Alzheimer's & Dementia

We aimed to estimate the frequency of each AT(N) (β‐amyloid deposition [A], pathologic tau [T], and neurodegeneration [N]) profile in different clinical diagnosis groups and to describe the longitudinal change in clinical outcomes of individuals in each group.

Longitudinal change in clinical outcomes and conversion risk of AT(N) profiles are assessed using linear mixed‐effects models and multivariate Cox proportional‐hazard models, respectively.

Participants with A+T+N+ showed faster clinical progression than those with A−T−N− and A+T±N−. Compared with A−T−N−, participants with A+T+N± had an increased risk of conversion from cognitively normal (CN) to incident prodromal stage of Alzheimer's disease (AD), and from MCI to AD dementia. A+T+N+ showed an increased conversion risk when compared with A+T±N−.

The 2018 research framework may provide prognostic information of clinical change and progression. It may also be useful for targeted recruitment of participants with AD into clinical trials.

New marker‐based criteria for the diagnosis of Alzheimer's disease (AD) were recently proposed. We describe their operational translation in 144 consecutive patients referred to our Memory Clinic.

Visual ratings of hippocampal atrophy and of cortical glucose hypometabolism in magnetic resonance imaging and positron emission tomography, and concentrations of total tau and Aβ1‐42 in cerebrospinal fluid were assessed in 12 patients with subjective memory complaints (SMCs) (Mini‐Mental State Examination [MMSE] score, 28.0 ± 1.1 [mean ± SD]), 37 with mild cognitive impairment (MCI) (MMSE, 25.1 ± 3.6), 55 with AD (MMSE, 21.1 ± 3.5), and 40 with non‐AD dementia (MMSE, 21.6 ± 5.5).

The sensitivity for AD of each individual biomarker was higher (65% to 87%) than for MCI (18% to 50%). Each biomarker's specificity for SMC and non‐AD dementias was good to moderate (83% and 53%). Positivity for at least one marker increased the probability 38 times of belonging to the AD group (P < 0.0001).

The new diagnostic criteria can be operationalized in clinical routines, but longitudinal studies of MCI patients will need to assess the criteria's prognostic value.

Amyloid positron emission tomography (PET) has become an important tool to identify amyloid‐β (Aβ) pathology in Alzheimer's disease (AD) patients. Here, we determined the diagnostic value of the amyloid PET tracer [¹⁸F]flutemetamol in relation to Aβ pathology at autopsy.

[¹⁸F]flutemetamol PET was carried out in a cohort of 68 patients included in a [¹⁸F]flutemetamol amyloid PET imaging end‐of‐life study (GE067‐007). At autopsy, AD pathology was determined and Aβ plaque pathology was classified into phases of its regional distribution (0–5).

[¹⁸F]flutemetamol PET was universally positive in cases with advanced stage postmortem Aβ pathology (Aβ phases 4 and 5). Negative amyloid PET was universally observed in nondemented or non‐AD dementia cases with initial Aβ phases 1 and 2, whereas 33.3% of the phase 3 cases were positive.

[¹⁸F]flutemetamol amyloid PET detects primarily advanced stages of Aβ pathology in preclinical and symptomatic AD cases.

We evaluated the relationship between florbetapir‐F18 positron emission tomography (FBP PET) and cerebrospinal fluid (CSF) biomarkers.

Alzheimer's Disease Neuroimaging Initiative‐Grand Opportunity and Alzheimer's Disease Neuroimaging Initiative 2 (GO/2) healthy control (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia subjects with clinical measures and CSF collected ±90 days of FBP PET data were analyzed using correlation and logistic regression.

In HC and MCI subjects, FBP PET anterior and posterior cingulate and composite standard uptake value ratios correlated with CSF amyloid beta (Aβ_1–42) and tau/Aβ_1–42 ratios. Using logistic regression, Aβ_1–42, total tau (t‐tau), phosphorylated tau_181P (p‐tau), and FBP PET composite each differentiated HC versus AD. Aβ_1–42 and t‐tau distinguished MCI versus AD, without additional contribution by FBP PET. Total tau and p‐tau added discriminative power to FBP PET when classifying HC versus AD.

Based on cross‐sectional diagnostic groups, both amyloid and tau measures distinguish healthy from demented subjects. Longitudinal analyses are needed.

Cross‐sectional findings using the tau tracer [¹⁸F]THK5317 (THK5317) have shown that [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) data can be approximated using perfusion measures (early‐frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single PET study can provide both functional and molecular information.

We included 16 patients with Alzheimer's disease who completed follow‐up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed‐effects models and annual percentage change maps were used to examine longitudinal change.

Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317.

Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity.

Subjective memory complaints are common in the elderly. Although memory complaints are associated with an increased risk of Alzheimer's disease in persons with cognitive impairment as well as in persons with normal cognition, they are commonly considered of less importance than objective cognitive measures. We hypothesized that the clinical relevance of subjective memory complaints might vary with educational background.

The study was performed within the Rotterdam Study, a prospective population‐based cohort study among 7983 persons 55 years and older. Subjective memory complaints and level of education were assessed in the baseline interview (1990 to 1993). During a mean follow‐up of 9.0 years we identified 568 incident Alzheimer's disease patients. We estimated the association between subjective memory complaints and risk of dementia by means of Cox proportional hazard models.

The association between subjective memory complaints and risk of Alzheimer's disease varied across levels of education. The risk of Alzheimer's disease associated with subjective memory complaints was higher in highly educated persons (age‐ and sex‐adjusted hazard ratio, 2.33; 95% confidence interval [CI], 1.00–5.49) than in persons with a low education (age‐ and sex‐adjusted hazard ratio, 1.53; 95% CI, 1.15–2.05) (P value for interaction, .02). In highly educated persons without objective cognitive impairment (Mini‐Mental State Examination score, 29 or 30) the risk of Alzheimer's disease was highest (age‐ and sex‐adjusted hazard ratio, 2.98; 95% CI, 1.76–5.02).

Especially in persons with a high level of education who still perform well on formal cognitive tests, subjective memory complaints might be an important first sign of imminent Alzheimer's disease.

Because no effective curative approaches are available, preventive approaches in the field of Alzheimer's disease (AD) are needed. We present the design of the ongoing Multidomain Alzheimer Preventive Trial (MAPT) Study. Several previous studies suggested that many factors may be involved in the occurrence of AD at late ages. Because of the probable multifactorial nature of AD, it seems logical to initiate multidomain interventions to examine their potential synergistic effects. The MAPT Study aims to evaluate the efficacy of a multidomain intervention (nutritional, physical, and cognitive training) and omega 3 treatment in the prevention of cognitive decline in frail elderly persons aged 70 years or over. The study also collects imaging and biological data that could be used in future AD prevention and treatment trials.

The MAPT Study is a 3‐year, randomized, controlled trial conducted by university hospital practitioners specializing in memory disorders in four French cities (Bordeaux, Limoges, Montpellier, and Toulouse). The study plans to enroll 1200 frail elderly subjects on the basis of at least one of the following criteria: subjective memory complaint spontaneously expressed to a general practitioner, limitation in one instrumental activity of daily living (IADL), and slow walking speed. To demonstrate the protective effect of interventions, subjects are randomized into one of the following four groups: omega 3 alone, multidomain intervention alone, omega 3 plus multidomain intervention, or placebo (n = 300 each). The principal outcome measure is a change in cognitive function at 3 years, as determined by the Grober and Buschke Test.

The MAPT Study is the first preventive trial involving multidomain interventions. Final results should be available in 2013.

Biomarkers that have been developed largely for the study of patients with clinically diagnosed Alzheimer's disease (AD) can also be used in the study of cognitively normal individuals who may harbor underlying AD pathology.

A meeting of invited experts on AD biomarkers was held on November 11 and 12, 2004 to review currently available data and to discuss unmet needs for biomarker research in presymptomatic AD.

Neuroimaging biomarkers have been studied to some extent in subjects at risk for AD. These imaging techniques include volumetric magnetic resonance imaging and positron emission tomography using either fluorodeoxyglucose or newer ligands that bind directly to amyloid plaque. Similarly, biochemical measures from cerebrospinal fluid or other physiologic fluids are emerging as potentially useful tools. Such biomarkers may be used either as diagnostic tools or as indicators of disease severity when followed longitudinally. A clinical diagnosis of asymptomatic individuals using biomarkers and studies involving asymptomatic subjects may raise logistical and ethical concerns.

The technical development of biomarkers that are used for presymptomatic AD diagnosis and for longitudinally measuring disease severity is evolving rapidly. Ethical and privacy considerations must be made before such biomarkers can be applied routinely to asymptomatic populations.

Cognitive and/or memory impairment are the main clinical markers currently used to identify subjects at risk of developing dementia. This study aimed to explore the relationship between the presence of neuropsychiatric symptoms and dementia incidence.

We analyzed the association between neuropsychiatric symptoms and incident dementia in a cohort of 1355 Mexican older adults from the general population over 3 years of follow‐up, modeling cumulative incidence ratios using Poisson models.

Five neuropsychiatric symptoms were associated with incident dementia: delusions, hallucinations, anxiety, aberrant motor behavior, and depression. The simultaneous presence of two symptoms had a relative risk, adjusted for mild cognitive impairment, diabetes, indicators of cognitive function, and sociodemographic factors, of 1.9 (95% confidence interval, 1.2–2.9), whereas the presence of three to five, similarly adjusted, had a relative risk of 3.0 (95% confidence interval, 1.9–4.8).

Neuropsychiatric symptoms are common in predementia states and may independently contribute as risk factors for developing dementia.