PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (92)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
1.  Medial Temporal Lobe Function and Structure in Mild Cognitive Impairment 
Annals of neurology  2004;56(1):27-35.
Functional magnetic resonance imaging (fMRI) was used to study memory-associated activation of medial temporal lobe (MTL) regions in 32 nondemented elderly individuals with mild cognitive impairment (MCI). Subjects performed a visual encoding task during fMRI scanning and were tested for recognition of stimuli afterward. MTL regions of interest were identified from each individual’s structural MRI, and activation was quantified within each region. Greater extent of activation within the hippocampal formation and parahippocampal gyrus (PHG) was correlated with better memory performance. There was, however, a paradoxical relationship between extent of activation and clinical status at both baseline and follow-up evaluations. Subjects with greater clinical impairment, based on the Clinical Dementia Rating Sum of Boxes, recruited a larger extent of the right PHG during encoding, even after accounting for atrophy. Moreover, those who subsequently declined over the 2.5 years of clinical follow-up (44% of the subjects) activated a significantly greater extent of the right PHG during encoding, despite equivalent memory performance. We hypothesize that increased activation in MTL regions reflects a compensatory response to accumulating AD pathology and may serve as a marker for impending clinical decline.
doi:10.1002/ana.20163
PMCID: PMC4335689  PMID: 15236399
2.  Symptom onset in autosomal dominant Alzheimer disease 
Neurology  2014;83(3):253-260.
Objective:
To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.
Methods:
We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.
Results:
We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10−16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.
Conclusions:
Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.
doi:10.1212/WNL.0000000000000596
PMCID: PMC4117367  PMID: 24928124
3.  The evolution of preclinical Alzheimer’s disease: Implications for prevention trials 
Neuron  2014;84(3):608-622.
As the field begins to test the concept of preclinical neurodegenerative disease, the hypothetical stage of disease when the pathophysiological process has begun in the brain but clinical symptoms are not yet manifest, a number of intriguing questions have already arisen. In particular, in preclinical Alzheimer’s disease (AD), the temporal relationship of amyloid markers to markers of neurodegeneration and their relative utility in the prediction of cognitive decline among clinically normal older individuals remains to be fully elucidated. Secondary prevention trials in AD have already begun in both genetic-at-risk and amyloid-at-risk cohorts, with several more trials in the planning stages, that should provide critical answers about whether intervention at this very early stage of disease can truly bend the curve of clinical progression.
doi:10.1016/j.neuron.2014.10.038
PMCID: PMC4285623  PMID: 25442939
4.  Everyday Cognition scale items that best discriminate between and predict progression from clinically normal to mild cognitive impairment 
Current Alzheimer research  2014;11(9):853-861.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
PMCID: PMC4247808  PMID: 25274110
Activities of daily living; Alzheimer’s disease; clinical assessment; daily functioning; clinically normal elderly; mild cognitive impairment
5.  Promising developments in neuropsychological approaches for the detection of preclinical Alzheimer’s disease: a selective review 
Recently published guidelines suggest that the most opportune time to treat individuals with Alzheimer’s disease is during the preclinical phase of the disease. This is a phase when individuals are defined as clinically normal but exhibit evidence of amyloidosis, neurodegeneration and subtle cognitive/behavioral decline. While our standard cognitive tests are useful for detecting cognitive decline at the stage of mild cognitive impairment, they were not designed for detecting the subtle cognitive variations associated with this biomarker stage of preclinical Alzheimer’s disease. However, neuropsychologists are attempting to meet this challenge by designing newer cognitive measures and questionnaires derived from translational efforts in neuroimaging, cognitive neuroscience and clinical/experimental neuropsychology. This review is a selective summary of several novel, potentially promising, approaches that are being explored for detecting early cognitive evidence of preclinical Alzheimer’s disease in presymptomatic individuals.
doi:10.1186/alzrt222
PMCID: PMC3978443  PMID: 24257331
6.  Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(9):1111-1122.
Importance
Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile.
Design, Setting, and Participants
We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites.
Main Outcomes and Measures
For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs.
Results
Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers.
Conclusions and Relevance
rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process.
doi:10.1001/jamaneurol.2014.1654
PMCID: PMC4240274  PMID: 25069482
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
7.  Amyloid Deposition Is Linked to Aberrant Entorhinal Activity among Cognitively Normal Older Adults 
The Journal of Neuroscience  2014;34(15):5200-5210.
Normal aging is often difficult to distinguish from the earliest stages of Alzheimer's disease. Years before clinical memory deficits manifest, amyloid-β deposits in the cortex in many older individuals. Neuroimaging studies indicate that a set of densely connected neocortical regions, referred to as the default network, is especially vulnerable to amyloid-β deposition. Yet, the impact of amyloid-β on age-related changes within the medial temporal lobe (MTL) memory system is less clear. Here we demonstrate that cognitively normal older humans, compared with young adults, show reduced ability to modulate hippocampal activations and entorhinal deactivations during an episodic memory task. Among older adults, amyloid-β deposition was associated with failure to modulate activity in entorhinal cortex, but not hippocampus. Furthermore, we show that entorhinal regions demonstrating amyloid-β-related dysfunction are directly connected to the neocortical regions of the default network. Together these findings link neocortical amyloid-β deposition to neuronal dysfunction specifically in entorhinal cortex, while aging is associated with more widespread functional changes across the MTL.
doi:10.1523/JNEUROSCI.3579-13.2014
PMCID: PMC3983800  PMID: 24719099
amyloid; default network; entorhinal cortex; fMRI; memory; preclinical Alzheimer's disease
8.  BRAIN ABNORMALITIES IN YOUNG ADULTS AT GENETIC RISK FOR AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE: A CROSS-SECTIONAL STUDY 
The Lancet. Neurology  2012;11(12):1048-1056.
Summary
Background
We previously detected functional brain imaging abnormalities in young adults at genetic risk for late-onset Alzheimer’s disease (AD). Here, we sought to characterize structural and functional magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma biomarker abnormalities in young adults at risk for autosomal dominant early-onset AD. Biomarker measurements were characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the world’s largest known autosomal dominant early-onset AD kindred, more than two decades before the carriers’ estimated median age of 44 at the onset of mild cognitive impairment (MCI) and before their estimated age of 28 at the onset of amyloid-β (Aβ) plaque deposition.
Methods
Biomarker data for this cross-sectional study were acquired in Antioquia, Colombia between July and August, 2010. Forty-four participants from the Colombian Alzheimer’s Prevention Initiative (API) Registry had structural MRIs, functional MRIs during associative memory encoding/novel viewing and control tasks, and cognitive assessments. They included 20 mutation carriers and 24 non-carriers, who were cognitively normal, 18-26 years old and matched for their gender, age, and educational level. Twenty of the participants, including 10 mutation carriers and 10 non-carriers, had lumbar punctures and venipunctures. Primary outcome measures included task-dependent hippocampal/parahippocampal activations and precuneus/posterior cingulate deactivations, regional gray matter reductions, CSF Aβ1-42, total tau and phospho-tau181 levels, and plasma Aβ1-42 levels and Aβ1-42/Aβ1-40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and AD-related search regions. Cognitive and fluid biomarkers were compared using Mann-Whitney tests.
Findings
The mutation carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ε4 carriers. Compared to the non-carriers, carriers had higher CSF Aβ1-42 levels (p=0·008), plasma Aβ1-42 levels (p=0·01), and plasma Aβ1-42/Aβ1-40 ratios (p=0·001), consistent with Aβ1-42 overproduction. They also had greater hippocampal/parahippocampal activations (as low as p=0·008, after correction for multiple comparisons), less precuneus/posterior cingulate deactivations (as low as p=0·001, after correction), less gray matter in several regions (p-values <0·005, uncorrected, and corrected p=0·008 in the parietal search region), similar to findings in the later preclinical and clinical stages of autosomal dominant and late-onset AD.
Interpretation
Young adults at genetic risk for autosomal dominant AD have functional and structural MRI abnormalities, along with CSF and plasma biomarker findings consistent with Aβ1-42 over-production. While the extent to which the underlying brain changes are progressive or developmental remain to be determined, this study demonstrates the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant AD.
Funding
Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias (1115-408-20512, 1115-545-31651), National Institute on Aging (R01 AG031581, P30 AG19610, UO1 AG024904, RO1 AG025526, RF1AG041705), National Institute of Neurological Disorders and Stroke (F31-NS078786) and state of Arizona.
doi:10.1016/S1474-4422(12)70228-4
PMCID: PMC4181671  PMID: 23137948
Alzheimer’s disease; biomarkers; preclinical; early-onset; dominantly inherited; MRI; functional MRI; cerebrospinal fluid; plasma; presenilin E280A mutation; amyloid; tau; genetics; prevention
9.  SIST-M-IR activities of daily living items that best discriminate clinically normal elderly from those with mild cognitive impairment 
Current Alzheimer research  2014;11(8):785-791.
Background
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-M-IR) 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.
Methods
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.
Results
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).
Conclusions
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.
PMCID: PMC4163929  PMID: 25212917
Activities of daily living; Alzheimer's disease; clinical assessment; daily functioning; clinically normal elderly; mild cognitive impairment
10.  Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer’s Disease 
The New England journal of medicine  2014;370(4):322-333.
BACKGROUND
Bapineuzumab, a humanized anti–amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer’s disease.
METHODS
We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer’s disease — one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations.
RESULTS
There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were −0.2 (P = 0.80) and −1.2 (P = 0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were −0.3 (P = 0.64) and 2.8 (P = 0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P = 0.62) and 0.9 (P = 0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers.
CONCLUSIONS
Bapineuzumab did not improve clinical outcomes in patients with Alzheimer’s disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.)
doi:10.1056/NEJMoa1304839
PMCID: PMC4159618  PMID: 24450891
11.  Regional fluorodeoxyglucose metabolism and instrumental activities of daily living across the Alzheimer's disease spectrum 
Background
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).
Objective
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.
Methods
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, cogniton, and behavior.
Results
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.
Conclusion
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.
doi:10.3233/JAD-131796
PMCID: PMC4133312  PMID: 24898635
18F-fluorodeoxyglucose positron emission tomography; Alzheimer's disease; instrumental activities of daily living; mild cognitive impairment
12.  Regional cortical thinning and cerebrospinal biomarkers predict worsening daily functioning across the Alzheimer disease spectrum 
Background
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.
Objective
To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects.
Methods
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.
Results
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-beta 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.
Conclusions
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.
doi:10.3233/JAD-132768
PMCID: PMC4111766  PMID: 24685624
Alzheimer's disease; cerebrospinal fluid; instrumental activities of daily living; magnetic resonance imaging; mild cognitive impairment
13.  In vivo characterization of the early states of the amyloid-beta network 
Brain  2013;136(7):2239-2252.
Alzheimer’s disease is a neurodegenerative disease that is associated with the abnormal accumulation of amyloid-β. Much is known about regional brain atrophy in Alzheimer’s disease, yet our knowledge about the network nature of Alzheimer’s disease-associated amyloid-β accumulation is limited. We use stepwise connectivity analysis of Pittsburgh Compound B positron emission tomography images to reveal the network properties of amyloid-β deposits in normal elderly subjects and clinical patients with Alzheimer’s disease. We found that amyloid-β accumulation in the medial temporal lobe is associated with accumulation in cortical regions such as orbitofrontal, lateral temporal and precuneus/posterior cingulate cortices in Alzheimer’s disease. In normal subjects, there was a predominant association between amyloid-β deposits in the hippocampus and the midline prefrontal/orbitofrontal regions, even in those with very low amyloid-β burden. Moreover, the orbitofrontal cortex, amygdala nucleus and hippocampus exhibit hub properties in the amyloid-β network that may be critical to understanding the putative spreading mechanisms of Alzheimer’s disease pathology in early stages.
doi:10.1093/brain/awt146
PMCID: PMC3692037  PMID: 23801740
Alzheimer’s disease; network; amyloid; graph theory; early stages
14.  Age and APOE genotype influence rate of cognitive decline in non-demented elderly 
Neuropsychology  2013;27(4):10.1037/a0032707.
Objective
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.
Method
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.
Results
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.
Conclusions
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.
doi:10.1037/a0032707
PMCID: PMC3831285  PMID: 23876113
Cognitive decline; Apolipoprotein E; Aging
15.  Amyloid-related imaging abnormalities (ARIA) in Alzheimer’s disease patients treated with bapineuzumab: A retrospective analysis 
Lancet neurology  2012;11(3):241-249.
Background
Amyloid-related imaging abnormalities (ARIA) have been reported in Alzheimer’s disease (AD) patients treated with bapineuzumab, a humanized monoclonal antibody to amyloid-β. ARIA includes MRI signal abnormalities suggestive of vasogenic edema and sulcal effusions (ARIA-E) and hemosiderin deposits (ARIA-H). A better understanding of the incidence and risk factors for ARIA may further the development of amyloid-modifying treatments for AD.
Methods
Two neuroradiologists independently reviewed (kappa=0.76) and then reached consensus reads on over 2500 FLAIR-MRIs from 262 participants in three phase 2 studies of bapineuzumab. Subjects (n=210) were included in risk analyses if they had no evidence of ARIA-E on pre-treatment MRI, received bapineuzumab, and had at least one post-treatment MRI.
Findings
36/210 (17%) subjects developed ARIA-E during treatment; 28 of these 36 (78%) did not report associated symptoms. Adverse events reported in 8 symptomatic patients included headache, confusion, neuropsychiatric and gastrointestinal symptoms. 15/36 of the ARIA-E cases (42%) were detected only on central review. 13/15 received additional infusions while ARIA-E was present, without any associated symptoms reported. ARIA-E incidence increased with bapineuzumab dose (Hazard Ratio [HR] 2.24 per mg/kg increase in dose; p<0·001) and with APOE ε4 allele number (HR 2.55 per allele; p<0·001).
Interpretation
ARIA appears to represent a spectrum of imaging findings with variable clinical correlates, with some cases remaining asymptomatic even when treated through ARIA-E. The increased risk of ARIA with APOE ε4 and bapineuzumab dose, and the time course in relation to dosing, is consistent with alterations in vascular amyloid burden.
doi:10.1016/S1474-4422(12)70015-7
PMCID: PMC4063417  PMID: 22305802
16.  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.
doi:10.1126/scitranslmed.3007941
PMCID: PMC4049292  PMID: 24648338
17.  APOE ε4 does not modulate amyloid-β associated neurodegeneration in preclinical Alzheimer’s disease 
Background and Purpose
Among cognitively normal older individuals, the relationship between the two hallmark proteins of Alzheimer’s disease (AD), amyloid-β (Aβ) and tau, the ε4 allele of apolipoprotein E (APOE ε4), and neurodegeneration is not well understood.
Materials and Methods
We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed effects model, we concurrently investigated main and interactive effects between APOE ε4 genotype and CSF Aβ1-42, CSF phospo-tau (p-tau181p) and CSF Aβ1-42, and APOE ε4 genotype and CSF p-tau181p on entorhinal cortex atrophy rate. We also examined the relationship between APOE ε4, CSF p-tau181p, and CSF Aβ1-42 on atrophy rate of other AD-vulnerable neuroanatomic regions.
Results
The full model with main and interactive effects demonstrated a significant interaction only between CSF p-tau181p and CSF Aβ1-42 on entorhinal cortex atrophy rate indicating elevated atrophy over time in individuals with increased CSF p-tau181p and decreased CSF Aβ1-42. APOE ε4 genotype was significantly and specifically associated with CSF Aβ1-42. However, the interaction between APOE ε4 genotype and either CSF Aβ1-42 or CSF p-tau181p on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.
Conclusions
Based upon our findings and building upon prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD where APOE ε4 primarily influences Alzheimer’s pathology via Aβ-related mechanisms and in turn, Aβ-associated neurodegeneration occurs only in the presence of phospho-tau.
doi:10.3174/ajnr.A3267
PMCID: PMC4041629  PMID: 22976236
preclinical AD; neurodegeneration; p-tau; amyloid-β; APOE
18.  The Ups and Downs of the Posteromedial Cortex: Age- and Amyloid-Related Functional Alterations of the Encoding/Retrieval Flip in Cognitively Normal Older Adults 
Cerebral Cortex (New York, NY)  2012;23(6):1317-1328.
Neural networks supporting memory function decline with increasing age. Accumulation of amyloid-β, a histopathological finding in Alzheimer's disease, is a likely contributor. Posteromedial cortices (PMCs) are particularly vulnerable to early amyloid pathology and play a role in both encoding and retrieval processes. The extent to which aging and amyloid influence the ability to modulate activity between these processes within the PMC was investigated by combining positron emission tomography-amyloid imaging with functional magnetic resonance imaging in cognitively normal older and young adults. Young subjects exhibited a marked decrease in activity during encoding and an increase during retrieval (also known as encoding/retrieval “flip”). Impaired ability to modulate activity was associated with increasing age, greater amyloid burden, and worse memory performance. In contrast, the hippocampus showed increased activity during both encoding and retrieval, which was not related to these variables. These findings support a specific link between amyloid pathology and neural dysfunction in PMC and elucidate the underpinnings of age-related memory dysfunction.
doi:10.1093/cercor/bhs108
PMCID: PMC3643714  PMID: 22586140
aging; amyloid; encoding; functional MRI; retrieval
20.  Mild to Moderate Alzheimer Dementia with Insufficient Neuropathological Changes 
Annals of neurology  2014;75(4):597-601.
Recently, ∼16% of participants in an anti-Aβ passive immunotherapy trial for mild-to-moderate Alzheimer disease (AD) had a negative baseline amyloid positron emission tomography (PET) scan. Whether they have AD or are AD clinical phenocopies remains unknown. We examined the 2005-2013 National Alzheimer's Coordinating Center autopsy database and found that ∼14% of autopsied subjects clinically diagnosed with mild-to-moderate probable AD have no or sparse neuritic plaques, which would expectedly yield a negative amyloid PET scan. More than half of these “Aβ-negative” subjects have low neurofibrillary tangle Braak stages. These findings support the implementation of a positive amyloid biomarker as an inclusion criterion in future anti-Aβ drug trials.
doi:10.1002/ana.24125
PMCID: PMC4016558  PMID: 24585367
21.  Cortical atrophy in presymptomatic Alzheimer’s disease presenilin 1 mutation carriers 
Background
Sporadic late-onset Alzheimer’s disease (AD) dementia has been associated with a ‘signature’ of cortical atrophy in paralimbic and heteromodal association regions measured with MRI.
Objective
To investigate whether a similar pattern of cortical atrophy is present in presymptomatic presenilin 1 E280A mutation carriers an average of 6 years before clinical symptom onset.
Methods
40 cognitively normal volunteers from a Colombian population with familial AD were included; 18 were positive for the AD-associated presenilin 1 mutation (carriers, mean age=38) whereas 22 were non-carriers. T1-weighted volumetric MRI images were acquired and cortical thickness was measured. A priori regions of interest from our previous work were used to obtain thickness from AD-signature regions.
Results
Compared to non-carriers, presymptomatic presenilin 1 mutation carriers exhibited thinner cortex within the AD-signature summary measure (p<0.008). Analyses of individual regions demonstrated thinner angular gyrus, precuneus and superior parietal lobule in carriers compared to non-carriers, with trend-level effects in the medial temporal lobe.
Conclusion
Results demonstrate that cognitively normal individuals genetically determined to develop AD have a thinner cerebral cortex than non-carriers in regions known to be affected by typical late-onset sporadic AD. These findings provide further support for the hypothesis that cortical atrophy is present in preclinical AD more than 5 years prior to symptom onset. Further research is needed to determine whether this method could be used to characterise the age-dependent trajectory of cortical atrophy in presymptomatic stages of AD.
doi:10.1136/jnnp-2012-303299
PMCID: PMC3632663  PMID: 23134660
22.  Apathy is associated with increased amyloid burden in mild cognitive impairment 
Apathy is the most common neuropsychiatric symptom in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. We sought to determine whether apathy is associated with cortical amyloid burden measured by Pittsburgh Compound B (PiB) positron emission tomography (PET) and regional hypometabolism measured by 18F-fluorodeoxyglocuse (FDG) PET in MCI. We found a significant association between increased apathy (lower Apathy Evaluation Scale score) and greater cortical PiB retention independent of age (prs=−0.46, p=0.03), but no significant association between apathy and regional FDG metabolism. These results suggest that increased apathy is associated with greater amyloid burden but not regional hypometabolism in MCI.
doi:10.1176/appi.neuropsych.12060156
PMCID: PMC3957217  PMID: 24247857
Alzheimer’s disease; amyloid; apathy; 18F-flourodeoxyglucose; mild cognitive impairment; Pittsburgh Compound B; positron emission tomography
23.  Amyloid deposition detected with florbetapir F 18 (18F-AV-45) is related to lower episodic memory performance in clinically normal older individuals 
Neurobiology of aging  2012;34(3):822-831.
The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 (18F-AV-45) amyloid PET, and cognition in healthy older control subjects (HC). Seventy-eight HC subjects were assessed with a brief cognitive test battery and PET imaging with florbetapir F 18. A standard uptake value ratio (SUVr) was computed for mean data from six cortical regions using a whole cerebellum reference region. Scans were also visually rated as amyloid positive (Aβ+) or amyloid negative (Aβ−) by three readers. Higher SUVr correlated with lower immediate memory (r=−0.33; p=0.003) and delayed recall scores (r=−0.25; p=0.027). Performance on immediate recall was also lower in the visually rated Aβ+ compared to Aβ− HC (p=0.04), with a similar trend observed in delayed recall (p=0.06). These findings support the hypothesis that higher amyloid burden is associated with lower memory performance among clinically normal older subjects. Longitudinal follow-up is ongoing to determine whether florbetapir F 18 may also predict subsequent cognitive decline.
doi:10.1016/j.neurobiolaging.2012.06.014
PMCID: PMC3518678  PMID: 22878163
24.  New ELISAs with high specificity for soluble oligomers of amyloid β-protein detect natural Aβ oligomers in human brain but not CSF 
Background
Soluble oligomers of amyloid β-protein (Aβ) have been increasingly linked to synaptic dysfunction, tau alteration and neuritic dystrophy in Alzheimer’s disease (AD) and mouse models. There is a great need for assays that quantify Aβ oligomers with high specificity and sensitivity.
Methods
We designed and validated two oligomer-specific (o-) ELISAs using either an Aβ aggregate-selective monoclonal for capture and a monoclonal to the free N-terminus for detection or the latter antibody for both capture and detection.
Results
The o-ELISAs specifically quantified pure oligomers of synthetic Aβ with sizes from dimers up to much larger assemblies and over a wide dynamic range of concentrations, whereas Aβ monomers were undetectable. Natural Aβ oligomers of similarly wide size and concentration ranges were measured in extracts of AD and control brains, revealing >1,000-fold higher concentrations of Aβ oligomers than monomers in the soluble fraction of AD cortex. The assays quantified the age-related rise in oligomers in hAPP transgenic mice. Unexpectedly, none of 90 human CSF samples gave a specific signal in either o-ELISA.
Conclusions
These new o-ELISAs with rigorously confirmed specificity can quantify oligomer burden in human and mouse brains for diagnostic and mechanistic studies and for AD biomarker development. However, our data raise the likelihood that the hydrophobicity of Aβ oligomers makes them very low or absent in aqueous CSF.
doi:10.1016/j.jalz.2012.11.005
PMCID: PMC3604133  PMID: 23375565
Alzheimer’s disease; amyloid β-peptide; oligomers; cerebrospinal fluid; brain extracts; ELISAs
25.  The parahippocampal gyrus links the default-mode cortical network with the medial temporal lobe memory system 
Human brain mapping  2013;35(3):1061-1073.
The default-mode network (DMN) is a distributed functional-anatomic network implicated in supporting memory. Current resting-state functional connectivity studies in humans remain divided on the exact involvement of medial temporal lobe (MTL) in this network at rest. Notably, it is unclear to what extent the MTL regions involved in successful memory encoding are connected to the cortical nodes of the DMN during resting-state. Our findings using functional connectivity MRI analyses of resting-state data indicate that the parahippocampal gyrus (PHG) is the primary hub of the DMN in the MTL during resting-state. Also, connectivity of the PHG is distinct from connectivity of hippocampal regions identified by an associative memory encoding task. We confirmed that several hippocampal encoding regions lack significant functional connectivity with cortical DMN nodes during resting-state. Additionally, a mediation analysis showed that resting-state connectivity between the hippocampus and posterior cingulate cortex — a major hub of the DMN — is indirect and mediated by the PHG. Our findings support the hypothesis that the MTL memory system represents a functional sub-network that relates to the cortical nodes of the DMN through parahippocampal functional connections.
doi:10.1002/hbm.22234
PMCID: PMC3773261  PMID: 23404748
Brain mapping; physiology; human; resting state; functional connectivity; brain networks; Magnetic Resonance Imaging; MTL; mediation; young adult

Results 1-25 (92)