Positive Amyloid Positron Emission Tomography Research Articles

18 F]FDG PET may differentiate cerebral amyloid angiopathy from Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) is a frequent cause of both intracerebral hemorrhage (ICH) and cognitive impairment in the elderly. Diagnosis relies on the Boston criteria, which use magnetic resonance imaging markers including ≥2 exclusively lobar cerebral microbleeds (lCMBs). Although amyloid positron emission tomography (PET) may provide molecular diagnosis, its specificity relative to Alzheimer's disease (AD) is limited due to the prevalence of positive amyloid PET in cognitively normal elderly. Using early-phase 11 C-Pittsburgh compound B as surrogate for tissue perfusion, a significantly lower occipital/posterior cingulate (O/PC) tracer uptake ratio in probable CAA relative to AD was recently reported, consistent with histopathological lesion distribution. We tested whether this finding could be reproduced using [18 F]fluorodeoxyglucose (FDG)-PET, a widely available modality that correlates well with early-phase amyloid PET in both healthy subjects and AD. From a large memory clinic database, we retrospectively included 14 patients with probable CAA (Boston criteria) and 21 patients with no lCMB fulfilling AD criteria including cerebrospinal fluid biomarkers. In all, [18 F]FDG-PET/computed tomography (CT) was available as part of routine care. No subject had a clinical history of ICH. Regional standardized [18 F]FDG uptake values normalized to the pons (standard uptake value ratio [SUVr]) were obtained, and the O/PC ratio was calculated. The SUVr O/PC ratio was significantly lower in CAA versus AD (1.02±0.14 vs. 1.19±0.18, respectively; p=0.024). Despite the small sample, our findings are consistent with the previous early-phase amyloid PET study. Thus, [18 F]FDG-PET may help differentiate CAA from AD, particularly in cases of amyloid PET positivity. Larger prospective studies, including in CAA-related ICH, are however warranted.

Change in cognitive function according to cholinesterase inhibitor use and amyloid PET positivity in patients with mild cognitive impairment

BackgroundCholinesterase inhibitors (ChEIs) are an FDA-approved symptomatic treatment for patients with Alzheimer’s disease (AD). Its efficacy in patients with mild cognitive impairment (MCI), however, is controversial. Nonetheless, ChEIs have often been used in patients with MCI. From the perspective that ChEIs were developed based on the pathomechanism of AD, the effect of ChEIs in MCI patients could be different depending on the amyloid burden. In this retrospective observational study, we aimed to investigate the influence of ChEIs and amyloid burden on cognitive change for 1 year in patients with MCI.MethodsWe included 111 patients with MCI with a Clinical Dementia Rating (CDR) score of 0.5, a 1-year follow-up cognitive assessment, and amyloid positron emission tomography (PET) performed within 6 months before or after the baseline cognitive assessment (73 ChEI users and 38 ChEI non-users) from the Neurocognitive Behavior Center of Seoul National University Bundang Hospital. Additionally, those who had a positive amyloid PET scan more than 6 months before the baseline cognitive assessment and those who had a negative amyloid PET scan more than 6 months after the 1-year follow-up cognitive assessment were also included. Among the total 111 patients, 25 ChEI users and 25 ChEI non-users were matched by baseline Mini-Mental State Examination (MMSE) score, age, educational level, CDR Sum of Boxes, and amyloid PET positivity using propensity score matching. Multiple linear regression analysis was performed to assess the influence of ChEI use and amyloid PET positivity on cognitive change for 1 year. Univariate and multivariate logistic regression analyses were performed to evaluate the association between ChEI use and disease progression to CDR 1 at the 1-year follow-up visit.ResultsChEI use or non-use was not associated with cognitive change for 1 year. Amyloid PET positivity or negativity did not change this non-association. Furthermore, progression to CDR 1 was related to low baseline MMSE score (OR 0.606, CI 0.381–0.873), but not with ChEI use or non-use, and not with amyloid PET result.ConclusionChEI use or non-use was not related to cognitive change at a 1-year follow-up visit in patients with or without amyloid burden. In addition, ChEI use or non-use could not predict disease progression to CDR 1 at 1-year follow-up visit.

Added value of cerebrospinal fluid multimarker analysis in diagnosis and progression of dementia.

Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as diagnostic tools for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain amyloid positron emission tomography (PET). We also investigated whether they help in differentiating AD from other dementias and examined their influence in tracing the progression to dementia. Amyloid-β (Aβ) 1-42, total tau (t-tau), phosphorylated tau, Aβ40 , Aβ38 , beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), neurogranin (ng), phosphorylated neurofilament heavy-chain, and α-synuclein (α-syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an amyloid PET scan. We also analyzed longitudinal clinical data from 239 subjects. Emerging CSF markers, especially ng/BACE-1 ratio (area under the curve = 0.77) and their combinations with core AD CSF markers (all AUCs >0.85), showed high accuracy to discriminate amyloid PET positivity. Subjects with AD had higher CSF BACE-1, ng, and α-syn levels than those with non-AD dementia. CSF t-tau/α-syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core AD ratios predicted a faster conversion from mild cognitive impairment (MCI) stage to AD and appeared to be helpful when core AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core AD markers, several emerging/core AD two-marker ratios, and CSF ng levels. These results suggest that emerging biomarkers in conjunction with core AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD, and predict a faster progression of dementia.

The solely A+ CSF Aβ42/40 ratio using Elecsys® assays performs similar to A/T and A/N ratios in predicting amyloid PET positivity

AbstractBackgroundpTau181/Aβ42 (A+/T+ as per A/T/(N) classification) and tTau/Aβ42 (A+/(N)+) ratios using fully automated Elecsys® cerebrospinal‐fluid (CSF) immunoassays have been shown to perform well in distinguishing amyloid‐positivity (A+) by positron emission tomography (PET) among patients with subjective and mild to severe cognitive impairment. Higher performance has also been demonstrated for the CSF Aβ42/40 ratio compared to CSF amyloid 42 (Aβ42) alone. We aimed to further evaluate the performance of the Elecsys® Aβ42/40 ratio in a clinical cohort.MethodsFrozen (‐80°C) CSF samples from 103 patients treated in the Centre for Cognitive Disorders, Technical University of Munich were selected based on availability of visual amyloid‐PET status (n=54 PET+; 49 PET‐) determined during standard treatment around the time of CSF collection. In total, 71 patients were undergoing treatment for mild cognitive impairment (MCI) (n=44) or mild to moderate dementia (n=27) due to Alzheimer’s disease (AD) and 32 patients for non‐AD related fronto‐temporal lobar degeneration (n=17), MCI (n=8), depression (n=5), alcohol dependence (n=1), or subjective cognitive impairment (SCD) (n=1). CSF was measured using Elecsys® assays. CSF status for Aβ42 , pTau181/Aβ42 , and tTau/Aβ42 CSF (positive/negative) was determined based on pre‐defined biomarker cutoffs previously established using a different pre‐analytical protocol in MCI/SCD patients with suspected AD (CSF positive if Aβ42<1000 pg/ml, pTau181/Aβ42>0.024, and tTau/Aβ42>0.028). Sensitivity and specificity were calculated for CSF‐cutoff‐based status and ROC analysis was performed to determine AUC each versus visual amyloid‐PET status.ResultsPre‐defined biomarker thresholds were considered off‐label due to deviation from recommended sample collection protocol and storage parameters. Point estimates for sensitivity and specificity for each biomarker were; CSF Aβ42 alone (sensitivity = 0.93, specificity = 0.57), pTau181/Aβ42 (0.96, 0.69), and tTau/Aβ42 (0.92, 0.69). For AUC point estimates (95% confidence interval) were; CSF Aβ42 alone [0.78 (0.68‐0.88)], pTau181/Aβ42 [0.88 (0.81‐0.95)], tTau/Aβ42 [0.87(0.80‐0.95)], and Aβ42/40 [0.90 (0.83‐0.95)].ConclusionFully automated Elecsys® cerebrospinal fluid (CSF) immunoassay predicted amyloid positivity with high accuracy. In this study, the solely A+ marker CSF Aβ42/40 ratio outperformed Aβ42 alone and performed similarly to Tau ratios. These results support those of previous studies showing high performance for the non‐Tau marker CSF Aβ42/40.

Multimodal in vivo and postmortem assessments of tau in Lewy body disorders

We compared regional retention of 18F-flortaucipir between 20 patients with Lewy body disorders (LBD), 12 Alzheimer’s disease patients with positive amyloid positron emission tomography (PET) scans (AD+Aβ) and 15 healthy controls with negative amyloid PET scans (HC−Aβ). In LBD subjects, we compared the relationship between 18F-flortaucipir retention and cerebrospinal fluid (CSF) tau, cognitive performance, and neuropathological tau at autopsy. The LBD cohort was stratified using an Aβ42 cut-off of 192 pg/mL to enrich for groups likely harboring tau pathology (LBD+Aβ = 11, LBD−Aβ = 9). 18F-flortaucipir retention was higher in LBD+AB than HC−Aβ in five, largely temporal-parietal regions with sparing of medial temporal regions. Higher retention was associated with higher CSF total-tau levels (p = 0.04), poorer domain-specific cognitive performance (p = 0.02–0.04), and greater severity of neuropathological tau in corresponding regions. While 18F-flortaucipir retention in LBD is intermediate between healthy controls and AD, retention relates to cognitive impairment, CSF total-tau, and neuropathological tau. Future work in larger autopsy-validated cohorts is needed to define LBD-specific tau biomarker profiles.

Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer's disease.

The links between β-amyloid (Aβ) and tau in Alzheimer's disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aβ pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aβ aggregation started. These results show that Aβ pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.

Predicting Amyloid Burden to Accelerate Recruitment of Secondary Prevention Clinical Trials

BackgroundScreening to identify individuals with elevated brain amyloid (Aβ+) for clinical trials in Preclinical Alzheimer’s Disease (PAD), such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) trial, is slow and costly. The Trial-Ready Cohort in Preclinical/Prodromal Alzheimer’s Disease (TRC-PAD) aims to accelerate and reduce costs of AD trial recruitment by maintaining a web-based registry of potential trial participants, and using predictive algorithms to assess their likelihood of suitability for PAD trials.ObjectivesHere we describe how algorithms used to predict amyloid burden within TRC-PAD project were derived using screening data from the A4 trial.DesignWe apply machine learning techniques to predict amyloid positivity. Demographic variables, APOE genotype, and measures of cognition and function are considered as predictors. Model data were derived from the A4 trial.SettingTRC-PAD data are collected from web-based and in-person assessments and are used to predict the risk of elevated amyloid and assess eligibility for AD trials.ParticipantsPre-randomization, cross-sectional data from the ongoing A4 trial are used to develop statistical models.MeasurementsModels use a range of cognitive tests and subjective memory assessments, along with demographic variables. Amyloid positivity in A4 was confirmed using positron emission tomography (PET).ResultsThe A4 trial screened N=4,486 participants, of which N=1323 (29%) were classified as Aβ+ (SUVR ≥ 1.15). The Area under the Receiver Operating Characteristic curves for these models ranged from 0.60 (95% CI 0.56 to 0.64) for a web-based battery without APOE to 0.74 (95% CI 0.70 to 0.78) for an in-person battery. The number needed to screen to identify an Aβ+ individual is reduced from 3.39 in A4 to 2.62 in the remote setting without APOE, and 1.61 in the remote setting with APOE.ConclusionsPredictive algorithms in a web-based registry can improve the efficiency of screening in future secondary prevention trials. APOE status contributes most to predictive accuracy with cross-sectional data. Blood-based assays of amyloid will likely improve the prediction of amyloid PET positivity.

Plasma amyloid assay as a pre-screening tool for amyloid positron emission tomography imaging in early\xa0stage Alzheimer\u2019s disease

IntroductionDue to the high cost and high failure rate of ascertaining amyloid positron emission tomography positivity (PET+) in patients with earlier stage Alzheimer’s disease (AD), an effective pre-screening tool for amyloid PET scans is needed.MethodsPatients with mild cognitive impairment (n = 33, 24.2% PET+, 42% females, age 74.4 ± 7.5, MMSE 26.8 ± 1.9) and mild dementia (n = 19, 63.6% PET+, 36.3% females, age 73.0 ± 9.3, MMSE 22.6 ± 2.0) were recruited. Amyloid PET imaging, Apolipoprotein E (APOE) genotyping, and plasma amyloid β (Aβ)1–40, Aβ1–42, and total tau protein quantification by immunomagnetic reduction (IMR) method were performed. Receiver operating characteristics (ROC) analysis and Youden’s index were performed to identify possible cut-off points, clinical sensitivities/specificities, and areas under the curve (AUCs).ResultsAmyloid PET+ participants had lower plasma Aβ1–42 levels than amyloid PET-negative (PET−) subjects. APOE ε4 carriers had higher plasma Aβ1–42 than non-carriers. We developed an algorithm involving the combination of plasma Aβ1–42 and APOE genotyping. The success rate for detecting amyloid PET+ patients effectively increased from 42.3 to 70.4% among clinically suspected MCI and mild dementia patients.ConclusionsOur results demonstrate the possibility of utilizing APOE genotypes in combination with plasma Aβ1–42 levels as a pre-screening tool for predicting the positivity of amyloid PET findings in early stage dementia patients.

Association of brain amyloidosis with the incidence and frequency of neuropsychiatric symptoms in ADNI: a multisite observational cohort study

ObjectiveTo investigate the relationship between amyloid burden and frequency of existing and incidence of new neuropsychiatric symptoms (NPS) in elderly with and without cognitive decline.Methods275 cognitively normal controls (NC), 100...

Willingness to Undergo a Risky Treatment to Improve Cognition Among Persons With Cognitive Impairment Who Received an Amyloid PET Scan.

To evaluate determinants of willingness to accept a treatment to return memory to normal among persons with cognitive impairment who received an amyloid positron emission tomography (PET) scan and their care partner and discordance in risk taking. Using data from CARE-IDEAS (n=1872 dyads), a supplement of the Imaging Dementia-Evidence for Amyloid Scanning study, we predicted scan recipient's willingness to accept a risky treatment, the risk care partners believed their care recipient would accept, and discordance in these perceptions. Scan recipients were willing to accept a treatment with a 27.94% (SD=34.36) risk of death. Care partners believed their care recipient would accept a 29.68% (SD=33.74) risk of death; thus, overestimating risk acceptance by 1.74 (SD=41.88) percentage points. A positive amyloid PET scan was associated with willingness to accept greater risk. Poorer functioning of the care recipient was associated with care partners believing their care recipient would accept more risk. The amyloid PET scan result was not significantly associated with discordance, but poorer functioning of the care recipient resulted in care partners overestimating risk. Scan recipients were willing to accept a treatment with a high risk of death. Discordance was affected by scan recipient's having poorer functioning.

Does informant-based reporting of cognitive symptoms predict amyloid positivity on positron emission tomography?

IntroductionResearchers are searching for clinical instruments to predict amyloid positivity for disease classification. Informant-based reports could detect disease status. This study compares subjective memory complaints captured by informant-based reports between positron emission tomography (PET)–positive and PET-negative patients and hypothesizes that amyloid PET positivity associates with increased informant-based cognitive complaints. MethodsNinety-eight amnestic mild cognitive impairment or mild dementia subjects were studied. Subjective report was captured by the informant-driven Alzheimer's Questionnaire (AQ) administered before PET. Differences in demographics and AQ score by diagnostic status and amyloid status were measured, and a receiver-operating characteristic curve was calculated. ResultsSixty-five mild cognitive impairment/Alzheimer's disease amyloid PET-positive and 33 amyloid PET-negative subjects were included. AQ was significantly higher (12.51 ± 4.95) for amyloid PET-positive subjects (9.06 ± 3.65; P = .001). ConclusionsAmyloid PET-positive subjects with Alzheimer's disease or mild cognitive impairment have more informant-based reports of cognitive decline, indicating utility for a brief informant measure.

Challenges associated with biomarker-based classification systems for Alzheimer's disease

IntroductionWe aimed to evaluate the consistency of the A/T/N classification system. MethodsWe included healthy controls, mild cognitive impairment, and dementia patients from Alzheimer's disease Neuroimaging Initiative. We assessed subject classification consistency with different biomarker combinations and the agreement and correlation between biomarkers. ResultsSubject classification discordance ranged from 12.2% to 44.5% in the whole sample; 17.3%–46.4% in healthy controls; 11.9%–46.5% in mild cognitive impairment, and 1%–35.7% in dementia patients. Amyloid, but not neurodegeneration biomarkers, showed good agreement both in the whole sample and in the clinical subgroups. Amyloid biomarkers were correlated in the whole sample, but not along the Alzheimer's disease continuum (as defined by a positive amyloid positron emission tomography). Neurodegeneration biomarkers were poorly correlated both in the whole sample and along the Alzheimer's disease continuum. The relationship between biomarkers was stage-dependent. DiscussionOur findings suggest that the current A/T/N classification system does not achieve the required consistency to be used in the clinical setting.

Evidence-based Interpretation of Amyloid-β PET Results: A Clinician's Tool.

Amyloid-β positron emission tomography (PET) allows for in vivo detection of fibrillar amyloid plaques, a pathologic hallmark of Alzheimer's disease (AD). However, amyloid-β PET interpretation is limited by the imperfect correlation between PET and autopsy, and the fact that it is positive in about 20% to 30% of cognitively normal individuals and non-AD dementias, especially when older or carrying the ε4 allele of apolipoprotein E (ApoE4). When facing a positive amyloid PET, clinicians have to evaluate the probability of a pathologic false positive as well as the probability of amyloid positivity being age-related, comorbid to a primary non-AD dementia (clinicopathologic false positive). These probabilities can be calculated to reach an evidence-based interpretation of amyloid-β. As literature review and calculations cannot be easily performed in the day-to-day clinic, we propose a clinician friendly, evidence-based Bayesian approach to the interpretation of amyloid-β PET results in the differential diagnosis of patients with cognitive impairment. We defined AD as a clinicopathologic entity in which amyloid-β is the primary cause of cognitive impairment. We systematically reviewed the literature to estimate the sensitivity and specificity of amyloid-β PET against neuropathologic examination. We inferred rates of clinicopathologic false positivity (non-AD dementia with comorbid amyloid) based on age-dependent and ApoE-dependent prevalence of amyloid positivity in normal individuals and AD patients provided in large meta-analyses published by the Amyloid Biomarker Study Group. We calculated positive predictive value (PPV) and negative predictive value (NPV) of amyloid-β PET, which are presented in a clinician-friendly table. PPV of PET is highest in young ApoE4- patients with high pre-PET probability of AD. In older ApoE4+ patients with low pre-PET probability of AD, positive amyloid-β PET scans must be interpreted with caution. A negative amyloid-β PET makes a diagnosis of AD unlikely except in old patients with high pre-PET probability of AD. This evidence-based approach might provide guidance to clinicians and nuclear medicine physicians to interpret amyloid-β PET results for early and differential diagnosis of patients with progressive cognitive impairment.

Amnestic MCI patients\u2019 experiences after disclosure of their amyloid PET result in a research context

BackgroundBiomarkers such as amyloid imaging are increasingly used for diagnosis in the early stages of Alzheimer’s disease. Very few studies have examined this from the perspective of the patient. To date, there is only limited evidence about how patients experience and value disclosure in an early disease stage.MethodsSemistructured interviews were carried out with 38 patients with amnestic mild cognitive impairment as part of an investigator-driven diagnostic trial (EudraCT, 2013-004671-12; registered on 20 June 2014) in which participants could opt to know the binary outcome (positive/negative) result of their amyloid positron emission tomography (PET) scan. Verbatim transcripts of the interviews were evaluated using qualitative content analysis and NVivo 11 software.ResultsEight of 38 patients received a positive amyloid PET scan result, and the remaining 30 patients received a negative amyloid PET scan result. After disclosure of the result to the patients, we interviewed each patient twice: 2 weeks after disclosure and 6 months after disclosure. Patients had difficulties in repeating the exact words used during disclosure of their amyloid PET scan result by the neurologist; yet, they could recall the core message of the result in their own words. Some patients were confused by the terminology of an amyloid-positive/negative test result. At 6 months, two of eight patients with a positive amyloid PET scan result experienced emotional difficulties (sadness, feeling worried). Three of 30 patients with a negative amyloid PET scan result started to doubt whether they had received the correct result. Patients reported that they experienced advantages after the disclosure, such as information about their health status, the possibility of making practical arrangements, medication, enjoying life more, and a positive impact on relationships. They also reported disadvantages following disclosure, such as having emotional difficulties, feeling worried about when their symptoms might worsen, the risk of a more patronizing attitude by relatives, and the possibility of a wrong diagnosis.ConclusionsThis exploratory study shows that the majority of patients can accurately recall the information received during disclosure. The experienced advantages and disadvantages reported by our patients depended on the outcome of the result (positive or negative) and the interval of the conducted interview (2 weeks or 6 months after amyloid PET disclosure). Discrepancies were found between patients’ expectations according to the interview prior to amyloid PET disclosure (Vanderschaeghe et al. [Neuroethics. 2017;10:281–97]) and their actual experiences after their amyloid PET disclosure.

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer\u2019s disease dementia

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer’s disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-β deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

Prevalence of Amyloid Positron Emission Tomographic Positivity in Poststroke Mild Cognitive Impairment

Mild cognitive impairment (MCI) is common after stroke and associated with poor outcome. However, the mechanisms underlying poststroke MCI (PS-MCI) are insufficiently understood. We performed amyloid-β positron emission tomography (PET) in a prospective cohort of stroke survivors to determine the role of amyloid pathology in PS-MCI. We studied 178 consecutive patients enrolled into the prospective DEDEMAS study (Determinants of Dementia After Stroke). Follow-up visits 6 months post stroke included detailed cognitive testing, standardized magnetic resonance imaging, and amyloid-β imaging using flutemetamol ((18)F) PET. MCI was defined by the modified Petersen criteria. Amyloid-positivity was assessed visually and quantitatively. Fifty-six (31%) patients agreed to undergo PET imaging. Thirty-eight (68%) patients who consented to PET imaging had PS-MCI. Visual assessment revealed amyloid PET positivity in 2 (5%) of the 38 PS-MCI patients and in 2 (11%) of the 18 cognitively healthy stroke survivors. There was no correlation between flutemetamol ((18)F) standardized uptake value ratios and cognitive scores in the 56 patients. PS-MCI patients had significant cognitive impairments on executive function (P<0.01) and memory tests (P<0.01) when compared with cognitively healthy stroke survivors (P<0.01). The prevalence of amyloid-pathology in patients with PS-MCI is not increased when compared with cognitively healthy stroke survivors and to recent estimates for cognitively healthy elderly subjects. Factors other than amyloid-pathology likely contribute to the development of PS-MCI. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01334749.

Sulcal morphology as a new imaging marker for the diagnosis of early onset Alzheimer's disease

We investigated the utility of sulcal width measures in the diagnosis of Alzheimer's disease (AD). Sixty-six biologically confirmed AD patients (positive amyloid positron emission tomography [PET] and/or AD cerebrospinal fluid profile) were contrasted to 35 controls with negative amyloid PET. Patients were classified into prodromal or dementia stages as well as into late onset (LOAD, n = 31) or early onset (EOAD, n = 35) subgroups according to their age of onset. An automated method was used to calculate sulcal widths and hippocampal volumes (HV). In EOAD, the greatest ability to differentiate patients from age-matched controls, regardless of severity, was displayed by sulcal width of the temporoparietal cortex. In this region, diagnosis accuracy was better than the HV, especially at prodromal stage. In LOAD, HV provided the best discrimination power from age-matched controls. In conclusion, sulcal width measures are better markers than the HV for identifying prodromal AD in patients aged <65 years. In contrast, in older patients, the risk of over-diagnosis from using only sulcal enlargement is important.

Defining Amyloid Pathology in Persons With and Without Dementia Syndromes

In this issue of JAMA, 2 articles from the Netherlands report findings from meta-analyses that assess the prevalence of amyloidpathologyasdeterminedbybiomarkers inpersonswith normal cognition, subjective cognitive impairment (SCI),or mild cognitive impairment (MCI)1andestimatetheprevalence of amyloid positivity on amyloid-β positron emission tomography (PET) in a wide variety of dementia syndromes.2 These reports are the largest andmost detailed to date and are critical assessments that help define the role of amyloid in the causation of cognitive impairment and dementia. Theearliestpathological change inAlzheimerdisease (AD), aggregationof cerebral amyloid-β, is presentup to 20years beforetheonsetofdementia.3,4Accuracy indeterminingthecause ofcognitive lossandsubsequentdementiaandeliminatingfalsepositivecases inclinical trialsevaluatingamyloid-relatedtherapeutics require a precise determination of the status of amyloid pathology. Further, therapy for AD requires initiation of treatment in the predementia phase when the neuropathology is limited and regeneration can potentially occur. Jansen et al1 conducted an individual participant metaanalysis to provide an estimate of the prevalence of amyloid pathology based on biomarker criteria in personswithout dementia.Theauthors includeddata from2914personswithnormal cognition, 697 with SCI, and 3972 with MCI. Amyloid pathologyprevalencewasestimatedandthe relationwithknown risk factors for AD-type dementia, including age, sex, education, and APOE genotype, was studied. Theauthors includedamyloidPETdata from29studiesand cerebrospinal fluid (CSF) amyloid-β1-42 data from 31 studies and estimated the probabilities of amyloid positivity according tocognitivestatus,APOE-e4status,andanagerangeof18to100 years.Theresultsprovideanappreciationofamyloidpathology across these variables. Amyloid positivity by agewas related to cognitivestatusandAPOEgenotype.Theinvestigatorsfoundthat atage90years,about40%oftheAPOE-e4noncarriersandmore than80%ofAPOE-e4carrierswithnormalcognitionhadevidence ofamyloidpositivity.Educationwas related toamyloidpositivity, but no correlationwas present for sex or biomarkermodality.PatientswithMCIhad20%to30%higherprevalenceratesof amyloidpositivitythanthosewithnormalcognitionorSCI.Thus, these findingsare inaccordwith theviewthatMCI is a risk state forAD.5 SomepatientswithadiagnosisofMCIhadnoevidence of amyloid positivity, suggesting that theMCI phenotype is not alwaysassociatedwithADpathology.Jansenetal1 speculatethat amyloid-negative individualswithMCIhavesyndromes includinghippocampal sclerosis, depression,orvasculardisease.The APOE-e4riskallelecomparedwithAPOE-e3wasassociatedwith an increased likelihoodofamyloidpositivityanddecreasedage atonset.TheAPOE-e2allelewasassociatedwith reduced likelihood of amyloid pathology and a later age of onset. The cognitive reserve hypothesis was supported in their analysis as highly educated persons had a higher prevalence of amyloid pathology than those with reduced levels of education and a lower and later onset for developingAD-type dementia. These findings support the view that education provides increased complexities of synaptic architecture and increased efficiencies of information processing in alternate and increased circuits and thusprovides protection and resistance against amyloid-related pathology. The central observation in thismeta-analysiswas that the identified risk factors for AD-type dementia are also the same risk factors for amyloidpositivity in personswithnormal cognition. This relationship supports the hypothesis that amyloid positivity in these persons indicated early AD. In addition, amyloid positivity in persons without dementia is also associatedwithmemory loss, lossof cognition, increasedamyloid deposition, brain atrophy, and mortality.5-8 The analysis byJansenetal1 indicatesa20to30-year intervalbetweenamyloid positivity and AD-type dementia. In another article, Ossenkoppele et al2 extend the findings related to amyloid pathology with a meta-analysis of individualparticipantdata toestimatethepresenceofamyloidpositivity onPET in awidevariety of dementia syndromes. The authors included data involving 1359 persons with clinically diagnosedADand538participantswithnon-ADdementia.Based on analyses that examined relationships between amyloid PET positivity and age, sex, education cognition, andAPOE-e4, the authorsdemonstratedthattheprevalenceofamyloidonPETdecreasedwithageinAD-diagnosedpatients,mostlywithAPOE-e4 noncarriers, and increased with age in most non-AD dementias.Thevalueoftheseobservationsisthatamyloidimagingmay be most critical in making the correct diagnosis in early-onset dementia, especially to rule in AD dementia.2 In addition, the investigatorsemphasize that theconcordancebetweenPETand pathology indicates that amyloid imaging has the potential to be used to rule out AD dementia regardless of age. Of note, 12% of patients with clinically diagnosed AD dementia had a negative amyloid PET scan, and this finding Related articles pages 1924 and 1939 Opinion

Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis.

Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. To use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes. The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies. Case reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data. Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy). Estimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status, using the generalized estimating equations method. The likelihood of amyloid positivity was associated with age and APOE ε4 status. In AD dementia, the prevalence of amyloid positivity decreased from age 50 to 90 years in APOE ε4 noncarriers (86% [95% CI, 73%-94%] at 50 years to 68% [95% CI, 57%-77%] at 90 years; n = 377) and to a lesser degree in APOE ε4 carriers (97% [95% CI, 92%-99%] at 50 years to 90% [95% CI, 83%-94%] at 90 years; n = 593; P < .01). Similar associations of age and APOE ε4 with amyloid positivity were observed in participants with AD dementia at autopsy. In most non-AD dementias, amyloid positivity increased with both age (from 60 to 80 years) and APOE ε4 carriership (dementia with Lewy bodies: carriers [n = 16], 63% [95% CI, 48%-80%] at 60 years to 83% [95% CI, 67%-92%] at 80 years; noncarriers [n = 18], 29% [95% CI, 15%-50%] at 60 years to 54% [95% CI, 30%-77%] at 80 years; frontotemporal dementia: carriers [n = 48], 19% [95% CI, 12%-28%] at 60 years to 43% [95% CI, 35%-50%] at 80 years; noncarriers [n = 160], 5% [95% CI, 3%-8%] at 60 years to 14% [95% CI, 11%-18%] at 80 years; vascular dementia: carriers [n = 30], 25% [95% CI, 9%-52%] at 60 years to 64% [95% CI, 49%-77%] at 80 years; noncarriers [n = 77], 7% [95% CI, 3%-18%] at 60 years to 29% [95% CI, 17%-43%] at 80 years. Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid imaging for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years.

Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse models.

Abnormalities in brains of Alzheimer's disease (AD) patients are thought to start long before the first clinical symptoms emerge. The identification of affected individuals at this ‘preclinical AD’ stage relies on biomarkers such as decreased levels of the amyloid-β peptide (Aβ) in the cerebrospinal fluid (CSF) and positive amyloid positron emission tomography scans. However, there is little information on the longitudinal dynamics of CSF biomarkers, especially in the earliest disease stages when therapeutic interventions are likely most effective. To this end, we have studied CSF Aβ changes in three Aβ precursor protein transgenic mouse models, focusing our analysis on the initial Aβ deposition, which differs significantly among the models studied. Remarkably, while we confirmed the CSF Aβ decrease during the extended course of brain Aβ deposition, a 20–30% increase in CSF Aβ40 and Aβ42 was found around the time of the first Aβ plaque appearance in all models. The biphasic nature of this observed biomarker changes stresses the need for longitudinal biomarker studies in the clinical setting and the search for new ‘preclinical AD’ biomarkers at even earlier disease stages, by using both mice and human samples. Ultimately, our findings may open new perspectives in identifying subjects at risk for AD significantly earlier, and in improving the stratification of patients for preventive treatment strategies.