Richard Mayeux

The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

The National Institute on Aging and the Alzheimers Association charged a workgroup with the task of revising the 1984 criteria for Alzheimers disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all‐cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial

The Dominantly Inherited Alzheimers Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimers disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimers disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

Altered DNA Methylation in Leukocytes with Trisomy 21

The primary abnormality in Down syndrome (DS), trisomy 21, is well known; but how this chromosomal gain produces the complex DS phenotype, including immune system defects, is not well understood. We profiled DNA methylation in total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with DS and normal controls and found gene-specific abnormalities of CpG methylation in DS, with many of the differentially methylated genes having known or predicted roles in lymphocyte development and function. Validation of the microarray data by bisulfite sequencing and methylation-sensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences in methylation (p<0.0001) for each of 8 genes tested: TMEM131, TCF7, CD3Z/CD247, SH3BP2, EIF4E, PLD6, SUMO3, and CPT1B, in DS versus control PBL. In addition, we validated differential methylation of NOD2/CARD15 by bisulfite sequencing in DS versus control T-cells. The differentially methylated genes were found on various autosomes, with no enrichment on chromosome 21. Differences in methylation were generally stable in a given individual, remained significant after adjusting for age, and were not due to altered cell counts. Some but not all of the differentially methylated genes showed different mean mRNA expression in DS versus control PBL; and the altered expression of 5 of these genes, TMEM131, TCF7, CD3Z, NOD2, and NPDC1, was recapitulated by exposing normal lymphocytes to the demethylating drug 5-aza-2′deoxycytidine (5aza-dC) plus mitogens. We conclude that altered gene-specific DNA methylation is a recurrent and functionally relevant downstream response to trisomy 21 in human cells.

Partial volume correction in quantitative amyloid imaging.

Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition.

Apolipoprotein E and familial longevity

Exceptional longevity is associated with substantial heritability. The ε4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ε2 allele with decreased mortality, although inconsistently. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n = 2307) and spouse controls (n = 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE ε4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p = 0.005 and OR, 0.70; p = 0.002) and the likelihood of carrying an APOE ε2 allele was higher (OR, 1.5; p = 0.007) among family members in the offspring generation than among their spouse controls. Our findings support the hypothesis that both reduction in the frequency of the ε4 allele and increase in the frequency of the ε2 allele contribute to longevity.

Cognitive function in families with exceptional survival

The authors investigated whether cognitive function may be used as an endophenotype for longevity by assessing the cognitive performance of a family-based cohort consisting of 1380 individuals from 283 families recruited for exceptional survival in field centers in Boston, New York, Pittsburgh, and Denmark. Cognitive performance was assessed in the combined offspring of the Long Life Family Study (LLFS) probands and their LLFS siblings as compared with their spouses cognitive performance. Our results indicate that the combined offspring of the LLFS probands and their siblings achieve significantly higher scores on both digit forward and backward tasks (p = 5 10(-5) and p = 8 10(-4) respectively) as well as on a verbal fluency task (p = 0.008) when compared with their spouse controls. No differences between groups were found for the other cognitive tests assessed. We conclude that LLFS family members in the offspring generation demonstrate significantly better performance on multiple tasks requiring attention, working memory, and semantic processing when compared with individuals without a family history of exceptional survival, suggesting that cognitive performance may serve as an important endophenotype for longevity.

Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Background To evaluate the prevalence rates of non-amnestic neurological symptoms of autosomal dominant Alzheimer’s disease (ADAD) in the DIAN Observational Study (DIAN–OBS) and the published literature. Analyses were conducted to clarify the prevalence of neurological manifestations of ADAD mutation carriers as a group. Methods Using the DIAN-OBS study database and 189 peer-reviewed publications on ADAD families, we extracted individual-level data on age of symptom onset, disease course from onset to death, and the presence of fourteen neurological findings that have been reported in association with ADAD and included symptomatic subjects only. The primary outcomes were the rates of various neurological symptoms and the contribution of age and specific mutations on the prevalence of the neurological symptoms. Analyses were done using descriptive statistics, comparisons of means and frequencies and multivariable linear regression. Findings Our meta-analysis dataset includes 1228 affected individuals, with detailed clinical descriptions of 753. The DIAN–OBS dataset included 107 individuals with detailed clinical data. The most prevalent non-amnestic cognitive manifestations in DIAN were those typical of mild-moderate Alzheimer’s disease, including visual agnosia (95% CI 45·7%–64·6%), aphasia (43·8%–62·7%), and behavioral changes (51·5%–70·0%). The prevalence of non-amnestic cognitive manifestations from the published literature were (95% CI 3·9%–7·2%) for visual agnosia, (20%–26%) for aphasia, and (28·4%–35·1%) for behavioral changes. Prevalence of non-cognitive neurological manifestations in DIAN was low, including myoclonus and spasticity (3·8%–15·0%), seizures (0·5%–9·1%) and moderate for parkinsonism (5·3%–17·1%). Whereas, in the published literature the prevalence was (95% CI 16·6%–22·2% and 12·5%–17·6%) for myoclonus and spasticity, (10·1%–15·0%) for parkinsonism, and (17·4%–23·2%) for seizures. Age of onset appears to influence the prevalence of several non-cognitive manifestations in both groups, stroke being more prevalent at older ages of onset with motor symptoms being more prevalent at younger age of onset and at an older age of onset. Further, symptoms were overall more common in later clinical stages of disease. Interpretation Comparing the prevalence of non-amnestic and non-cognitive clinical features in DIAN with the published literature indicates that previous reports of non-cognitive features are likely overestimated whereas DIAN identifies higher non-amnestic cognitive symptoms in addition to memory impairment. The non-cognitive clinical manifestations of AD appear to be in a minor fraction of mild-moderate ADAD and is likely influenced by disease severity, environmental and genetic factors in addition to genetic status. The results of this work clarify the clinical presentations of ADAD including the effects of age and disease stage. Attention to these neurologic symptoms and screening for ADAD mutations are warranted if present. Future work is needed to determine the factors which cause these neurologic symptoms.BACKGROUNDnAutosomal dominant familial Alzheimers disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD.nnnMETHODSnWe prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms.nnnFINDINGSnThe DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimers disease, including visual agnosia (55·1%, 95% CI 45·7-64·6), aphasia (57·9%, 48·6-67·3), and behavioural changes (61·7%, 51·5-70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9-7·2], aphasia [23·0%, 20·0-26·0], and behavioural changes [31·7%, 28·4-35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8-15·0), and seizures (2·8%, 0·5-5·9) and moderate for parkinsonism (11·2%, 5·3-17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6-22·2 and 15·0%, 12·5-17·6, respectively), parkinsonism (12·5%, 10·1-15·0), and seizures (20·3%, 17·4-23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04-1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90-0·97, p=0·0007; seizures 0·95, 0·92-0·98, p=0·0018; corticobulbar deficits 0·91, 0·86-0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74-0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease.nnnINTERPRETATIONnThe non-cognitive clinical manifestations of Alzheimers disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimers disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms.nnnFUNDINGnNational Institutes of Health and German Center for Neurodegenerative Diseases.

Exceptional memory performance in the Long Life Family Study

Research to understand variability at the highest end of the cognitive performance distribution has been scarce. Our aim was to define a cognitive endophenotype based on exceptional episodic memory (EM) performance and to investigate familial aggregation of EM in families from the Long Life Family Study (LLFS). Using a sample of 1911 nondemented offspring of long-lived probands, we created a quantitative phenotype, EM (memory z ≥ 1.5), and classified LLFS families as EM and non-EM families based on the number of EM offspring. We then assessed differences in memory performance between LLFS relatives in the parental generation of EM families and those in non-EM families using multivariate analysis adjusted for APOE Apolipoprotein E genotype. LLFS relatives in the proband generation from EM families showed better EM performance than those from non-EM families (β = 0.74, standard error = 0.19, p = 1.4 × 10(-4)). We demonstrated that there is a familial correlation of the EM endophenotype, suggesting that genetic variants might influence memory performance in long-lived families.

Common Genetic Variants on 6q24 Associated With Exceptional Episodic Memory Performance in the Elderly

IMPORTANCEnThere are genetic influences on memory ability as we age, but no specific genes have been identified.nnnOBJECTIVEnTo use a cognitive endophenotype, exceptional episodic memory (EEM) performance, derived from nondemented offspring from the Long Life Family Study (LLFS) to identify genetic variants that may be responsible for the high cognitive performance of LLFS participants and further replicate these variants using an additional 4006 nondemented individuals from 4 independent elderly cohorts.nnnDESIGN, SETTING, AND PARTICIPANTSnA total of 467 LLFS participants from 18 families with 2 or more offspring that exhibited exceptional memory performance were used for genome-wide linkage analysis. Adjusted multivariate linear analyses in the 40-megabase region encompassing the linkage peak were conducted using 4 independent replication data sets that included 4006 nondemented elderly individuals. Results of the individual replication cohorts were combined by meta-analysis.nnnMAIN OUTCOME MEASUREnEpisodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA.nnnRESULTSnHeritability estimates indicated a significant genetic component for EEM (h2 = 0.21; SE = 0.09). Genome-wide linkage analysis revealed that EEM was linked to the 6q24 region (maximum logarithm of odds score, 3.64). Association analysis in LLFS families identified single-nucleotide polymorphisms (SNPs) nominally associated with EEM in the 40-megabase window encompassing the linkage peak. Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P ≤ .05). Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SNPs rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P = .009 and P = .013, respectively). With meta-analysis restricted to individuals lacking an APOE ε4 allele, SNP rs6902875 became statistically significant (meta-analysis, P = 6.7 × 10-5). Haplotype analysis incorporating the 2 SNPs flanking rs6902875 (rs9321334 and rs4897574) revealed that the A-A-C haplotype was significantly associated with episodic memory performance (P = 2.4 × 10-5). This genomic region harbors monooxygenase dopamine β-hydroxylase-like 1 gene (MOXD1), implicated in the biosynthesis of norepinephrine, which is prominently involved in cognitive functions.nnnCONCLUSIONS AND RELEVANCEnThe results provide strong evidence for potential candidate genes related to EEM on 6q24. Identifying the genes will help in understanding the biological basis of memory performance and allow interventions for enhancement of cognitive function.

No association of ALOX5AP polymorphisms with risk of MRI-defined brain infarcts

The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene has been associated with stroke. The majority of the reported ALOX5AP associations have considered non-radiologically confirmed infarcts as the stroke phenotype. We assessed the association of genetic variants in ALOX5AP with stroke defined by the presence of infarcts on brain magnetic resonance imaging (MRI). We studied 202 persons with MRI-defined brain infarcts and 487 healthy individuals of Caribbean Hispanic ancestry. Another sample of European ancestry comprised 1823 persons with MRI-defined brain infarct and 7578 control subjects. Subjects were genotyped for the 4 single nucleotide polymorphisms (SNPs) that define ALOX5AP HapA haplotype. No association was found between SNPs and MRI-defined brain infarcts. Our data do not support the hypothesis that variants in ALOX5AP are associated with risk of MRI-defined brain infarcts.