This study examined the impact of age and apolipoprotein E (APOE) genotype on the rate of cognitive decline in non-demented elderly participants in a simulated Alzheimer’s disease (AD) primary prevention treatment trial carried out by the Alzheimer’s Disease Cooperative Study.
Cognitive tests were administered at baseline and at four subsequent annual evaluations to 417 non-demented participants (172 men, 245 women) between the ages of 74 and 93 (mean=79.13 ± 3.34). APOE genotyping was available for 286 of the participants.
Four-year decline was evident on measures of orientation, memory, executive function and language. Faster decline was evident in APOE ε4+ (a genetic risk factor for AD; n=73) than ε4− participants (n=213), even after controlling for education, gender, ethnicity, and baseline functional and cognitive abilities. This discrepancy increased with increasing age indicating an age X genotype interaction.
These results are consistent with population-based studies, and extend the findings to a carefully-screened sample that meets inclusion and exclusion criteria for an AD primary prevention trial. The interaction between age and APOE genotype on rate of decline suggests that preclinical disease may be over represented in olderε4+ individuals. Thus, APOE genotype and age should be considered in the design of AD primary prevention treatment trials.
Cognitive decline; Apolipoprotein E; Aging
The Alzheimer's Disease Cooperative Study Prevention Instrument Project is a longitudinal study that recruited 644 cognitively healthy older subjects (aged between 75 and 93 years, 58% women) at baseline and evaluated their cognitive change over 4 years. The study was structured like a clinical trial to anticipate a prevention trial and to determine the performance of novel trial instruments in a longitudinal non-interventional trial framework. Behavioral symptoms were assessed at baseline.
The existence of participant-reported behavioral symptoms at baseline predicted conversion to Clinical Dementia Rating scale score ≥0.5 over the 4-year period.
The results imply that early anxiety and depression may be harbingers of future cognitive decline, and that patients exhibiting such symptoms, even in the absence of co-occurring cognitive symptoms, should be closely followed over time.
Aging; Depression; Anxiety; Mild cognitive impairment; Alzheimer's disease
The current study examined the association between pulse pressure (PP) and CSF-based biomarkers for Alzheimer disease, including β-amyloid 1–42 (Aβ1–42) and phosphorylated tau (P-tau) protein, in cognitively normal older adults.
One hundred seventy-seven cognitively normal, stroke-free older adult participants (aged 55–100 years) underwent blood pressure assessment for determination of PP (systolic − diastolic blood pressure) and lumbar puncture for measurement of CSF Aβ1–42 and P-tau. Pearson correlations and multiple linear regression, controlling for age, sex, APOE genotype, and body mass index, evaluated the relationship between PP and Alzheimer disease biomarkers.
PP elevation was associated with increased P-tau (r = 0.23, p = 0.002), reduced Aβ1–42 (r = −0.19, p = 0.01), and increased P-tau to Aβ1–42 ratio (r = 0.27, p < 0.001). After controlling for covariates, PP remained associated with P-tau (β = 0.18, p = 0.0196) and P-tau to Aβ1–42 ratio (β = 0.0016, p < 0.001) but was no longer associated with Aβ1–42 (β = −0.1, p = 0.35). Post hoc multivariate analyses indicated that increased PP was associated with all biomarkers in younger participants (aged 55–70 years) (Aβ1–42: p = 0.050; P-tau: p = 0.003; P-tau to Aβ ratio: p = 0.0007) but not older participants (aged 70–100 years).
PP elevation is associated with increased CSF P-tau and decreased Aβ1–42 in cognitively normal older adults, suggesting that pulsatile hemodynamics may be related to amyloidosis and tau-related neurodegeneration. The relationship between PP and CSF biomarkers is age-dependent and observed only in participants in the fifth and sixth decades of life.
We sought cognitive event-related potential (ERP) biomarkers of “Preclinical Alzheimer’s disease” (Pre-AD) using an incidental verbal learning paradigm with high sensitivity to prodromal AD. Seven elderly persons, with normal cognition at the time of ERP recordings, but who showed subsequent cognitive decline or AD pathology at autopsy (n=5, mean Braak stage=2.8), were compared to 12 “robust” normal elderly (RNE) who remained cognitively normal (Mfollow-up=9.0 years). EEG was recorded during a word repetition paradigm (semantically congruous (50%) and incongruous target words repeat ~10–140 seconds later). The RNE P600 congruous word repetition ERP effects (New minus Old congruous words) were significantly larger than in Pre-AD (mean amplitudes = 3.28 vs. 0.10 µV, p= 0.04). High group discrimination (84%) was achieved (by a P600 amplitude cutoff of ~1.5 µV). Abnormal P600 word repetition effects in cognitively normal elderly persons may be an important sign of synaptic dysfunction and Preclinical AD.
Mild Cognitive Impairment; EEG; memory; Alzheimer’s disease; Event-related potentials
Subjective cognitive complaints are a criterion for the diagnosis of mild cognitive impairment (MCI), despite their uncertain relationship to objective memory performance in MCI. We aimed to examine self-reported cognitive complaints in subgroups of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) MCI cohort to determine whether they are a valuable inclusion in the diagnosis of MCI or, alternatively, if they contribute to misdiagnosis. Subgroups of MCI were derived using cluster analysis of baseline neuropsychological test data from 448 ADNI MCI participants. Cognitive complaints were assessed via the Everyday Cognition (ECog) questionnaire, and discrepancy scores were calculated between self- and informant-report. Cluster analysis revealed Amnestic and Mixed cognitive phenotypes as well as a third Cluster-Derived Normal subgroup (41.3%), whose neuropsychological and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker profiles did not differ from a “robust” normal control group. This cognitively intact phenotype of MCI participants overestimated their cognitive problems relative to their informant, whereas Amnestic MCI participants with objective memory impairment underestimated their cognitive problems. Underestimation of cognitive problems was associated with positive CSF AD biomarkers and progression to dementia. Overall, there was no relationship between self-reported cognitive complaints and objective cognitive functioning, but significant correlations were observed with depressive symptoms. The inclusion of self-reported complaints in MCI diagnostic criteria may cloud rather than clarify diagnosis and result in high rates of misclassification of MCI. Discrepancies between self- and informant-report demonstrate that overestimation of cognitive problems is characteristic of normal aging while underestimation may reflect greater risk for cognitive decline.
Mild cognitive impairment; Awareness; Cluster analysis; Diagnostic errors; Neuropsychology; Dementia; Alzheimer disease
We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this method’s susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of ‘true positive’ cases and removal of ‘false positive’ cases.
Alzheimer’s disease; Alzheimer’s Disease Neuroimaging Initiative; biomarker; cluster analysis; dementia; mild cognitive impairment; neuropsychology; progression
Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer's disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease.
To compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF.
Eighty-one participants (12 AD, 23 MCI, 46 NC) were compared on CVRi using voxel-wise analyses. Region-of-interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume.
Voxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior cingulate). MCI participants exhibited intermediate CVRi values within cortical and medial temporal areas. Significant CVRi clusters were larger and more widespread than those of parallel CBF analyses. Among MCI and AD participants, subcortical CVRi elevation was associated with lower Dementia Rating Scale score (r = −0.52, p = 0.001, for both thalamus and caudate), and caudate CVRi correlated with WML volume (r = 0.45, p = 0.001).
Cortical and subcortical CVRi is elevated in AD, particularly within the caudate and thalamus, where it is associated with decreased cognitive performance and increased WMLs. Findings suggest CVRi may play a role in cognitive decline and cerebrovascular disease in MCI and AD.
Alzheimer's disease; cerebral blood flow; cerebrovascular resistance; mild cognitive impairment
A secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer’s disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline.
The value of screening for cognitive impairment, including dementia and Alzheimer's disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimer's Foundation of America and the Alzheimer's Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient-centered management of dementia.
Alzheimer; Dementia; Screening; Detection; Health care; Policy; Priority; Quality; Medicare; Annual wellness visit; Cognitive impairment; Cost-benefit analysis; Management; Patient-centered
To compare patients with autopsy-confirmed Alzheimer’s disease (AD, #14) and Dementia with Lewy bodies (DLB) on the frequency of behaviors related to frontal systems dysfunction and the association of these behaviors with dementia severity.
Cross-sectional survey of longitudinal cohort.
University Alzheimer’s disease research center.
Volunteer sample of 19 DLB and 38 AD participants with autopsy-confirmed diagnoses, similar in age (DLB: 77.3, AD: 77.5), education (15.2, 14.7), and Mini-Mental State Examination (MMSE) score (20.6, 20.5), with impairment ranging from mild deficits to moderate dementia.
The Frontal Systems Behavior Scale (FrSBe)-Family Rating Form assessing patient apathy, disinhibition, and executive dysfunction by a knowledgeable informant.
A two-way analysis of variance with the FrSBe total as the dependent variable revealed a significant MMSE by diagnosis interaction (F(1,53)=9.34, p=.004). Mean FrSBe total for AD patients showed significant impairment across the range of dementia severity, while it was relatively preserved for DLB patients in early stage of disease. The interaction term showed the same pattern for the executive dysfunction (F(1,53)=7.62, p=.008), disinhibition (F(1,53)=4.90, p=.031), and apathy (F(1,53)=9.77, p=.003) subscales.
While frontal behavioral symptoms in AD patients were present regardless of stage of dementia, DLB patients showed significant frontal dysfunction only in later stages. Results suggest that frontal subcortical circuits associated with behaviors assessed by the FrSBe are affected early in AD but not until later stages in DLB. Assessing specific behaviors related to frontal systems, coupled with stage of cognitive decline, may aid in clinical differentiation of AD and DLB.
Dementia with Lewy bodies; Alzheimer’s disease; Frontal systems; Behavioral symptoms
The knowledge that one carries the apolipoprotein E (APOE) ε4 allele risk factor for Alzheimer’s disease was recently found to have little short-term psychological risk. The authors investigated the impact of knowledge of carrying the risk allele on subjective ratings of memory and objective memory test performance of older adults.
Using a nested case-control design, the authors administered objective verbal and visual memory tests and self-rating scales of memory function to 144 cognitively normal older adults (ages 52–89) with known APOE genotype who knew (ε4+, N=25; ε4−, N=49) or did not know (ε4+, N=25; ε4−, N=45) their genotype and genetic risk for Alzheimer’s disease prior to neuropsychological evaluation.
Significant genotype-by-disclosure interaction effects were observed on several memory rating scales and tests of immediate and delayed verbal recall. Older adults who knew their ε4+ genotype judged their memory more harshly and performed worse on an objective verbal memory test than did ε4+ adults who did not know. In contrast, older adults who knew their ε4− genotype judged their memory more positively than did ε4− adults who did not know, but these groups did not differ in objective memory test performance.
Informing older adults that they have an APOE genotype associated with an increased risk of Alzheimer’s disease can have adverse consequences on their perception of their memory abilities and their performance on objective memory tests. The patient’s knowledge of his or her genotype and risk of Alzheimer’s disease should be considered when evaluating cognition in the elderly.
Vascular risk factors and cerebral blood flow (CBF) reduction have been linked to increased risk of cognitive impairment and Alzheimer's disease (AD); however the possible moderating effects of age and vascular risk burden on CBF in late life remain understudied. We examined the relationships among elevated vascular risk burden, age, CBF, and cognition. Seventy-one non-demented older adults completed an arterial spin labeling MR scan, neuropsychological assessment, and medical history interview. Relationships among vascular risk burden, age, and CBF were examined in a priori regions of interest (ROIs) previously implicated in aging and AD. Interaction effects indicated that, among older adults with elevated vascular risk burden (i.e., multiple vascular risk factors), advancing age was significantly associated with reduced cortical CBF whereas there was no such relationship for those with low vascular risk burden (i.e., no or one vascular risk factor). This pattern was observed in cortical ROIs including medial temporal (hippocampus, parahippocampal gyrus, uncus), inferior parietal (supramarginal gyrus, inferior parietal lobule, angular gyrus), and frontal (anterior cingulate, middle frontal gyrus, medial frontal gyrus) cortices. Furthermore, among those with elevated vascular risk, reduced CBF was associated with poorer cognitive performance. Such findings suggest that older adults with elevated vascular risk burden may be particularly vulnerable to cognitive change as a function of CBF reductions. Findings support the use of CBF as a potential biomarker in preclinical AD and suggest that vascular risk burden and regionally-specific CBF changes may contribute to differential age-related cognitive declines.
aging; vascular risk factors; arterial spin labeling; cognition
Education may reduce risk of dementia through passive reserve, by increasing neural substrate. We tested the hypotheses that education is associated with thicker cortex and reduced rates of atrophy in brain regions related to literacy and intellectual ability. Healthy older adults and those with mild cognitive impairment were categorized into High (≥18 yrs) and Low (≤13 yrs) education groups. Higher education was associated with thinner cortices in several areas, but one-year atrophy rates in these areas did not differ by education group. These results do not support a passive reserve model in which early life education protects against dementia by increasing cortical thickness. Connectivity and synaptic efficiency, or other lifestyle factors may more directly reflect cognitive reserve.
Brain reserve; cortical thickness; education; hippocampal volume; literacy; Mild Cognitive Impairment (MCI); aging
The current study explored the value of visuospatial findings for predicting the occurrence of visual hallucinations (VH) in a sample of patients with Dementia with Lewy bodies (DLB) compared to patients with Alzheimer’s disease (AD).
Retrospective analysis of 55 autopsy-confirmed DLB and 55 demographically-similar, autopsy-confirmed AD cases determined whether severe initial visuospatial deficits on the WISC-R Block Design subtest predicted the development of VH. Visuospatial deficits were considered severe if Block Design z-scores were 2.5 or more standard deviations below the mean of a well-characterized normal control group (Severe-VIS; DLB: n=35, AD: n=26) and otherwise were considered mild (Mild-VIS; DLB: n=20, AD: n=29).
Forty percent of the Severe-VIS DLB group had baseline VH compared to 0% of Mild-VIS DLB patients. Only 8% of the Severe-VIS and 3% Mild-VIS AD patients had baseline VH. During the follow-up period (mean=5.0 years), an additional 61% of the Severe-VIS but only 11% of the Mild-VIS DLB patients developed VH. In that period, 38% of the Severe-VIS and 20% of the Mild-VIS AD patients developed VH. After considering initial MMSE score and rate of decline, logistic regression analyses found that performance on Block Design significantly predicted the presence of VH in the DLB group but not the AD group.
The presence of early, severe deficits on neuropsychological tests of visuospatial skill increases the likelihood that patients with suspected DLB will develop the prototypical DLB syndrome. The presence of such deficits may identify those DLB patients whose syndrome is driven by alpha-synuclein pathology rather than AD pathology and may inform treatment plans as well as future research.
Lewy body disease; Hallucinations, visual; Alzheimer’s disease; Visuospatial cognition
Given the importance of identifying dementia prodromes for future treatment efforts, we examined two methods of diagnosing mild cognitive impairment (MCI) and determined whether empirically-derived MCI subtypes of these diagnostic methods were consistent with one another as well as with conventional MCI subtypes (i.e., amnestic, non-amnestic, single-domain, multi-domain). Participants were diagnosed with MCI using either conventional Petersen/Winblad criteria (n = 134; >1.5 SDs below normal on one test within a cognitive domain) or comprehensive neuropsychological criteria developed by Jak et al. (2009) (n = 80; >1 SD below normal on two tests within a domain), and the resulting samples were examined via hierarchical cluster and discriminant function analyses. Results showed that neuropsychological profiles varied depending on the criteria used to define MCI. Both criteria revealed an Amnestic subtype, consistent with prodromal Alzheimer’s disease (AD), and a Mixed subtype that may capture individuals in advanced stages of MCI. The comprehensive criteria uniquely yielded Dysexecutive and Visuospatial subtypes, whereas the conventional criteria produced a subtype that performed within normal limits, suggesting its susceptibility to false positive diagnostic errors. Whether these empirically-derived MCI subtypes correspond to dissociable neuropathologic substrates and represent reliable prodromes of dementia will require additional follow-up.
Mild cognitive impairment; Amnestic MCI; Non-amnestic MCI; Dementia; Cluster analysis; Neuropsychology
To investigate which neuropsychological tests predict eventual progression to Alzheimer’s disease (AD) in both Hispanic and non-Hispanic individuals. Although our approach was exploratory, we predicted that tests that underestimate cognitive ability in healthy aging Hispanics might not be sensitive to future cognitive decline in this cultural group.
We compared first-year data of 22 older adults (11 Hispanic) who were diagnosed as cognitively normal but eventually developed AD (decliners), to 60 age- and education-matched controls (27 Hispanic) who remained cognitively normal. To identify tests that may be culturally biased in our sample, we compared Hispanic with non-Hispanic controls on all tests and asked which tests were sensitive to future decline in each cultural group.
Compared to age-, education-, and gender-matched non-Hispanic controls, Hispanic controls obtained lower scores on tests of language, executive function, and some measures of global cognition. Consistent with our predictions, some tests identified non-Hispanic, but not Hispanic, decliners (vocabulary, semantic fluency). Contrary to our predictions, a number of tests on which Hispanics obtained lower scores than non-Hispanics nevertheless predicted eventual progression to AD in both cultural groups (e.g., Boston Naming Test [BNT], Trails A and B).
Cross-cultural variation in test sensitivity to decline may reflect greater resistance of medium difficulty items to decline and bilingual advantages that initially protect Hispanics against some aspects of cognitive decline commonly observed in non-Hispanics with preclinical AD. These findings highlight a need for further consideration of cross-cultural differences in neuropsychological test performance and development of culturally unbiased measures.
preclinical Alzheimer’s disease; Spanish–English bilingual; Hispanic; verbal fluency; object naming
Temporal sequence learning is a critical aspect of episodic memory that may be dependent on the temporal and frontal lobes. Since amnestic mild cognitive impairment (aMCI) and normal aging may result in changes within the temporal and frontal lobes, the present study investigated temporal sequence learning in patients with aMCI, cognitively normal older adults, and young adults.
On each trial of a temporal sequence task, circles appeared one at a time at the end of each arm of a computerized radial 8-arm maze. Participants were asked to reproduce the temporal sequence by placing numbered circles (1-8) on the arms of the 8-arm maze. Participants were presented with the same fixed sequence on each trial until the sequence was replicated without any errors, or until 15 trials were presented.
Individuals with aMCI required significantly more trials to learn the temporal sequence compared to older adults (p <. 05). Older adults required significantly more trials to learn the sequence than young adults (p <. 05). Older adults and individuals with aMCI committed significantly more Trial 1 errors (p <. 05) than young adults; however, there were no significant differences between the aMCI and older adult groups on Trial 1.
The results suggest that temporal sequence learning deficits are detectable in aMCI. These deficits may disrupt a number of cognitive processes, such as episodic memory, that are important for the execution of daily activities. The results suggest that although temporal sequence learning declines with normal aging, this decline is greater in individuals who have a diagnosis of aMCI and are at higher risk for developing AD.
Using whole-brain pulsed arterial spin labeling magnetic resonance imaging, resting cerebral blood flow (CBF) was measured in 20 mild cognitive impairment (MCI; 11 ɛ3 and 9 ɛ4) and 40 demographically matched cognitively normal (CN; 27 ɛ3 and 13 ɛ4) participants. An interaction of apolipoprotein (APOE) genotype (ɛ3 and ɛ4) and cognitive status (CN and MCI) on quantified gray-matter CBF corrected for partial volume effects was found in the left parahippocampal and fusiform gyri (PHG/FG), right middle frontal gyrus, and left medial frontal gyrus. In the PHG/FG, CBF was elevated for CN ɛ4 carriers but decreased for MCI ɛ4 carriers. The opposite pattern was seen in frontal regions: CBF was decreased for CN ɛ4 carriers but increased for MCI ɛ4 carriers. Cerebral blood flow in the PHG/FG was positively correlated with verbal memory for CN ɛ4 adults (r=0.67, P=0.01). Cerebral blood flow in the left medial frontal gyrus was positively correlated with verbal memory for MCI ɛ4 adults (r=0.70, P=0.05). Findings support dynamic pathophysiologic processes in the brain associated with Alzheimer's disease risk and indicate that cognitive status and APOE genotype have interactive effects on CBF. Correlations between CBF and verbal memory suggest a differential neurovascular compensatory response in posterior and anterior cortices with cognitive decline in ɛ4 adults.
apolipoprotein E; arterial spin labeling; cognition; mild cognitive impairment
Neuropsychological studies have shown that patients with Frontotemporal dementia (FTD) perform worse than patients with Alzheimer’s disease (AD) on tests of conceptualization and verbal fluency, but better on tests of memory and visuospatial functions. However, it is not known if these distinct cognitive profiles are robust enough to be detected using a relatively brief dementia screening instrument such as the Mattis Dementia Rating Scale (MDRS). To address this issue, the MDRS subscale profiles of patients with autopsy-confirmed FTD (n = 17) or AD (n = 34) were compared. Results showed distinct cognitive profiles in which FTD patients performed worse than AD patients on the Initiation/Perseveration and Conceptualization subscales while performing better on the Memory and Construction subscales. The distinct subscale profiles correctly classified 85% of AD patients and 76% of FTD patients. Profiles were maintained in a subset of mildly-to-moderately demented patients (MDRS ≥ 105) and correctly classified 89% of these patients. In addition, FTD patients (mean = 30.0 points/year) declined faster than AD patients (mean = 14.8 points/year) on MDRS total and specific subscale scores. These results suggest that the MDRS may be a useful adjunct to other clinical measures for distinguishing FTD from AD and tracking the progression of the disorder.
Frontotemporal dementia; Alzheimer’s disease; Mattis Dementia Rating Scale; Rate of progression; Cognitive profile; Functional impairment
Increased susceptibility of the aging brain to both chronic stress and incipient dementia-related neuropathology may accelerate cognitive decline. We investigated associations between chronic stress and diagnostic change in 62 individuals (mean age=78.7) participating in an Alzheimer’s disease research center longitudinal study. Subjects, diagnosed at baseline as cognitively normal (CN) or Mild Cognitive Impairment (MCI) were followed an average of 2.5 years. Senior neurologists, blind to detailed measures of stress and cognition, assigned diagnoses annually. Logistic regression analyses assessed accuracy with which measures of stress (event-based ratings, cortisol levels) predicted conversion to MCI and dementia. Eleven individuals with MCI at baseline received a dementia diagnosis during follow-up. Sixteen converted from CN to MCI. Prolonged, highly stressful experiences were associated with conversion from MCI to dementia. The cortisol awakening response, with age and education, was associated with diagnostic change to MCI. Cortisol measures were not associated with progression from MCI to dementia, and there was no association between stressful experiences and change to MCI. Mechanisms associated with the transition from normal cognition to MCI may differ from those associated with diagnostic change to dementia. These findings could facilitate identification of interventional strategies to reduce risk of decline at different stages of susceptibility.
chronic stress; aging; Alzheimer’s disease; mild cognitive impairment; dementia; diurnal rhythm; cortisol awakening response
Bilinguals outperform monolinguals on measures of executive control, but it is not known how bilingualism introduces these advantages. To address this question, we investigated whether language-control failures increase with aging-related declines in executive control. Eighteen younger and 18 older Spanish-English bilinguals completed a verbal-fluency task, in which they produced words in 18 categories (9 in each language), and a flanker task. Performance on both tasks exhibited robust effects of aging, but cross-language and within-language errors on the verbal-fluency task differed in a number of ways. Within-language errors occurred relatively often and decreased with higher levels of education in both younger and older bilinguals. In contrast, cross-language intrusions (e.g., inadvertently saying an English word on a Spanish-language trial) were rarely produced, were not associated with education level, and were strongly associated with flanker-task errors in older but not younger bilinguals. These results imply that executive control plays a role in maintaining language selection, but they also suggest the presence of independent forces that prevent language-selection errors.
aging; bilingualism; lexical access; attention; frontal lobe
The current study investigated the relationship between bilingual language proficiency and onset of probable Alzheimer’s disease (AD) in 44 Spanish-English bilinguals at the UCSD Alzheimer’s Disease Research Center. Degree of bilingualism along a continuum was measured using Boston Naming Test (BNT) scores in each language. Higher degrees of bilingualism were associated with increasingly later age-of-diagnosis (and age of onset of symptoms), but this effect was driven by participants with low education level (a significant interaction between years of education and bilingualism) most of whom (73%) were also Spanish-dominant. Additionally, only objective measures (i.e., BNT scores), not self-reported degree of bilingualism, predicted age-of-diagnosis even though objective and self-reported measures were significantly correlated. These findings establish a specific connection between knowledge of two languages and delay of AD onset, and demonstrate that bilingual effects can be obscured by interactions between education and bilingualism, and by failure to obtain objective measures of bilingualism. More generally, these data support analogies between the effects of bilingualism and “cognitive reserve” and suggest an upper limit on the extent to which reserve can function to delay dementia.
Memory tests are sensitive to early identification of Alzheimer’s disease (AD) but less useful as the disease advances. However, assessing particular types of recognition memory may better characterize dementia severity in later stages of AD. We sought to examine patterns of recognition memory deficits in individuals with AD and mild cognitive impairment (MCI). Memory performance and global cognition data were collected from participants with AD (n=37), MCI (n=37), and cognitively intact older adults (normal controls, NC; n=35). One-way analyses of variance (ANOVAs) examined differences between groups on yes/no and forced-choice recognition measures. Individuals with amnestic MCI performed worse than NC and nonamnestic MCI participants on yes/no recognition, but were comparable on forced-choice recognition. AD patients were more impaired across yes/no and forced-choice recognition tasks. Individuals with mild AD (≥120 Dementia Rating Scale, DRS) performed better than those with moderate-to-severe AD (<120 DRS) on forced-choice recognition, but were equally impaired on yes/no recognition. There were differences in the relationships between learning, recall, and recognition performance across groups. Although yes/no recognition testing may be sensitive to MCI, forced-choice procedures may provide utility in assessing severity of anterograde amnesia in later stages of AD. Implications for assessment of insufficient effort and malingering are also discussed.
Recognition memory; Alzheimer’s disease; Mild cognitive impairment; Dementia severity; Neuropsychology
Functional magnetic resonance imaging (fMRI) of older adults at risk for Alzheimer’s disease (AD) by virtue of their cognitive (i.e., mild cognitive impairment [MCI]) and/or genetic (i.e., apolipoprotein E [APOE] ε4 allele) status demonstrate divergent brain response patterns during memory encoding across studies. Using arterial spin labeling MRI, we examined the influence of AD risk on resting cerebral blood flow (CBF) as well as the CBF and blood oxygenation level dependent (BOLD) signal response to memory encoding in the medial temporal lobes (MTL) in 45 older adults (29 cognitively normal [14 APOE ε4 carriers and 15 noncarriers]; 16 MCI [8 APOE ε4 carriers, 8 noncarriers]). Risk groups were comparable in terms of mean age, years of education, gender distribution, and vascular risk burden. Individuals at genetic risk for AD by virtue of the APOE ε4 allele demonstrated increased MTL resting state CBF relative to ε4 noncarriers, whereas individuals characterized as MCI showed decreased MTL resting state CBF relative to their cognitively normal peers. For percent change CBF, there was a trend toward a cognitive status by genotype interaction. In the cognitively normal group, there was no difference in percent change CBF based on APOE genotype. In contrast, in the MCI group, APOE ε4 carriers demonstrated significantly greater percent change in CBF relative to ε4 noncarriers. No group differences were found for BOLD response. Findings suggest that abnormal resting state CBF and CBF response to memory encoding may be early indicators of brain dysfunction in individuals at risk for developing AD.
Apolipoprotein E; cerebral blood flow; functional; hippocampus; magnetic resonance imaging; memory; mild cognitive impairment
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology