Clinically Normal Research Articles

Age and neurodegeneration imaging biomarkers in persons with Alzheimer disease dementia

To examine neurodegenerative imaging biomarkers in Alzheimer disease (AD) dementia from middle to old age. Persons with AD dementia and elevated brain β-amyloid with Pittsburgh compound B (PiB)-PET imaging underwent [(18)F]-fluorodeoxyglucose (FDG)-PET and structural MRI. We evaluated 3 AD-related neurodegeneration biomarkers: hippocampal volume adjusted for total intracranial volume (HVa), FDG standardized uptake value ratio (SUVR) in regions of interest linked to AD, and cortical thickness in AD-related regions of interest. We examined associations of each biomarker with age and evaluated age effects on cutpoints defined by the 90th percentile in AD dementia. We assembled an age-, sex-, and intracranial volume-matched group of 194 similarly imaged clinically normal (CN) persons. The 97 participants with AD dementia (aged 49-93 years) had PiB SUVR ≥1.8. A nonlinear (inverted-U) relationship between FDG SUVR and age was seen in the AD group but an inverse linear relationship with age was seen in the CN group. Cortical thickness had an inverse linear relationship with age in AD but a nonlinear (flat, then inverse linear) relationship in the CN group. HVa showed an inverse linear relationship with age in both AD and CN groups. Age effects on 90th percentile cutpoints were small for FDG SUVR and cortical thickness, but larger for HVa. In persons with AD dementia with elevated PiB SUVR, values of each neurodegeneration biomarker were associated with age. Cortical thickness had the smallest differences in 90th percentile cutpoints from middle to old age, and HVa the largest differences.

Decreased hippocampal metabolism in high-amyloid mild cognitive impairment

IntroductionHippocampal volume (HV), cortical metabolism, and thickness are decreased in mild cognitive impairment (MCI). Hippocampal metabolism (HM) studies comparing MCI and clinically normal (CN) elderly gave inconsistent results. As hippocampus is a key region in Alzheimer's disease, we hypothesized that HM is specifically decreased in high-amyloid MCI. MethodsOverall, 250 CN and 45 MCI underwent three-dimensional magnetic resonance imaging, fludeoxyglucose-positron emission tomography, and fluorodeoxyglucose-positron emission tomography (PET), and Pittsburgh Compound B (PiB) PET. We investigated the interaction between clinical and amyloid status on HM, HV, cortical metabolism, and thickness using linear models, covarying age, gender, and education. Analyses were conducted with and without correction for multiple comparisons and for partial volume effects. ResultsVolume-adjusted HM was decreased in high-amyloid MCI but close to normal in low-amyloid MCI and in high-amyloid CN. Both MCI groups had hippocampal atrophy, although less severe in low-amyloid MCI. High-amyloid CN and high-amyloid MCI had cortical hypometabolism. DiscussionHM is decreased when both cognitive impairment and amyloid are present.

AV1451 PET IMAGING IN THE SPECTRUM OF ALZHEIMER’S DISEASE FROM CLINICALLY NORMAL TO DEMENTIA

Tau (AV1451) PET has recently been introduced, and its ability to distinguish among clinically normal, mild cognitive impairment and dementia in the Alzheimer disease (AD) spectrum has not been established. We studied 121 clinically normal (CN) amyloid negative (A-), 54 CN amyloid positive (A+), 19 mild cognitively impaired (MCI) A-, 16 MCI A+ and 32 dementia with elevated amyloid (A+) (28 probable AD, 1 possible AD, 1 posterior cortical atrophy, and 2 logopenic PPA) (age range 52-94 yrs across entire group) with MR, 11C PIB PET and 18F-AV1451 PET imaging. Regional uptake of AV1451 was quantitated using the ratio uptake in each of 46 atlas regions scaled to the crus (SUVR). A+ was defined as PIB SUVR >1.4. Within each region of interest (ROI), we examined group-wise differences in AV1451 SUVR in CN A+ versus CN A-, MCI A+ versus CN A+, MCI A+ versus MCI A-, and dementia A+ versus MCI A+. The area under the receiver operating characteristic curve (AUROC) was calculated. We created medial temporal (MT, from amygdala, entorhinal cortex, parahippocampal), lateral temporal (LT, from fusiform, lingual, inferior temporal, middle temporal) and lateral parietal (LP, from angular, supramarginal, inferior parietal) meta-ROIs to facilitate between-group comparisons. There were significant elevations in AV1451 SUVR in MT (AUROC=0.66; p<0.001) and LT (AUROC=0.63; p=0.008) in CN A+ versus CN A-. There were significant elevations (all p≤0.001) in all 3 meta-ROIs in MCI A+ versus CN A+ (AUROCs: MT= 0.77, LT=0. 87, LP=0.81), MCI A+ versus MCI A- (AUROCs: MT=0.88, LT=0.94, LP=0.84), and in dementia A+ versus MCI A+ (AUROCs: MT=0.85, LT=0.86, LP=0.82). See Figure (PIB+= A+).

BLOOD GENE EXPRESSION CHANGES IMPLICATED IN ALZHEIMER’S DISEASE

Studies aimed at predicting risk for Alzheimer’s disease (AD) are needed to improve the outcomes of clinical trials directed at treating this currently incurable disease. Brain expression studies have implicated transcriptional regulation as a functional mechanism important in AD etiology. Our hypothesis is that there may be gene expression changes that can be detected in peripheral blood prior to the onset of cognitive symptoms; we tested this in a cohort of subjects with clinically diagnosed AD dementia, amnestic MCI (aMCI) and clinically normal (CN) individuals with PiB-PET amyloid imaging. RNA was isolated from blood, using the PAXgene Blood RNA system, for 44 clinically diagnosed AD dementia, 56 aMCI, 82 CN-PiB-positive and 61 CN-PiB-negative subjects from the Mayo Clinic Study of Aging (MCSA). Gene expression measures were collected using the Illumina Whole-Genome DASL array. Transcript profiling analysis was performed in R using linear regression, including technical and biological covariates. Genome-wide genotypes are being imputed to the 1000 genomes reference set to facilitate eQTL analysis. The most significant genes were tested for replication in an independent cohort of 103 ADs and 213 Controls collected as part of the Alzheimer’s disease Neuroimaging Initiative (ADNI). Profiling analysis of the AD dementia vs CN PiB-neg groups identified 48 candidate genes (un-adjusted p<5E-03), of which 26 could be evaluated in the ADNI cohort. 9/26 achieved nominal significance, of which 7 were in a direction consistent with the discovery cohort. To identify disease relevant changes that occur prior to cognitive decline, we compared results from AD dementia vs PiB-neg and PiB-pos vs PiB-neg profiling analyses. We identified 90 genes that were nominally significant in both, 89 of which were in a consistent direction (31 down-regulated; 58 up-regulated). eQTL analysis will be performed to determine if the differentially expressed genes are associated with regulatory variants. Blood gene expression measures represent a feasible putative biomarker for AD dementia with tremendous potential. Analysis across two cohorts identified remarkable consistency in direction of association for genes with nominal significance. We identify a set of 89 genes that represent potential early, disease relevant, transcriptional changes that can be pursued further.

TAU BURDEN IS ASSOCIATED WITH SUBJECTIVE COGNITIVE CONCERNS IN THE CONTEXT OF β-AMYLOID BURDEN IN PRECLINICAL AD

Alzheimer’s disease (AD) is characterized by the deposition of β-amyloid (Aβ) and paired helical filament tau. The relationship of these deposits to the preclinical manifestations of the AD phenotype can now be evaluated in vivo with positron emission tomography (PET). Endorsement of subjective cognitive concerns (SCC) is associated with Aβ in this early phase of the disease trajectory, but until now, a relationship between SCC and regional tau deposition has not been interrogated. We aimed to elucidate the relationship between entorhinal cortical (EC) and inferior temporal (IT) tau, neocortical Aβ and SCC in clinically-normal (CN) older adults. Seventy-three CN (CDR = 0) participants (77yrs (SD=6.2), 58% female, 28% Aβ+, 28% APOEε4 carriers) participating in the Harvard Aging Brain Study underwent T807 (aka AV1451) and PiB PET imaging within 6 months of responding to three SCC questionnaires. An SCC composite was created using z-transformed memory subscales from the Memory Functioning Questionnaire, the Everyday Cognition Scale, and the adapted Structured Telephone Inventory for Dementia Assessment. Greater EC tau was associated with greater SCC (β=0.39, p<.001) after taking into account age, depressive symptoms, sex and education. IT tau was marginally associated (β=0.18, p=.16). After interactions between tau and Aβ were included, no interactive effect of EC tau and Aβ was found on SCC (p=.93), but an IT and Aβ interaction was now marginally associated with greater SCC (p=.07). This is the first study to demonstrate regionally-specific patterns of association between tau burden and SCC. Specifically, EC tau was strongly associated with greater SCC, but the effect was independent of Aβ burden. Increasing IT tau deposition, on the other hand, was related to greater SCC only within the context of increasing Ab burden. As such, both tau and Aβ are associated with SCC and appear to become multiplicative under certain circumstances. It is possible that IT tau-driven SCC reflects individuals likely on the AD trajectory, whereas EC-related SCC captures a range of phenomena including normal aging, in which EC tauopathy is very common. It remains to be seen whether regional tau underlies qualitatively different SCC phenotypes.

Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum

The availability of antemortem biomarkers for Alzheimer's disease (AD) enables monitoring the evolution of neurodegenerative processes in real time. Pittsburgh compound B (PIB) positron emission tomography (PET) was used to select participants in the Mayo Clinic Study of Aging and the Mayo Alzheimer's Disease Research Center with elevated β-amyloid, designated as “A+,” and hippocampal volume and 18fluorodeoxyglucose (FDG) positron emission tomography were used to characterize participants as having evidence of neurodegeneration (“N+”) at the baseline evaluation. There were 145 clinically normal (CN) A+ individuals, 62 persons with mild cognitive impairment (MCI) who were A+ and 20 with A+ AD dementia. Over a period of 1–6 years, MCI A+N+ individuals showed declines in medial temporal, lateral temporal, lateral parietal, and to a lesser extent, medial parietal regions for both FDG standardized uptake value ratio and gray matter volume that exceeded declines seen in the CN A+N+ group. The AD dementia group showed declines in the same regions on FDG standardized uptake value ratio and gray matter volume with rates that exceeded that in MCI A+N+. Expansion of regional involvement and faster rate of neurodegeneration characterizes progression in the AD pathway.

Lamellipodin-Deficient Mice: A Model of Rectal Carcinoma.

During a survey of clinical rectal prolapse (RP) cases in the mouse population at MIT animal research facilities, a high incidence of RP in the lamellipodin knock-out strain, C57BL/6-Raph1tm1Fbg (Lpd-/-) was documented. Upon further investigation, the Lpd-/- colony was found to be infected with multiple endemic enterohepatic Helicobacter species (EHS). Lpd-/- mice, a transgenic mouse strain produced at MIT, have not previously shown a distinct immune phenotype and are not highly susceptible to other opportunistic infections. Predominantly male Lpd-/- mice with RP exhibited lesions consistent with invasive rectal carcinoma concomitant to clinically evident RP. Multiple inflammatory cytokines, CD11b+Gr1+ myeloid-derived suppressor cell (MDSC) populations, and epithelial cells positive for a DNA damage biomarker, H2AX, were elevated in affected tissue, supporting their role in the neoplastic process. An evaluation of Lpd-/- mice with RP compared to EHS-infected, but clinically normal (CN) Lpd-/- animals indicated that all of these mice exhibit some degree of lower bowel inflammation; however, mice with prolapses had significantly higher degree of focal lesions at the colo-rectal junction. When Helicobacter spp. infections were eliminated in Lpd-/- mice by embryo transfer rederivation, the disease phenotype was abrogated, implicating EHS as a contributing factor in the development of rectal carcinoma. Here we describe lesions in Lpd-/- male mice consistent with a focal inflammation-induced neoplastic transformation and propose this strain as a mouse model of rectal carcinoma.

Functional Activities Questionnaire Items that Best Discriminate and Predict Progression from Clinically Normal to Mild Cognitive Impairment.

Impairment in instrumental activities of daily living (IADL) emerges in the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. Some IADL scales are sensitive to early deficits in MCI, but none have been validated for detecting subtle functional changes in clinically normal (CN) elderly at risk for AD. Data from 624 subjects participating in the Alzheimer's Disease Neuroimaging Initiative and 524 subjects participating in the Massachusetts Alzheimer's Disease Research Center, which are two large cohorts including CN elderly and MCI subjects, were used to determine which Functional Activities Questionnaire items best discriminate between and predict progression from CN to MCI. We found that "Remembering appointments" and "assembling tax records" best discriminated between CN and MCI subjects, while worse performance on "paying attention and understanding a TV program", "paying bills/balancing checkbook", and "heating water and turning off the stove" predicted greater hazard of progressing from a diagnosis of CN to MCI. These results demonstrate that certain questions are especially sensitive in detecting the earliest functional changes in CN elderly at risk for AD. As the field moves toward earlier intervention in preclinical AD, it is important to determine which IADL changes can be detected at that stage and track decline over time.

Free and cued memory in relation to biomarker-defined abnormalities in clinically normal older adults and those at risk for Alzheimer’s disease

ObjectivesFurthering our understanding of the relationship between amyloidosis (Aβ), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimer's disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD. MethodsA total of 260 clinically normal (CN) older adults (CDR=0) from the Harvard Aging Brain study were grouped according to preclinical AD stages including Stage 0 (Aβ-/ND-), Stage 1 (Aβ+/ND-), Stage 2 (Aβ+/ND+), and suspected non-Alzheimer’s associated pathology (SNAP; Aβ-/ND+). General linear models controlling for age, sex, and education were used to assess for stage-based performance differences on cognitive composites of executive functioning, processing speed, and memory in addition to free and cued delayed recall on the Selective Reminding Test (SRT) and Memory Capacity Test (MCT). ResultsGlobal memory performance differed between preclinical stages with Stage 2 performing worse compared with Stage 0. When examining free and cued paradigms by memory test, only the MCT (and not the SRT) revealed group differences. More specifically, Stage 1 was associated with decrements in free recall compared with Stage 0 while Stage 2 was associated with decrements in both free and cued recall. There was a trend for the SNAP group to perform worse on free recall compared with Stage 0. Finally, there was no association between preclinical stage and global composites of executive functioning or processing speed. ConclusionsClinically normal older adults with underlying evidence of amyloidosis and neurodegeneration exhibit subtle, yet measurable differences in memory performance, but only on a challenging associative test. The sensitivity of free vs. cued memory paradigms may be dependent on preclinical stage such that reduced free recall is associated with amyloidosis alone (Stage 1) while a decline in cued recall may represent progression to amyloidosis and neurodegeneration (Stage 2). These findings may have practical applications for clinical assessment and clinical trial design.

Odor identification and Alzheimer disease biomarkers in clinically normal elderly.

Our objective was to investigate cross-sectional associations between odor identification ability and imaging biomarkers of neurodegeneration and amyloid deposition in clinically normal (CN) elderly individuals, specifically testing the hypothesis that there may be an interaction between amyloid deposition and neurodegeneration in predicting odor identification dysfunction. Data were collected on 215 CN participants from the Harvard Aging Brain Study. Measurements included the 40-item University of Pennsylvania Smell Identification Test and neuropsychological testing, hippocampal volume (HV) and entorhinal cortex (EC) thickness from MRI, and amyloid burden using Pittsburgh compound B (PiB) PET. A linear regression model with backward elimination (p < 0.05 retention) evaluated the cross-sectional association between the University of Pennsylvania Smell Identification Test and amyloid burden, HV, and EC thickness, assessing for effect modification by PiB status. Covariates included age, sex, premorbid intelligence, APOE ε4 carrier status, and Boston Naming Test. In unadjusted univariate analyses, worse olfaction was associated with decreased HV (p < 0.001), thinner EC (p = 0.003), worse episodic memory (p = 0.03), and marginally associated with greater amyloid burden (binary PiB status, p = 0.06). In the multivariate model, thinner EC in PiB-positive individuals (interaction term) was associated with worse olfaction (p = 0.02). In CN elderly, worse odor identification was associated with markers of neurodegeneration. Furthermore, individuals with elevated cortical amyloid and thinner EC exhibited worse odor identification, elucidating the potential contribution of olfactory testing to detect preclinical AD in CN individuals.

Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals.

Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes. To determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals. Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women). The Aβ status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ-/ND-), stage 1 (Aβ(+)/ND-), stage 2 (Aβ(+)/ND(+)), and suspected non-Alzheimer disease pathology (Aβ-/ND(+)). Cognition was assessed with a composite of neuropsychological tests administered annually. The Aβ(+) CN individuals were more likely to be classified as ND+: 59.6% of Aβ(+) CN individuals were ND(+), whereas 31.9% of Aβ- CN individuals were ND(+) (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04). The co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.

Everyday cognition scale items that best discriminate between and predict progression from clinically normal to mild cognitive impairment.

Impairment in instrumental activities of daily living (IADL) starts as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer's disease (AD) dementia. However, most IADL scales have not shown IADL alterations in clinically normal (CN) elderly. The objective of this study was to determine which of the IADL-related Everyday Cognition (ECog) scale items are most sensitive for detection of early functional changes. We assessed 290 CN and 495 MCI participants from the Alzheimer's Disease Neuroimaging Initiative. We performed logistic regression analyses predicting the probability of CN vs. MCI diagnosis using only the 17 participant-based and 17 informant-based ECog items related to IADL. We then performed Cox regression analyses to predict progression from CN to MCI. All analyses were adjusted for demographic characteristics. We found that worse performance on "remembering a few shopping items" (participant and informant-based p<0.0001), "remembering appointments" (participant and informant-based p<0.0001), "developing a schedule in advance of anticipated events" (participant-based p=0.007), "balancing checkbook" (participant-based p=0.02), and "keeping mail and papers organized" (informant-based p=0.002) best discriminated MCI from CN. We found that worse performance on "keeping mail and papers organized" (participant-based Hazard Ratio (HR)=2.27, p=0.07) marginally predicted greater hazard of progressing from CN to MCI. Our results indicate that a few simple questions targeting early functional changes, addressed either to the individual or informant, can effectively distinguish between CN elderly and individuals with MCI. Additionally, one of the above questions related to organization suggested which CN individuals are likely to progress to MCI.

SIST-M-IR activities of daily living items that best discriminate clinically normal elderly from those with mild cognitive impairment.

Activities of daily living (ADL) impairment is a hallmark of Alzheimer's disease (AD) dementia, but impairment in instrumental ADL (IADL) has been reported in mild cognitive impairment (MCI). The Structured Interview and Scoring Tool-Massachusetts Alzheimer's Disease Research Center (MADRC)-Informant Report (SIST-MIR) includes 60 graded items that assist in scoring the Clinical Dementia Rating; it assesses the spectrum of cognitive and ADL changes relevant to early AD. Of the 60 SIST-M-IR items, 41 address IADL; we aimed to determine which of these best discriminate individuals with MCI from clinically normal (CN) elderly. We assessed 447 subjects participating in the MADRC longitudinal cohort (289 CN, 158 MCI). We performed logistic regression analyses predicting the probability of CN vs. MCI diagnosis using the SIST-M-IR items. Analyses were adjusted for demographic characteristics. We found that 4 SIST-M-IR items best discriminated between CN and MCI subjects (MCI performing worse than CN): "participating in games that involve retrieving words" (p=0.0001), "navigating to unfamiliar areas" (p=0.001), "performing mental tasks involved in a former primary job" (p=0.002), and "fixing things or finishing projects" (p=0.002). Our results point to the earliest functional changes seen in elderly at risk for AD, which could be captured by a few simple questions. Honing the sensitivity of clinical assessment tools will help clinicians differentiate those individuals with normal aging from those who are developing cognitive impairment.

Regional fluorodeoxyglucose metabolism and instrumental activities of daily living across the Alzheimer's disease spectrum.

Impairment in instrumental activities of daily living (IADL) begins as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer's disease (AD) dementia. IADL impairment in AD dementia has been associated with inferior parietal, inferior temporal, and superior occipital hypometabolism using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). To investigate the relationship between regional FDG metabolism and IADL in clinically normal (CN) elderly, MCI, and mild AD dementia subjects cross-sectionally and longitudinally. One hundred and four CN, 203 MCI, and 95 AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative underwent clinical assessments every 6 to 12 months for up to three years and baseline FDG PET. The subjective, informant-based Functional Activities Questionnaire was used to assess IADL. General linear models and mixed effects models were used, covarying for demographics, cognition, and behavior. The cross-sectional analysis revealed middle frontal and orbitofrontal hypometabolism were significantly associated with greater IADL impairment. Additionally, the interaction of diagnosis with posterior cingulate and with parahippocampal hypometabolism showed a greater decline in IADL performance as metabolism decreased for the AD dementia relative to the MCI group, and the MCI group relative to the CN group. The longitudinal analysis showed that baseline middle frontal and posterior cingulate hypometabolism were significantly associated with greater rate of increase in IADL impairment over time. These results suggest that regional synaptic dysfunction, including the Alzheimer-typical medial parietal and less typical frontal regions, relates to daily functioning decline at baseline and over time across the early AD spectrum.

The relevance of beta-amyloid on markers of Alzheimer's disease in clinically normal individuals and factors that influence these associations.

Aberrant accumulation of beta-amyloid (Aβ) is thought to be an early event in a biological cascade that eventually leads to Alzheimer's disease (AD). Along these lines, many clinically normal (CN) older individuals have evidence of beta-amyloid (Aβ) accumulation, which may be indicative of preclinical AD. However, relationships between Aβ and "downstream" AD markers are often inconsistent across studies. These inconsistencies may be due to the presence of other age-related processes that also influence AD markers, as well as additional risk factors that interact with Aβ to influence downstream changes. For instance, it is possible that the effect of Aβ is modified by neurodegeneration, genetics, sex-differences and cognitive reserve. Thus, a multivariate approach to determining risk of AD within CN participants may be more appropriate than reliance on Aβ status alone. An understanding of how additional risk factors interact with Aβ to influence an individual's trajectory towards AD is essential for characterizing preclinical AD and has implications for prevention trials.

Regional cortical thinning and cerebrospinal biomarkers predict worsening daily functioning across the Alzheimer's disease spectrum.

Impairment in instrumental activities of daily living (IADL) heralds the transition from mild cognitive impairment (MCI) to dementia and is a major source of burden for both the patient and caregiver. To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. Two hundred and twenty nine CN, 395 MCI, and 188 AD dementia subjects participating in the Alzheimer's Disease Neuroimaging Initiative underwent baseline magnetic resonance imaging, baseline lumbar puncture, and clinical assessments, including the Functional Activities Questionnaire used to measure IADL, every 6 to 12 months up to 3 years. General linear regression and mixed effects models were employed. IADL impairment was associated with the interactions between lower inferior temporal cortical thickness and diagnosis (p < 0.0001), greater lateral occipital cortical thickness and diagnosis (p < 0.0001), and greater amyloid-β 1-42 (Aβ1-42) and diagnosis (p = 0.0002) at baseline (driven by AD dementia). Lower baseline supramarginal (p = 0.02) and inferior temporal (p = 0.05) cortical thickness, lower Aβ1-42 (p < 0.0001), and greater total tau (t-tau) (p = 0.02) were associated with greater rate of IADL impairment over time. Temporal atrophy is associated with IADL impairment in mild AD dementia at baseline, while baseline parietal and temporal atrophy, lower CSF Aβ1-42, and greater t-tau predict worsening IADL impairment over time across the AD spectrum. These results emphasize the importance of assessing IADL at the stage of MCI and even at the transition from CN to MCI.

COMPARISON BETWEEN SEMIQUANTITATIVE MEASURES AND READER CONCORDANCE OF AMYLOID LOAD BASED ON 18F-FLUTEMETAMOL VERSUS 11C-PIB IN COGNITIVELY INTACT OLDER ADULTS

are associated with different patterns of regional brain atrophy is unresolved. We sought to determine whether the presence of b-amyloid (Ab) in the brain accelerates regional atrophy in a clinically-normal (CN) population in a region-specific manner, and to identify regions in which agerelated atrophy is significantly affected by early AD, measured by Ab PET.Methods: In 80 CN subjects with longitudinal volume measurements and Florbetapir PET, we used linear mixed effects models to determine the effects of Ab PET SUVR and age on longitudinal atrophy rates in 43 FreeSurfer regions of interest, while accounting for confounding variables including sex, ApoEe4 genotype, intracranial volume, white matter lesions, and tau levels. Results: Rates of atrophy in several temporal lobe regions were associated with Ab SUVR, with the strongest associations in entorhinal cortex and amygdala. When subjects were dichotomized into Ab+ and Absubgroups, high atrophy rates in distinct regions of the occipital, parietal, frontal, and cingulate cortices distinguished Ab+ versus Absubjects. Age was associated with atrophy rates in the insula, fusiform gyrus, and isthmus cingulate. There was a positive interaction between age and Ab status in predicting atrophy rates in pallidum, postcentral gyrus, and parahippocampal gyrus, indicating accelerated atrophy associated with the presence of Ab. In contrast, there was a negative interaction between age and Ab status in superior temporal gyrus, supramarginal gyrus, and lateral orbitofrontal gyrus indicating reduced atrophy associated with Ab. Conclusions: Brain Ab deposition largely accelerates atrophy of the same regions that show age-related atrophy, supporting a model in which age-related tau tangle accumulation in temporal lobe drives neurodegeneration and is accelerated by the presence of AD. The effects of age and Ab on brain atrophy rates may represent the combined effects of neurodegeneration, and compensatory processes responding to neurodegeneration.

Development of a Psychometrically Equivalent Short Form of the Face–Name Associative Memory Exam for use Along the Early Alzheimer’s Disease Trajectory

Neuropsychologists are developing more challenging and specific tests to detect early and subtle changes in cognition related to preclinical Alzheimer’s disease (AD). The 16-item Face–Name Associative Memory Exam (FNAME-16) is a challenging paired associative memory test able to detect subtle memory changes associated with biomarker evidence of preclinical AD. However, as individuals progress along the AD trajectory, measures that are sensitive at the preclinical stage may become too challenging by the stage of Mild Cognitive Impairment (MCI). Our goal was to develop a modified version of the face–name and face–occupation paired associative memory task (FNAME-12) with fewer stimuli and additional learning trials suitable for use in MCI. We administered the FNAME-12A, an alternate version FNAME 12B, the original FNAME-16, and a series of other neuropsychological measures to 65 clinically normal (CN) older adults (aged 65 to 85) and a subsample characterized by MCI (n = 18). The FNAME-12 exhibited psychometric equivalence with the FNAME-16 (r = .77, p < .001) and was correlated with other measures of episodic and semantic memory. The alternate form, FNAME-12B, was highly correlated with FNAME-12A (r = .76, p < .001). Mean performance on the FNAME 12A, stratified by education, was generated. The task could be completed by our MCI group yet remained challenging in the CN group, providing evidence for its utility along the AD trajectory.

Assessment of serum amyloid A testing of horses and its clinical application in a specialized equine practice

To compare serum amyloid A (SAA) concentration, plasma fibrinogen concentration, total WBC count, and serum albumin-to-globulin concentration ratio (A:G ratio) in clinically normal (CN) and clinically abnormal (CA) horses. Prospective cohort study. 111 CN horses and 101 CA horses hospitalized at a specialty clinical practice. Shortly after admission, a blood sample (20 mL) was collected from each horse for a CBC, serum protein electrophoresis, and determination of plasma fibrinogen concentration; SAA concentration was assessed with a previously validated immunoturbidometric assay. Similar testing of a subset of CA horses was conducted at various points during treatment. Total WBC count, A:G ratio, and SAA concentration were determined for all 212 horses; data regarding plasma fibrinogen concentration were available for 127 horses (of which 47 were CN and 80 were CA). Median SAA concentration, total WBC count, and plasma fibrinogen concentration and mean A:G ratio differed significantly between CN horses and CA horses. Correlations between these variables were poor to weak. For discrimination of CN horses from CA horses, the SAA assay had sensitivity of 53% and specificity of 94% (diagnostic accuracy, 75%); for the other assessments, accuracy ranged from 59% to 62%. Repeated assessment of SAA concentration in some CA horses revealed a gradual return to normal concentrations. Results indicated that assessment of SAA concentration can provide valuable information regarding the clinical state of horses and may be more useful for patient monitoring and as a prognostic indicator than are traditional markers of inflammation.

Computer-aided differential diagnosis system for Alzheimer’s disease based on machine learning with functional and morphological image features in magnetic resonance imaging

Alzheimer’s disease (AD) is a dementing disorder and one of the major public health problems in countries with greater longevity. The cerebral cortical thickness and cerebral blood flow (CBF), which are considered as morphological and functional image features, respectively, could be decreased in specific cerebral regions of patients with dementia of Alzheimer type. Therefore, the aim of this study was to develop a computer-aided classification system for AD patients based on machine learning with the morphological and functional image features derived from a magnetic resonance (MR) imaging system. The cortical thicknesses in ten cerebral regions were derived as morphological features by using gradient vector trajectories in fuzzy membership images. Functional CBF maps were measured with an arterial spin labeling technique, and ten regional CBF values were obtained by registration between the CBF map and Talairach atlas using an affine transformation and a free form deformation. We applied two systems based on an arterial neural network (ANN) and a support vector machine (SVM), which were trained with 4 morphological and 6 functional image features, to 15 AD patients and 15 clinically normal (CN) subjects for classification of AD. The area under the receiver operating characteristic curve (AUC) values for the two systems based on the ANN and SVM with both image features were 0.901 and 0.915, respectively. The AUC values for the ANN-and SVM-based systems with the morphological features were 0.710 and 0.660, respectively, and those with the functional features were 0.878 and 0.903, respectively. Our preliminary results suggest that the proposed method may have potential for assisting radiologists in the differential diagnosis of AD patients by using morphological and functional image features.