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1.  Subtle Cognitive Decline and Biomarker Staging in Preclinical Alzheimer’s Disease 
The NIA-AA criteria for “preclinical” Alzheimer’s disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and “subtle cognitive decline,” which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define “subtle cognitive decline” using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.
PMCID: PMC4634634  PMID: 26402771
Alzheimer’s disease; Alzheimer’s Disease Neuroimaging Initiative; amyloid; biomarkers; cerebrospinal fluid; dementia; neurodegeneration; neuropsychology; preclinical Alzheimer’s disease; subtle cognitive decline
2.  Age and APOE genotype influence rate of cognitive decline in non-demented elderly 
Neuropsychology  2013;27(4):10.1037/a0032707.
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.
PMCID: PMC3831285  PMID: 23876113
Cognitive decline; Apolipoprotein E; Aging
3.  The Preclinical Alzheimer Cognitive Composite 
JAMA neurology  2014;71(8):961-970.
As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes.
To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study).
With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies.
For the 2 studies that collected data on Aβ levels (ADNI and AIBL), we estimate decline in a preclinical AD “Aβ-positive” placebo group and compare them with an “Aβ-negative” group. For the study that did not include data on Aβ levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-ɛ4 and by clinical progression.
In ADNI, Aβ-positive participants showed more decline than did Aβ-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, −1.239 [0.522] [95% CI, −2.263 to −0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (−1.009 [0.406] [95% CI, −1.805 to −0.213]; P = .01) and 36 months (−1.404 [0.452] [95% CI, −2.290 to −0.519]; P = .002). In the ADCS-PI study, APOE-ɛ4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, −0.742 [0.294] [95% CI, −1.318 to −0.165]; P = .01) and 36 months (−1.531 [0.469] [95% CI, −2.450 to −0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, −4.471 [0.702] [95% CI, −5.848 to −3.094]; P < .001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% α level, we project 80% power to detect effects in the range of Δ = 0.467 to 0.733 on the ADCS-PACC.
Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.
PMCID: PMC4439182  PMID: 24886908
4.  Pulse Pressure in Relation to Tau-Mediated Neurodegeneration, Cerebral Amyloidosis, and Progression to Dementia in Very Old Adults 
JAMA neurology  2015;72(5):546-553.
Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear.
To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia.
In this retrospective cohort study, 877 participants without dementia (55–91 years of age) from the Alzheimer’s Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1–42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months tracked progression to dementia.
Regression and analysis of covariance analyses investigated relationships between pulse pressure and distinct cerebral spinal fluid biomarker profiles. Very old participants (80 years or older) were compared with younger participants (55–79 years of age) on clinical measures and pulse pressure × age group interactions were investigated. Survival analysis examined the effect of baseline pulse pressure on progression to dementia. Covariates were age, sex, apolipoprotein E genotype, body mass index, vascular risk factors, and antihypertensive medication use.
Individuals with a P-tau-positive biomarker profile exhibited mean (SD) elevated pulse pressure regardless of age (62.0 [15.6]mmHg for a P-tau-positive biomarker vs 57.4 [14.0]mmHg for P-tau-negative biomarker; P = .04). In very old participants, a further increase in pulse pressure was observed in those exhibiting both P-tau elevation and β-amyloid 1–42 reduction vs either biomarkers alone (69.7 [16.0]mmHg for both positive biomarkers vs 63.18 [13.0]mmHg for P-tau alone vs 60.1 [16.4]mmHg for β-amyloid 1–42 alone vs 56.6 [14.5]mmHg for negative biomarkers; P = .003). Those with higher baseline pulse pressure progressed to dementia more rapidly (95%CI, 1.000–1.048; P = .05; hazard ratio = 1.024). Systolic pressure exhibited similar relationships with Alzheimer disease biomarkers and progression to dementia in the very old subgroup (P < .05) but showed no associations in the young old subgroup (P > .10). Diastolic pressure was reduced in young old participants with isolated phosphorylated tau elevation (P = .04).
Pulse pressure, an index of vascular aging, was associated with neurodegenerative change prior to the onset of dementia across a broad age range. Among those with more advanced age, higher pulse pressure was also associated with cerebral amyloidosis in the presence of neurodegeneration and more rapid progression to dementia. Diastolic contributions to these biomarker associations were limited to young old participants whereas systolic contributions were found only in very old participants.
PMCID: PMC4428938  PMID: 25822631
5.  APOE interacts with age to modify rate of decline in cognitive and brain changes in Alzheimer’s disease 
To determine (1) whether age-standardized cognitive declines and brain morphometric change differ between Young-Old (YOAD) and Very-Old (VOAD) patients with Alzheimer’s disease (AD) and (2) whether apolipoprotein E (APOE) genotype modifies these neuropsychological and morphometric changes.
Baseline and 12-month follow up neuropsychological and morphometric measures were examined for healthy control and AD individuals. The two AD groups were further divided into subgroups on the basis of the presence of at least one APOE ε4 allele.
The YOAD showed more severe deficits andsteeper declines in cognition than the VOAD. Moreover, the presence of an APOE ε4 allele had a more deleterious effect on the YOAD than the VOAD on cognition and brain structure both cross-sectionally and longitudinally.
Results underscore the importance of integrating an individual’s age and genetic susceptibility—and their interaction—when examining neuropsychological and neuroimaging changes in the early stages of Alzheimer’s disease.
PMCID: PMC3815680  PMID: 23896613
Alzheimer’s disease; APOE genotype; cognition; morphometry; MRI; longitudinal
6.  Which Language Declines More? Longitudinal versus Cross-Sectional Decline of Picture Naming in Bilinguals with Alzheimer’s Disease 
In this study, we investigated dual-language decline in non-balanced bilinguals with probable Alzheimer’s Disease (AD) both longitudinally and cross-sectionally. We examined patients’ naming accuracy on the Boston Naming Test (BNT: Kaplan et al., 1983) over three testing sessions (longitudinal analysis) and compared their performance to that of matched controls (cross-sectional analysis). We found different longitudinal and cross-sectional patterns of decline: Longitudinally, the non-dominant language seemed to decline more steeply than the dominant language, but, cross-sectionally, differences between patients and controls were larger for the dominant than for the non-dominant language, especially at the initial testing session. This differential pattern of results for cross-sectional versus longitudinal decline was supported by correlations between decline measures and BNT item characteristics. Further studies will be needed to better characterize the nature of linguistic decline in bilinguals with AD; however, these results suggest that representational robustness of individual lexical representations, rather than language membership, might determine the time course of decline for naming in bilinguals with AD.
PMCID: PMC4209950  PMID: 24725624
Alzheimer’s disease; bilinguals; picture naming; longitudinal; cross-sectional
7.  Tracking early decline in cognitive function in older individuals at risk for Alzheimer's disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument 
JAMA neurology  2015;72(4):446-454.
Several large-scale Alzheimer's disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic.
To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline.
Design, Setting, and Participants
Longitudinal study over the course of 48 months at participating Alzheimer's Disease Cooperative Study (ADCS) sites. The study included 468 healthy older individuals (Clinical Dementia Rating Scale [CDR] Global = 0, above cut-off on modified Mini-Mental State Exam and Free and Cued Selective Reminding Test) (mean age= 79.4 years ±3.6). All subjects and their study partners completed the Self and Partner CFI annually. Subjects also underwent concurrent annual neuropsychological assessment and apolipoprotein E (APOE) genotyping.
Main outcomes and measures
Comparison of CFI scores between clinical progressors (Clinical Dementia Rating Scale [CDR] ≥ 0.5) and non-progressors (CDR remained = 0), as well as between APOE ε4 carriers and non-carriers were performed. Correlations of change between the CFI and neuropsychological performance were assessed longitudinally.
At 48 months, group differences between clinical progressors and non-progressors were significant for CFI Self, CFI Partner, and CFI Self+Partner total scores. At month 48, APOE ε4 carriers showed greater progression than non-carriers on CFI Partner and CFI Self+Partner scores. Both CFI Self and CFI Partner scores were associated with longitudinal cognitive decline, although findings suggest self report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment.
Conclusions and Relevance
Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, yet informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.
PMCID: PMC4397164  PMID: 25706191
8.  The Multilingual Naming Test in Alzheimer’s Disease: Clues to the Origin of Naming Impairments 
The current study explored the picture naming performance of patients with Alzheimer’s disease (AD). First, we evaluated the utility of the Multilingual Naming Test (MINT; Gollan et al., 2011), which was designed to assess naming skills in speakers of multiple languages, for detecting naming impairments in monolingual AD and amnestic mild cognitive impairment (MCI). If the MINT were sensitive to linguistic impairment in AD, using it in clinical practice might have advantages over using tests exclusively designed for English monolinguals. We found that the MINT can be used with both monolinguals and bilinguals: A 32-item subset of the MINT is best for distinguishing monolingual patients from controls, while the full MINT is best for assessing degree of bilingualism and language dominance in bilinguals. We then investigated the cognitive mechanisms underlying naming impairment in AD. To this end, we explored which MINT item characteristics best predicted performance differences between monolingual patients and controls. We found that contextual diversity and imageability, but not word frequency (nor words’ number of senses), contributed unique variance to explaining naming impairments in AD. These findings suggest a semantic component to the naming impairment in AD (modulated by names’ semantic richness and network size).
PMCID: PMC4356120  PMID: 23298442
Picture naming; Bilingualism; Bilingual index scores; Language dominance; Frequency; Imageability; Contextual diversity; Number of senses
9.  Prototype Learning and Dissociable Categorization Systems in Alzheimer’s Disease 
Neuropsychologia  2013;51(9):1699-1708.
Recent neuroimaging studies suggest that prototype learning may be mediated by at least two dissociable memory systems depending on the mode of acquisition, with A/Not-A prototype learning dependent upon a perceptual representation system located within posterior visual cortex and A/B prototype learning dependent upon a declarative memory system associated with medial temporal and frontal regions. The degree to which patients with Alzheimer’s disease (AD) can acquire new categorical information may therefore critically depend upon the mode of acquisition. The present study examined A/Not-A and A/B prototype learning in AD patients using procedures that allowed direct comparison of learning across tasks. Despite impaired explicit recall of category features in all tasks, patients showed differential patterns of category acquisition across tasks. First, AD patients demonstrated impaired prototype induction along with intact exemplar classification under incidental A/Not-A conditions, suggesting that the loss of functional connectivity within visual cortical areas disrupted the integration processes supporting prototype induction within the perceptual representation system. Second, AD patients demonstrated intact prototype induction but impaired exemplar classification during A/B learning under observational conditions, suggesting that this form of prototype learning is dependent on a declarative memory system that is disrupted in AD. Third, the surprisingly intact classification of both prototypes and exemplars during A/B learning under trial-and-error feedback conditions suggests that AD patients shifted control from their deficient declarative memory system to a feedback-dependent procedural memory system when training conditions allowed. Taken together, these findings serve to not only increase our understanding of category learning in AD, but to also provide new insights into the ways in which different memory systems interact to support the acquisition of categorical knowledge.
PMCID: PMC4354875  PMID: 23751172
AD; category learning; classification learning; memory systems; semantic memory
10.  The New Qualitative Scoring MMSE Pentagon Test (QSPT) as a Valid Screening Tool between Autopsy-Confirmed Dementia with Lewy Bodies and Alzheimer's Disease 
Visual-constructional apraxia is a prominent feature of dementia with Lewy bodies (DLB) that might help to clinically distinguish it from Alzheimer's disease (AD). The main goal of this study was to assess performance on the copy intersecting-pentagon item of the Mini-Mental State Examination with the new Qualitative Scoring method for the Pentagon copy Test (QSPT). In order to determine which aspects of the drawings might differentiate DLB from AD, pentagon drawings of autopsy-verified DLB (n = 16) and AD (n = 15) patients were assessed using the QSPT. The qualitative scoring encompasses the assessment of different parameters of the drawing, such as number of angles, distance/intersection, closure/opening, rotation, and closing-in. The QSPT scores were compared between groups using linear analyses and artificial neural network analyses at four different time points. Linear analyses showed that during the first evaluation, number of angles was the only parameter that showed a significant difference between DLB and AD patients. A gradual decline in other parameters and total pentagon score occurred in both groups during subsequent years, with greater decline for the DLB group. The artificial neural network analyses using auto-contractive maps showed that, with disease progression, DLB became related to relatively lower qualitative pentagon scores, whereas AD became related to relatively higher qualitative scores. These findings suggest that the QSPT might be a sensitive measure of visuo-constructive abilities able to differentiate DLB from AD at disease onset and as the diseases progress, but further studies on larger population are necessary in order to establish its clinical relevance.
PMCID: PMC4346244  PMID: 24284368
Alzheimer's disease; autopsy-confirmed; copy of pentagons; dementia with Lewy bodies
11.  Accounting for Functional Loss in Alzheimer’s Disease and Dementia with Lewy Bodies: Beyond Cognition 
The relative contributions of cognitive, motor and behavioral deficits to the impairment of physical or instrumental activities of daily living (ADL) may differ in patients with Dementia with Lewy Bodies (DLB) and Alzheimer’s Disease (AD).
Multiple linear regression analyses were used to identify the amount of variability in physical self-maintenance and instrumental ADL ratings predicted by cognitive, motor, and behavioral indices separately for patients with autopsy-diagnosed DLB (n=39) or AD (n=39).
Motor dysfunction accounted for significant variance in physical ADL in DLB (R2 change=0.17), whereas behavioral (R2 change=0.23) and motor dysfunction (R2 change=0.13) accounted for significant variance in AD. Motor (R2 change=0.32) and cognitive (R2 change=0.10) dysfunction accounted for significant variance in instrumental ADL in DLB, whereas cognitive (R2 change=0.36) and behavioral (R2 change=0.12) dysfunction accounted for significant variance in AD.
Cognitive, motor, and behavioral deficits contribute differently to ADL changes in DLB and AD. Thus, treatments designed to ameliorate a certain aspect of AD or DLB (e.g., cognitive dysfunction) may have a larger impact on everyday function in one disorder than the other.
PMCID: PMC4339266  PMID: 23850331
Dementia with Lewy Bodies; Alzheimer’s Disease; Activities of Daily Living; Cognition; Behavior; Motor Function
12.  The Alzheimer's Disease Cooperative Study Prevention Instrument Project: Longitudinal Outcome of Behavioral Measures as Predictors of Cognitive Decline 
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.
PMCID: PMC4307008  PMID: 25685141
Aging; Depression; Anxiety; Mild cognitive impairment; Alzheimer's disease
13.  Pulse pressure is associated with Alzheimer biomarkers in cognitively normal older adults 
Neurology  2013;81(23):2024-2027.
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.
PMCID: PMC3854831  PMID: 24225352
14.  Abnormal P600 word repetition effect in elderly persons with Preclinical Alzheimer’s disease 
Cognitive neuroscience  2013;4(0):10.1080/17588928.2013.838945.
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.
PMCID: PMC3841188  PMID: 24090465
Mild Cognitive Impairment; EEG; memory; Alzheimer’s disease; Event-related potentials
15.  Subjective Cognitive Complaints Contribute to Misdiagnosis of Mild Cognitive Impairment 
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.
PMCID: PMC4172502  PMID: 25156329
Mild cognitive impairment; Awareness; Cluster analysis; Diagnostic errors; Neuropsychology; Dementia; Alzheimer disease
16.  Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates 
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.
PMCID: PMC4133291  PMID: 24844687
Alzheimer’s disease; Alzheimer’s Disease Neuroimaging Initiative; biomarker; cluster analysis; dementia; mild cognitive impairment; neuropsychology; progression
17.  Cortical and Subcortical Cerebrovascular Resistance Index in Mild Cognitive Impairment and Alzheimer's Disease 
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.
PMCID: PMC4089500  PMID: 23666173
Alzheimer's disease; cerebral blood flow; cerebrovascular resistance; mild cognitive impairment
18.  The A4 Study: Stopping AD before Symptoms Begin? 
Science translational medicine  2014;6(228):228fs13.
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.
PMCID: PMC4049292  PMID: 24648338
19.  Improving dementia care: The role of screening and detection of cognitive impairment 
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.
PMCID: PMC4049530  PMID: 23375564
Alzheimer; Dementia; Screening; Detection; Health care; Policy; Priority; Quality; Medicare; Annual wellness visit; Cognitive impairment; Cost-benefit analysis; Management; Patient-centered
20.  Neuropsychiatric Features of Frontal Lobe Dysfunction in Autopsy-Confirmed Patients with Lewy Bodies and “Pure” Alzheimer’s Disease 
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.
PMCID: PMC3664517  PMID: 23567425
Dementia with Lewy bodies; Alzheimer’s disease; Frontal systems; Behavioral symptoms
21.  Effect of Knowledge of APOE Genotype on Subjective and Objective Memory Performance in Healthy Older Adults 
The American journal of psychiatry  2014;171(2):201-208.
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.
PMCID: PMC4037144  PMID: 24170170
22.  Interactive effects of vascular risk burden and advanced age on cerebral blood flow 
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.
PMCID: PMC4083452  PMID: 25071567
aging; vascular risk factors; arterial spin labeling; cognition
23.  Distinct cognitive profiles and rates of decline on the Mattis Dementia Rating Scale in autopsy-confirmed frontotemporal dementia and Alzheimer’s disease 
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.
PMCID: PMC2864090  PMID: 18419836
Frontotemporal dementia; Alzheimer’s disease; Mattis Dementia Rating Scale; Rate of progression; Cognitive profile; Functional impairment
24.  Higher Education is Not Associated with Greater Cortical Thickness in Brain Areas Related to Literacy or Intelligence in Normal Aging or Mild Cognitive Impairment 
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.
PMCID: PMC3488147  PMID: 22905705
Brain reserve; cortical thickness; education; hippocampal volume; literacy; Mild Cognitive Impairment (MCI); aging
25.  Early Visuospatial Deficits Predict the Occurrence of Visual Hallucinations in Autopsy-Confirmed Dementia with Lewy Bodies 
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.
PMCID: PMC3260388  PMID: 21997600
Lewy body disease; Hallucinations, visual; Alzheimer’s disease; Visuospatial cognition

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