MÉTODOS: 88 indivíduos (46 controles saudáveis ​​e 42 pacientes com CCL amnéstico), emparelhados por idade e nível educacional, foram avaliados com extensa bateria neuropsicológica e o MBT. RESULTADOS: Um desempenho significativamente melhor foi detectada no grupo controle; todas as escalas do MBT foram preditivas do diagnóstico de CCL (p<0,01). O MBT apresentou alta sensibilidade (69%) e alta especificidade (88%), com valor preditivo (VP) positivo de 93% e e VP negativo de 55% para a recordação dos itens associados (associative paired recall). Diferença estatisticamente significativa (c2=14,164, p<0,001) foi obtida quando foram comparadas as áreas sob as curvas (AUC) do MBT (0,88) e o Mini-Exame do Estado Mental (MEEM) (0,70). CONCLUSÃO: A versão argentina do MBT correlacionou-se significativamente com o MEEM e com a bateria de memória e é uma ferramenta útil na detecção de CCL. As características operacionais do MBT são bem adequadas, superando outros testes usualmente utilizados para a detecção de CCL.

The Memory Binding Test: Development of Two Alternate Forms into Spanish and Catalan.

BACKGROUND: The Memory Binding Test (MBT) is emerging as a promising tool for the detection of subtle memory impairment suggestive of Alzheimer's disease (AD). For such a test to be widely accessed and used, the availability of both alternate forms and language adaptations is required. OBJECTIVES: To develop a thorough methodology for obtaining alternate forms (A and B) of the MBT in Spanish and Catalan and to assess their equivalence. METHOD: According to the original development of the test, frequency was taken as the lexical variable of reference for the Spanish and Catalan adaptations. A crossed design protocol by form and language was used to compare the MBT results in a sample of 290 cognitively normal middle-aged participants. Pairwise Intraclass Correlation Coefficients (ICCs) were calculated among the six possible combinations. RESULTS: The Spanish and Catalan lists of words for the MBT A and B resulting from the adaptation process as well as the original lists in English are presented. ICC indices for the comparisons between forms and languages ranged from 0.56 to 0.82. CONCLUSION: The MBT A and B in Spanish and Catalan showed similar outcomes and can be considered equivalent. Moreover, the thorough methodology presented here for the transcultural adaptation and equivalence study, could serve as a model for future adaptations of the MBT and other verbal tests.

Psychometric Properties of the Memory Binding Test: Test-Retest Reliability and Convergent Validity.

BACKGROUND: Episodic memory testing is fundamental for the diagnosis of Alzheimer's disease (AD). Although the Free and Cued Selective Reminding Test (FCSRT) is widely used for this purpose, it may not be sensitive enough for early detection of subtle decline in preclinical AD. The Memory Binding Test (MBT) intends to overcome this limitation. OBJECTIVES: To analyze the test-retest reliability of the MBT and its convergent validity with the FCRST. METHODS: 36 cognitively healthy participants of the ALFA Study, aged 45 to 65, were included for the test-retest study and 69 for the convergent analysis. They were visited twice in a period of 6 ± 2 weeks. Test-retest reliability was determined by the calculation of the intra-class correlation coefficient (ICC). Score differences were studied by computing the mean percentage of score variation between visits and visualized by Bland-Altman plots. Convergent validity was determined by Pearson's correlations. RESULTS: ICC values in the test-retest reliability analysis of the MBT direct scores ranged from 0.64 to 0.76. Subjects showed consistent practice effects, with mean amounts of score increasing between 10% and 26%. Pearson correlation between MBT and FCSRT direct scores showed r values between 0.40 and 0.53. The FCSRT displayed ceiling effects not observed in the MBT. CONCLUSIONS: The MBT shows adequate test-retest reliability and overall moderate convergent validity with the FCSRT. Unlike the FCSRT, the MBT does not have ceiling effects and it may therefore be especially useful in longitudinal studies, facilitating the measurement of subtle memory performance decline and the detection of very early AD.

Memory Binding Test Predicts Incident Amnestic Mild Cognitive Impairment.

BACKGROUND: The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly. OBJECTIVE: We aimed to assess the predictive validity of the MBT for incident aMCI. METHODS: In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately. RESULTS: Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR) = 2.44, 95% confidence interval: 1.30-4.56, p = 0.005). When varying the prediction window from 4-7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33-3.12, p: 0.0007-0.04). CONCLUSION: Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease.

Decreased neprilysin immunoreactivity in Alzheimer disease, but not in pathological aging.

Although evidence suggests that extensive cortical beta-amyloid (Abeta) deposition is essential in Alzheimer disease (AD), it is also detected in nondemented elderly individuals with pathologic aging (PA). Given evidence that neutral endopeptidase (NEP) or neprilysin, a key enzyme for clearance of Abeta, is decreased in AD, the goal of the present study was to determine if NEP was also decreased in PA. We measured NEP immunoreactivity in frontal cortex of 12 AD and six PA cases and compared this with 10 normal (N) elderly individuals. None had any significant other pathology, and they were similar with respect to age, sex, and postmortem delay. In addition, Abeta1-40 and Abeta1-42 were measured by enzyme-linked immunosorbent assay (ELISA), whereas tau, synaptophysin, and alpha-synuclein were measured on Western blots. The AD cases had more neuritic plaques, neurofibrillary tangles, higher Braak stage, and more tau immunoreactivity in frontal cortex than both PA and N. In contrast, both PA and AD had more senile plaques and Abeta1-42 than N. NEP immunoreactivity was decreased in AD but not in PA. The decrease was unlikely the result of neuronal or synaptic loss because NEP immunoreactivity in frontotemporal degeneration with comparable degrees of synaptic loss as the AD cases was not different from control subjects. Although NEP enzyme activity was decreased in approximately half the AD cases, on average, it was not decreased compared with N or PA. The results add further evidence that PA is distinct from AD and indicate that decreased Abeta degradation by NEP is unlikely to contribute significantly to amyloid deposition in PA or, in many cases, of AD.