Subtype of mild cognitive impairment and progression to dementia and death

BACKGROUND: Mild cognitive impairment (MCI) represents a common cognitive state between normal cognitive aging and dementia. There is limited information about the heterogeneity of MCI and how this heterogeneity may influence the clinical course of MCI. We determined the longitudinal course of subtypes of MCI and assessed the rate of progression to dementia and to death. METHODS: As part of the Alzheimer's Disease Research Centers of California, we studied 327 patients with MCI (250 with amnestic MCI, 34 with single nonmemory MCI, and 43 with multiple domain MCI) who were followed longitudinally. We determined if subtype of MCI was independently associated with time to dementia diagnosis and time to death using Cox proportional hazard models, and type of dementia using Fisher's exact test. RESULTS: Mean age of the patients with MCI was 72.9 +/- 9.3 years and mean Mini-Mental State Examination score was 25.7 +/- 4.3. After a mean follow-up of 3.1 years, 199 (65%) progressed to dementia and 80 (24%) died. After multivariate adjustment, compared to those with amnestic MCI, patients with single nonmemory or multiple subtype MCI were less likely to receive a diagnosis of dementia (HR = 0.60; 95% CI 0.35-1.05 and HR = 0.71; 95% CI 0.44-1.14) but more likely to die (HR = 2.57; 95% CI 1.13-5.84 and HR = 1.73; 95% CI 0.72-4.18), but these results were of borderline statistical significance. There were significant differences in the type of dementia diagnosed across MCI subtypes (p = 0.006). Among the patients who progressed to Alzheimer's disease, 76% had prior amnestic MCI; of the patients who progressed to vascular dementia, 50% had prior amnestic MCI; all patients who progressed to a frontal dementia syndrome had single nonmemory MCI previously. CONCLUSIONS: The majority of patients with MCI progressed to dementia and a significant proportion died. Subtype of MCI may influence rates of progression to death and to dementia and has a major influence on subsequent type of dementia diagnosis.     

Atrial fibrillation and risk of dementia in non-demented elderly subjects with and without mild cognitive impairment

OBJECTIVES: Mild cognitive impairment (MCI) is regarded as a precursor to dementia, but not all patients with MCI actually develop dementia. As Alzheimer and vascular dementia are thought to share many common etiopathogenetic mechanisms, we investigated whether the vascular risk factor atrial fibrillation affects the risk of conversion to dementia for different MCI subtypes diagnosed according to international criteria. METHODS: One hundred and eighty elderly outpatients with MCI and 431 elderly outpatients with a normal cognition were followed up for a mean of 3 and 4 years, respectively. The risk of conversion to dementia associated with atrial fibrillation was studied in both samples using a Cox proportional hazards model adjusted for socio-demographic and medical variables. RESULTS: Overall conversion rate to dementia was 10.5 (8.0-13.8 per 100 person-years) in the MCI group and 2.2 (1.5-3.1 per 100 person-years) in the normal cognition group. Atrial fibrillation was significantly associated with conversion to dementia [hazard ratio (HR): 4.63; 95% confidence interval: 1.72-12.46] in the MCI group but not in the cognitively normal group (HR: 1.10; 95% confidence interval: 0.40-3.03). DISCUSSION: Current diagnostic criteria for MCI subtypes define heterogeneous populations, but atrial fibrillation can be useful in identifying people with increased risk of conversion to dementia.     

A Single Baseline Amyloid Positron Emission Tomography Could Be Sufficient for Predicting Alzheimer’s Disease Conversion in Mild Cognitive Impairment

ObjectiveBaseline amyloid burden in mild cognitive impairment (MCI) has been linked to conversion to Alzheimer’s disease (AD), but the comparison of baseline and longitudinal changes in amyloid burden for predicting AD remains unresolved. The objectives of this study aimed to compare the prognostic ability of baseline and longitudinal changes in amyloid burden in MCI patients. MethodsSeventy-five individuals with MCI were recruited and examined annually by clinical interviews for a mean follow-up of 24 months (range, 11.6–42.0). [18F]Florbetaben positron emission tomography (PET) scans were performed. T1-weighted 3D volumes were acquired for co-registration, and to define regions of interest. We examined whether baseline and longitudinal amyloid burden changes can improve AD conversion by Cox proportional hazard model analysis and receiver operating characteristic (ROC) curve analysis. ResultsCox proportional hazards model analysis showed that baseline amyloid burden was significantly associated with increased risk of conversion to AD (hazard ratio [HR]=10.0; 95% confidence interval [CI], 1.15–85.39; p=0.04), but longitudinal amyloid burden changes was not (HR=0.2; 95% CI, 0.02–1.18; p=0.07). When predicting AD, longitudinal amyloid burden changes had better ROC accuracy of 65.2% (95% CI, 48.4–82.0) than baseline amyloid burden of 59.6% (95% CI, 40.3–79.0), without statistical significance in pairwise comparison. ConclusionA single baseline amyloid PET could be sufficient in the prediction of AD conversion in MCI.     

Mild cognitive impairment represents early-stage Alzheimer disease

BACKGROUND: Mild cognitive impairment (MCI) is considered to be a transitional stage between aging and Alzheimer disease (AD). OBJECTIVE: To determine whether MCI represents early-stage AD by examining its natural history and neuropathologic basis. DESIGN: A prospective clinical and psychometric study of community-living elderly volunteers, both nondemented and minimally cognitively impaired, followed up for up to 9.5 years. Neuropathologic examinations were performed on participants who had undergone autopsy. SETTING: An AD research center. PARTICIPANTS: All participants enrolled between July 1990 and June 1997 with Clinical Dementia Rating (CDR) scores of 0 (cognitively healthy; n = 177; mean age, 78.9 years) or 0.5 (equivalent to MCI; n = 277; mean age, 76.9 years). Based on the degree of clinical confidence that MCI represented dementia of the Alzheimer type (DAT), 3 subgroups of individuals with CDR scores of 0.5 were identified: CDR 0.5/DAT, CDR 0.5/incipient DAT, and CDR 0.5/uncertain dementia. MAIN OUTCOME MEASURE: Progression to the stage of CDR 1, which characterizes mild definite DAT. RESULTS: Survival analysis showed that 100% of CDR 0.5/DAT participants progressed to greater dementia severity over a 9.5-year period. At 5 years, rates of progression to a score of CDR 1 (or greater) for DAT were 60.5% (95% confidence interval [CI], 50.2%-70.8%) for the CDR 0.5/DAT group, 35.7% (95% CI, 21.0%-50.3%) for the CDR 0.5/incipient DAT group, 19.9% (95% CI, 8.0%-31.8%) for the CDR 0.5/uncertain dementia group, and 6.8% (95% CI, 2.2%-11.3%) for CDR 0/controls. Progression to greater dementia severity correlated with degree of cognitive impairment at baseline. Twenty-four of the 25 participants with scores of CDR 0.5 had a neuropathologic dementing disorder, which was AD in 21 (84%). CONCLUSIONS: Individuals currently characterized as having MCI progress steadily to greater stages of dementia severity at rates dependent on the level of cognitive impairment at entry and they almost always have the neuropathologic features of AD. We conclude that MCI generally represents early-stage AD.     

The Roles of Apathy and Depression in Predicting Alzheimer Disease: A Longitudinal Analysis in Older Adults With Mild Cognitive Impairment

ObjectiveApathy and depression have each been associated with an increased risk of conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).These symptoms often co-occur and the contribution of each to risk of AD is not clear.MethodsNational Alzheimer's Coordinating Center participants diagnosed with MCI at baseline and followed until development of AD or loss to follow-up (n = 4,932) were included. The risks of developing AD in MCI patients with neuropsychiatric symptoms (NPS) (apathy only, depression only, or both) were compared to that in those without NPS in a multivariate Cox regression survival analysis adjusting for baseline cognitive impairment, years of smoking, antidepressant use, and AD medication use.ResultsThirty-seven percent (N = 1713) of MCI patients developed AD (median follow-up 23 months). MCI patients with both apathy and depression had the greatest risk (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.17–1.61; p < 0.0001; Wald χ² = 14.70; df = 1). Those with apathy only also had a greater risk (HR = 1.24; 95% CI: 1.05–1.47; p = 0.01; Wald χ² = 6.22; df = 1), but not those with depression only (HR = 1.08; 95% CI: 0.95–1.22; p=0.25; Wald χ² = 1.30; df = 1). Post-hoc analyses suggested depression may exacerbate cognitive decline in MCI patients with apathy (odds ratio = 0.70; 95% CI 0.52–0.95; p = 0.02; Wald χ² = 5.28; df = 1), compared to those without apathy.ConclusionMCI patients with apathy alone or both apathy and depression are at a greater risk of developing AD compared to those with no NPS. Interventions targeting apathy and depression may reduce risk of AD.     

Progression of white matter hyperintensities in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia: a comparison with normal aging.

OBJECTIVE: The objective of this study was to investigate cross-sectional and longitudinal white matter hyperintensity (WMH) changes in older subjects with clinically diagnosed dementia. METHODS: Fluid-attenuated inversion recovery images were acquired one year apart in subjects with dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), Alzheimer disease (AD), and also healthy elderly comparison subjects. WMH volume was quantified using an automated technique. RESULTS: Baseline WMH (as a percent of brain volume) was significantly greater compared with healthy subjects (N=33, geometric mean WMH: 0.4%) in subjects with AD (N=23 [1.3%], analysis of variance post hoc p <0.001) but not PDD (N=13 [0.6%]) or DLB (N=14 [0.4%]). Increase in WMH volume (as a percent of brain volume) was not significantly different (Kruskal-Wallis p=0.4) between groups (AD median change: 0.08%; DLB: 0.025%; PDD: 0.07%, healthy: 0.02%). Severity of baseline WMH, rather than diagnosis or severity of dementia, was a significant predictor of lesion progression. Rate of change of WMH had no association with change in global cognitive performance. CONCLUSIONS: Significant WMH progression occurs in degenerative dementias with rates influenced by severity of lesions at baseline rather than dementia type or cognitive decline.     

Risk factors of transition from mild cognitive impairment to Alzheimer's disease and death: A cohort study

BackgroundKnowledge of risk factors is essential for developing strategies that prevent or minimise transitions from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and death. The aim of this study was to assess risk factors for progression to AD and death among Chinese individuals with cognitive impairment.MethodsWe conducted a multisite, population-based cohort study on 437 community-dwelling elderly MCI residents in Taiyuan, China from 2010 to 2014. MCI, AD, death from AD and death from a cause other than AD were specified as disease states during the natural history of dementia. Transition-specific Cox model was fitted and hazard ratio (HR) with 95% confidence intervals (CIs) was estimated.ResultsAnalyses showed that risk factors played different roles in affecting transitions to AD and death. Risk factors for transition from MCI to AD were being female (HR: 1.82; 95%CI: 1.20–2.77), older age (HR: 3.09; 95%CI: 1.81–5.25), reading occasionally (HR: 1.79; 95%CI: 1.11–2.89), current smoking (HR: 1.74; 95%CI: 1.15–2.65), light–moderate alcohol drinker (HR: 2.24; 95%CI: 1.42–3.53), cerebrovascular disease (HR: 2.70; 95%CI: 1.68–4.34), hyperlipidemia (HR: 1.87; 95%CI: 1.16–3.02) and diabetes (HR: 1.81; 95%CI: 1.18–2.77). Only cerebrovascular disease (HR: 3.04; 95%CI: 1.22–7.58) was a significant risk factor for transition from MCI to death from a cause other than AD. Older age (HR: 10.68; 95%CI: 1.16–97.93) and low level education (HR: 0.14; 95%CI: 0.05–0.44) were significant predictors for transition from AD to death from a cause other than AD.ConclusionsParticipants with advanced age, low-level education, history of harmful alcohol consumption or smoking, cerebrovascular disease, hyperlipidemia, diabetes or who were female were at increased risk of transitioning to AD or death. Strategies to control modifiable risk factors in specific disease stage should be implemented to decrease the conversion to AD or death among Chinese patients with MCI.     

Supplemental use of antioxidant vitamins and subsequent risk of cognitive decline and dementia

There are conflicting reports about the potential role of vitamin antioxidants in preventing and/or slowing the progression of various forms of cognitive impairment including Alzheimer's disease (AD). We examined longitudinal data from the Canadian Study of Health and Aging, a population-based, prospective 5-year investigation of the epidemiology of dementia among Canadians aged 65+ years. Our primary objective was to examine the association between supplemental use of antioxidant vitamins and subsequent risk of significant cognitive decline (decrease in 3MS score of 10 points or more) among subjects with no evidence of dementia at baseline (n=894). We also explored the relationship between vitamin supplement use and incident vascular cognitive impairment (VCI; including a diagnosis of vascular dementia, possible AD with vascular components and VCI but not dementia), dementia (all cases) and AD. After adjusting for potential confounding factors assessed at baseline, subjects reporting a combined use of vitamin E and C supplements and/or multivitamin consumption at baseline were significantly less likely (adjusted OR 0.51; 95% CI 0.29-0.90) to experience significant cognitive decline during a 5-year follow-up period. Subjects reporting any antioxidant vitamin use at baseline also showed a significantly lower risk for incident VCI (adjusted OR 0.34, 95% CI 0.13-0.89). A reduced risk for incident dementia or AD was not observed. Our findings suggest a possible protective effect for antioxidant vitamins in relation to cognitive decline but randomized controlled trials are required for confirmation.     

Non-native language use and risk of incident dementia in the elderly

Cognitive reserve is invoked to explain the protective effects of education and cognitively-stimulating activities against all-cause dementia and Alzheimer's disease (AD). For non-native English speakers (n-NES), speaking English may be a cognitive activity associated with lower dementia risk. We hypothesized that n-NES have lower risk of incident dementia/AD and that educational level might modify this relationship. Participants took part in the Einstein Aging Study (Bronx, NY), a longitudinal study of aging and dementia. All (n = 1779) spoke fluent English and self-reported birthplace and whether English was their first language. n-NES additionally reported mother tongue, age of English acquisition, and current percentile-use of a non-English language. Nested Cox proportional hazards models progressively adjusted for gender, race, education, and immigrant and marital status estimated hazard ratios (HR) for incident dementia/AD as a function of n-NES status. 390 (22%) participants were n-NES. 126 incident dementia cases occurred during 4174 person-years of follow-up (median 1.44; range 0-16); 101 individuals met criteria for probable/possible AD. There was no statistically-significant association between n-NES status and incident dementia in the fully-adjusted model (HR 1.26; 95% CI 0.76-2.09; p = 0.36). Results were similar for AD. Stratification of education into three groups revealed increased risk of dementia for n-NES with ≥ 16 years of education (HR 3.97; 95% CI 1.62-9.75; p = 0.003). We conclude that n-NES status does not appear to have an independent protective effect against incident dementia/AD, and that n-NES status may contribute to risk of dementia in an education-dependent manner.     

Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study

BACKGROUND: It remains unknown whether depression and apolipoprotein E genotype are risk factors for incident mild cognitive impairment (MCI). OBJECTIVE: To determine whether elderly individuals with depression (measured by the short Geriatric Depression Scale) are at increased risk of developing incident MCI. DESIGN: Prospective cohort study. SETTING: Primary care clinic. PARTICIPANTS: A cohort of 840 cognitively normal elderly subjects without depression at recruitment who were followed up prospectively for a median of 3.5 years (range, 0.4-12.8 years). Subjects who developed depression (score of >/=6 on the short Geriatric Depression Scale; depression cohort) were compared with all remaining subjects (referent cohort). MAIN OUTCOME MEASURES: Incidence of MCI (primary outcome) and incidence of MCI or dementia (composite secondary outcome). RESULTS: Individuals in the depression cohort were at significantly increased risk of subsequent incident MCI (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1) after adjusting for age (time scale), sex, and education, and considering dementia as a competing outcome. The association was stronger in men but did not vary by severity of depression. We observed a synergistic interaction between apolipoprotein E genotype (epsilon3/epsilon4 or epsilon4/epsilon4) and depression (joint effect HR, 5.1; 95% CI, 1.9-13.6; test for additive interaction, P = .03). We found a similar association between depression and the subsequent composite outcome of incident MCI or dementia (HR, 2.6; 95% CI, 1.6-4.3). CONCLUSIONS: Cognitively normal elderly individuals who develop depression are at increased risk of subsequent MCI. We found a synergistic interaction between depression and apolipoprotein E genotype.     

Cerebrospinal fluid tau protein and periventricular white matter lesions in patients with mild cognitive impairment: implications for 2 major pathways

BACKGROUND: Mild cognitive impairment (MCI) may be a heterogeneous condition rather than a uniform disease entity. OBJECTIVE: To develop reliable tools that aid in identifying patients at risk of developing Alzheimer disease (AD) among heterogeneous populations with MCI to maximize the benefits of emerging therapies for AD. DESIGN: A 2-year prospective study. SETTING: Clinical follow-up in an outpatient memory clinic. PATIENTS: Seventy-two consecutive older patients with memory complaints. MAIN OUTCOME MEASURES: Cerebrospinal fluid tau levels, severity of periventricular and deep white matter lesions, silent brain infarction on magnetic resonance imaging, plasma homocysteine levels, apolipoprotein E genotype, and other vascular risk factors were assessed at baseline. RESULTS: Fifty-seven patients were diagnosed as having amnestic MCI. Forty-one patients with (AD-converted MCI group) or without (progressive MCI group) conversion to dementia and AD progressed over time, whereas the other 16 patients remained cognitively stable (stable MCI group). The stable MCI group was characterized by normal cerebrospinal fluid tau levels and a high grade of periventricular white matter lesions (PWMLs). The progressive MCI and AD-converted MCI groups had increased cerebrospinal fluid tau levels and low grades of PWMLs. A logistic regression model showed that age was significantly associated with developing PWMLs (P =.03; odds ratio, 1.15; 95% confidence interval, 1.0-1.3). CONCLUSIONS: Tau-related AD pathologic conditions and possibly ischemic PWMLs represent 2 major etiologies in the development of MCI, reflecting heterogeneity in the clinical progression. Because the progressive type of MCI may be a primary target of clinical trials that aim at secondary prevention of dementia, these patients should be identified by appropriate biomarkers and neuroimaging techniques.     

Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study

OBJECTIVE: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. METHODS: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.     

Incidence and risk factors for mild cognitive impairment: a population-based three-year follow-up study of cognitively healthy elderly subjects

BACKGROUND: Mild cognitive impairment (MCI) has attracted considerable interest as a potential predictor of Alzheimer's disease (AD). Both the apolipoprotein E (ApoE) epsilon4 allele and vascular factors have been associated with a higher risk for AD, recently they have also been linked to the risk of MCI. OBJECTIVES: To estimate the incidence of MCI among cognitively healthy elderly subjects during a 3-year follow-up, and to evaluate the impact of demographic and vascular factors as well as the ApoE epsilon4 allele on the conversion to MCI. METHODS: At baseline, the cognitive abilities of 806 out of 1,150 eligible subjects (aged 60-76 years) from a population-based sample were examined. Cognitively intact subjects (n = 747) were followed for an average of 3 years. RESULTS: 66 subjects (8.8%) had converted to MCI. The global incidence rate of MCI was 25.94/1,000 person-years. Persons with higher age (OR 1.08, 95% CI 1.01-1.16), ApoE epsilon4 allele carriers (OR 2.04, 95% CI 1.15-3.64) and persons with medicated hypertension (OR 1.86, 95% CI 1.05-3.29) were more likely to convert to MCI than those individuals of lower age and without an ApoE epsilon4 allele or medicated hypertension. Persons with high education (OR 0.79, 95% CI 0.70-0.89) were less likely to convert to MCI than persons with low or no education. In subjects with both the ApoE epsilon4 allele and medicated hypertension, the crude OR for conversion was 3.92 (95% CI 1.81-8.49). In subjects with cardiovascular disease, the crude OR for conversion was 2.13 (95% CI 1.26-3.60). Gender, elevated blood pressure, diabetes or cerebrovascular disease had no significant effect on the conversion to MCI. CONCLUSION: Higher age, the presence of at least one ApoE epsilon4 allele and medicated hypertension are independent risk factors, but high education is a protective factor for MCI. The results suggest that vascular factors may have an important role in the pathogenesis of MCI.     

Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment

CONTEXT: Cerebrospinal fluid tau protein and beta-amyloid 42 (Abeta42) protein are altered even in very mild Alzheimer disease (AD). So far, few data exist for subjects with mild cognitive impairment (MCI). OBJECTIVE: To investigate the potential of cerebrospinal fluid tau and Abeta42 for predicting progression from MCI to AD in a longitudinal study of 28 patients with MCI who received follow-up for 18 months. DESIGN: An 18-month prospective study. SETTING: Clinical follow-up study of community-residing subjects with MCI. MAIN OUTCOME MEASURES: Cerebrospinal fluid tau and Abeta42 concentrations were measured using enzyme-linked immunosorbent assay at baseline. The potential of both biomarkers was evaluated to predict the progression to dementia, the end point of this study, using multiple logistic regression analysis. RESULTS: Of 28 subjects with MCI, 12 progressed to dementia (2 to frontotemporal dementia; 10 to AD). Six subjects had progressive MCI, and 10 subjects showed stable MCI. Cerebrospinal fluid tau levels were significantly elevated in patients who progressed to probable AD (P =.002) and subjects with progressive MCI (P =.003) compared with subjects who had stable MCI. Cerebrospinal fluid Abeta42 levels were significantly lower in patients who progressed to probable AD (P =.007) and those with progressive MCI (P =.04) than in subjects with stable MCI. Logistic regression analysis identified elevated tau protein level as a predictor of cognitive deterioration (P =.02), whereas a delayed verbal recall score at baseline was significantly associated with the development of probable AD (P =.03). CONCLUSION: Our results indicate that altered tau and Abeta42 concentrations may be detectable in subjects who are clinically diagnosed as having MCI but demonstrate the pathological changes of AD.     

Neuropsychological prediction of conversion to Alzheimer disease in patients with mild cognitive impairment

CONTEXT: The likelihood of conversion to Alzheimer disease (AD) in mild cognitive impairment (MCI) and the "optimal" early markers of conversion need to be established. OBJECTIVES: To evaluate conversion rates to AD in subtypes of MCI and to identify neuropsychological measures most predictive of the time to conversion. DESIGN: Patients were followed up semiannually and controls annually. Subtypes of MCI were determined by using demographically adjusted regression norms on neuropsychological tests. Survival analysis was used to identify the most predictive neuropsychological measures. SETTING: Memory disorders clinic. PARTICIPANTS: One hundred forty-eight patients reporting memory problems and 63 group-matched controls. MAIN OUTCOME MEASURE: A consensus diagnosis of probable AD. RESULTS: At baseline, 108 patients met criteria for amnestic MCI: 87 had memory plus other cognitive domain deficits and 21 had pure memory deficits. The mean duration of follow-up for the 148 patients was 46.6 +/- 24.6 months. In 3 years, 32 (50.0%) of 64 amnestic-"plus" and 2 (10.0%) of 20 "pure" amnestic patients converted to AD (P = .001). In 148 patients, of 5 a priori predictors, the percent savings from immediate to delayed recall on the Selective Reminding Test and the Wechsler Adult Intelligence Scale-Revised Digit Symbol Test were the strongest predictors of time to conversion. From the entire neuropsychological test battery, a stepwise selection procedure retained 2 measures in the final model: total immediate recall on the Selective Reminding Test (odds ratio per 1-point decrease, 1.10; 95% confidence interval, 1.05-1.14; P < .0001) and Digit Symbol Test coding (odds ratio, 1.06; 95% confidence interval, 1.01-1.11; P = .01). The combined predictive accuracy of these 2 measures for conversion by 3 years was 86%. CONCLUSIONS: Mild cognitively impaired patients with memory plus other cognitive domain deficits, rather than those with pure amnestic MCI, constituted the high-risk group. Deficits in verbal memory and psychomotor speed/executive function abilities strongly predicted conversion to AD.     

The new Alzheimer’s criteria in a naturalistic series of patients with mild cognitive impairment

To test the validity of the new diagnostic criteria for Alzheimer’s disease (AD) in a naturalistic series of patients with mild cognitive impairment (MCI). Ninety consecutive MCI patients were enrolled in a longitudinal study on the natural history of cognitive impairment. Medial temporal (MT) atrophy on MRI was defined as hippocampal volume below the fifth percentile of the distribution in healthy elders, abnormal CSF was based on Sjogren’s cutoffs for Abeta42 and tau, and temporoparietal hypometabolism on 18F-FDG PET based on Herholz’s t sum score. Patients were followed clinically to detect conversion to AD (MCI-AD), non-AD dementia (MCI-nAD), or no conversion (MCI-NC). The 24 MCI-AD and 15 MCI-nAD patients had sociodemographic, clinical, and neuropsychological baseline features similar to the 51 MCI-NC patients. All MCI patients with MT atrophy converted to AD, as did all those with abnormal CSF, but only 48 and 35% of those without MT atrophy or abnormal CSF converted (p on logrank test = 0.0007 and 0.001). Prediction of AD conversion was enhanced when positivity to either MT atrophy or abnormal CSF was considered, with only 15% of those MCI patients negative on both converting to AD (p < 0.0005). Markers were not predictive of non-AD dementia conversion. The accuracy of either MT atrophy or abnormal CSF in discriminating MCI-AD from MCI-NC was good (AUC 0.82, 95% CI 0.70–0.95). MT atrophy and abnormal CSF are the single most robust predictors of conversion to AD in MCI patients, and their combination enhances prediction. AD markers are not predictive of conversion to non-AD dementia.     

Late-life depression as a risk factor for mild cognitive impairment or Alzheimer's disease in 30 US Alzheimer's disease centers

Identification of potentially modifiable risk factors for cognitive deterioration is important. We conducted a prospective study of 5,607 subjects with normal cognition and 2,500 subjects with mild cognitive impairment (MCI) at 30 Alzheimer's Disease Centers in the Unites States between 2005 and 2011. Cox regression was used to determine whether depression predicted transition from normal to MCI, or MCI to Alzheimer's disease (AD). Over an average of 3.3 visits, 15% of normal subjects transitioned to MCI (62/1000 per year), while 38% of MCI subjects transitioned to AD (146/1000 per year). At baseline, 22% of participants had recent (within the last two years) depression defined by clinician judgment; 9% and 17% were depressed using the Geriatric Depression Scale (GDS score ≥5) and the Neuropsychiatric Inventory Questionnaire (NPI-Q), respectively. At baseline, depressed subjects performed significantly worse on cognitive tests. Those always depressed throughout follow-up had an increased risk for progression from normal to MCI (RR = 2.35; 95% CI 1.93-3.08) versus never depressed. Normal subjects, identified as depressed at first visit but subsequently improved, were found to have lower risk of progression (RR 1.40 (1.01-1.95)). The 'always depressed' had only a modest increased risk of progression from MCI to AD (RR = 1.21 (1.00-1.46). Results were similar using time-dependent variables for depression or when defining depression via the GDS or NPI-Q. We found no effect of earlier depression (>2 years past). The effect of recent depression did not differ by antidepressant treatment, APOE4 allele status, or type of MCI. In conclusion, late-life depression is a strong risk factor for normal subjects progressing to MCI.     

Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia

BACKGROUND: White matter hyperintensities (WMH) have an effect on cognition and are increased in severity among individuals with amnestic mild cognitive impairment (aMCI). The influence of WMH on progression of aMCI to Alzheimer's disease (AD) is less clear. METHODS: Data were drawn from a three-year prospective, double blind, placebo controlled clinical trial that examined the effect of donepezil or vitamin E on progression from aMCI to AD. WMH from multiple brain regions were scored on MR images obtained at entry into the trial from a subset of 152 study participants using a standardized visual rating scale. Cox proportional hazards models adjusting for age, education and treatment arm were used to investigate the role of WMH on time to progression. RESULTS: 55 of the 152 (36.2 %) aMCI subjects progressed to AD. Only periventricular hyperintensities (PVH) were related to an increased risk of AD within three years (HR = 1.59, 95 % CI = 1.24 - 2.05, p-value < 0.001). Correcting for medial temporal lobe atrophy or the presence of lacunes did not change statistical significance. CONCLUSION: PVH are associated with an increased risk of progression from aMCI to AD. This suggests that PVH, an MRI finding thought to represent cerebrovascular damage, contributes to AD onset in vulnerable individuals independent of Alzheimer pathology.     

The effect of MAPT H1 and APOE ε4 on transition from mild cognitive impairment to dementia

Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimer's disease (AD). We prospectively followed three longitudinal independent samples (total n=319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio =1.45; 95% CI=1.04-2.02; p=0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio=1.47; 95% CI= 1.06-2.04; p=0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio=2.24, 95% CI =1.40-3.58; p=0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-β and tau brain deposition.     

Impact of depressive symptoms on the rate of progression to dementia in patients affected by mild cognitive impairment. The Italian Longitudinal Study on Aging

BACKGROUND: Mild cognitive impairment (MCI) is often a prodromal of dementia and depressive symptoms have been suggested as risk factor for dementing disorders. We evaluated the possible impact of depressive symptoms on the rate of progression to dementia in MCI patients after a 3.5-year follow-up; and the interaction between depressive symptoms and vascular risk factors for conversion to dementia. METHODS: A total of 2,963 individuals from a sample of 5,632 65-84 year old subjects were evaluated at the first (1992-1993), and second survey (1995-1996) of the Italian Longitudinal Study on Aging (ILSA), a prospective cohort study. MCI and dementia were classified using current clinical criteria. Depressive symptoms were measured with the Geriatric Depression Scale. RESULTS: Among the 2,963 participants, 139 prevalent MCI patients were diagnosed at the first survey. During the 3.5-year follow-up, 14 MCI patients progressed to dementia, and we did not find any significant relationship between depressive symptoms and rate of progression to dementia (RR 1.42, 95% CI, 0.48-4.23, chi2 0.40, p < 0.53). No socio-demographic variables or vascular risk factors modified the association between depressive symptoms and conversion to dementia. CONCLUSIONS: In our population, depressive symptoms were not associated with the rate of progression to dementia in MCI patients. Our findings did not support a role of socio-demographic variables or vascular risk factors in the association of depressive symptoms and conversion to dementia.