Marissa D. Zwan

Amyloid burden and metabolic function in early-onset Alzheimer's disease: parietal lobe involvement

Alzheimers disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimers disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimers disease and 20 healthy controls. Parametric non-displaceable binding potential images of [(11)C]Pittsburgh compound-B and standardized uptake value ratio images of [(18)F]fluorodeoxyglucose were generated using cerebellar grey matter as reference tissue. Nine [(11)C]Pittsburgh compound-B-negative patients were excluded. The remaining patients were categorized into younger (n=45, age: 56 ± 4 years) and older (n=46, age: 69 ± 5 years) groups, based on the median age (62 years) at time of diagnosis. Younger patients showed more severe impairment on visuo-spatial function, attention and executive function composite scores (P<0.05), while we found a trend towards poorer memory performance for older patients (P=0.11). Differences between groups were assessed using a general linear model with repeated measures (gender adjusted) with age as between subjects factor, region (frontal, temporal, parietal and occipital and posterior cingulate cortices) as within subjects factor and [(11)C]Pittsburgh compound-B binding/[(18)F]fluorodeoxyglucose uptake as dependent variables. There was no main effect of age for [(11)C]Pittsburgh compound-B or [(18)F]fluorodeoxyglucose, suggesting that overall, the extent of amyloid deposition or glucose hypometabolism did not differ between groups. Regional distributions of [(11)C]Pittsburgh compound-B binding and [(18)F]fluorodeoxyglucose uptake (both P for interaction <0.05) differed between groups, however, largely due to increased [(11)C]Pittsburgh compound-B binding and decreased [(18)F]fluorodeoxyglucose uptake in the parietal cortex of younger patients (both P<0.05). Linear regression analyses showed negative associations between visuo-spatial functioning and parietal [(11)C]Pittsburgh compound-B binding for younger patients (standardized β: -0.37) and between visuo-spatial functioning and occipital binding for older patients (standardized β: -0.39). For [(18)F]fluorodeoxyglucose, associations were found between parietal uptake with visuo-spatial (standardized β: 0.55), attention (standardized β: 0.39) and executive functioning (standardized β: 0.37) in younger patients, and between posterior cingulate uptake and memory in older patients (standardized β: 0.41, all P<0.05). These in vivo findings suggest that clinical differences between younger and older patients with Alzheimers disease are not restricted to topographical differentiation in downstream processes but may originate from distinctive distributions of early upstream events. As such, increased amyloid burden, together with metabolic dysfunction, in the parietal lobe of younger patients with Alzheimers disease may contribute to the distinct cognitive profile in these patients.

Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia.

Objective: To examine the relationships between apolipoprotein E (APOE) ɛ4 dose and in vivo distributions of both fibrillary amyloid burden and glucose metabolism in the same Alzheimer disease dementia patients, selected for abnormal amyloid imaging. Methods: Twenty-two APOE ɛ4 negative, 40 heterozygous, and 22 homozygous Alzheimer disease dementia patients underwent dynamic (90 minutes) [11C]Pittsburgh compound B (PIB) and static [18F]fluorodeoxyglucose (FDG) PET scans. Parametric nondisplaceable binding potential images of [11C]PIB and standardized uptake value ratio images of [18F]FDG were generated using cerebellar gray matter as reference tissue. Frontal, parietal, temporal, posterior cingulate, and occipital cortices were selected as regions of interest. Results: Multivariate general linear models with adjustment for age, sex, and Mini-Mental State Examination showed main effects of APOE ɛ4 dose on distributions of both [11C]PIB (p for trend <0.05) and [18F]FDG (p for trend <0.01). More specifically, a univariate general linear model of individual regions showed increased [11C]PIB binding in frontal cortex of APOE ɛ4 noncarriers compared with APOE ɛ4 carriers (p < 0.05). In contrast, APOE ɛ4 carriers had reduced [18F]FDG uptake in occipital cortex (p < 0.05) and a borderline significant effect in posterior cingulate (p = 0.07) in a dose-dependent manner. Conclusion: We found a reversed APOE ɛ4 dose effect for amyloid deposition in the frontal lobe, whereas APOE ɛ4 carriership was associated with more profound metabolic impairment in posterior parts of the cortex. These findings suggest that APOE genotype has a differential effect on the distribution of amyloid plaques and glucose metabolism. This may have important implications for emerging therapies that aim to directly intervene in the disease process.

Concordance between cerebrospinal fluid biomarkers and [11C]PIB PET in a memory clinic cohort.

BACKGROUND Two approaches are available for measuring Alzheimers disease (AD) pathology in vivo. Biomarkers in cerebrospinal fluid (CSF) include amyloid-β1-42 (Aβ42) and tau. Furthermore, amyloid deposition can be visualized using positron emission tomography (PET) and [11C]Pittsburgh compound-B ([11C]PIB). OBJECTIVE We investigated concordance between CSF biomarkers and [11C]PIB PET as markers for AD pathology in a memory clinic cohort. METHODS We included 64 AD patients, 34 non-AD dementia patients, 22 patients with mild cognitive impairment (MCI), and 16 controls. [11C]PIB scans were visually rated as positive or negative. CSF biomarkers were considered abnormal based on Aβ42 alone (<550 ng/L), a more lenient Aβ42 cut-off (<640 ng/L) or a combination of both Aβ42 and tau ((373 + 0.82 tau)/Aβ42 > 1). Concordance between CSF biomarkers and [11C]PIB PET was determined. RESULTS Overall, concordance between [11C]PIB PET and CSF Aβ42 (<550 ng/L) was 84%. In discordant cases, [11C]PIB PET was more often AD-positive than Aβ42. When a more lenient Aβ42 cut-point (<640 ng/L) or a combination of Aβ42 and tau was used, concordance with [11C]PIB PET appeared to be even higher (90% and 89%). This difference is explained by a subgroup of mostly MCI and AD patients with Aβ42 levels just above cut-off. Now, in discordant cases, CSF was more often AD-positive than [11C]PIB PET. CONCLUSION Concordance between CSF Aβ42 and [11C]PIB PET was good in all diagnostic groups. Discordance was mostly seen in MCI and AD patients close to the cut-point. These results provide convergent validity for the use of both types of biomarkers as measures of AD pathology.

Long-term effects of amyloid, hypometabolism, and atrophy on neuropsychological functions.

Objective: To assess how amyloid deposition, glucose hypometabolism, and cerebral atrophy affect neuropsychological performance in patients with Alzheimer disease (AD) dementia, patients with mild cognitive impairment (MCI), and controls over time. Methods: A total of 41 patients with AD dementia, 28 patients with MCI, and 19 controls underwent [11C]–Pittsburgh compound B (11C-PiB) and [18F]-2-fluoro-2-deoxy-d-glucose (18F-FDG)–PET and MRI scans at baseline. We extracted global binding potential for 11C-PiB, the number of abnormal voxels for 18F-FDG, and gray matter volumes using SIENAX for MRI as measures of amyloid, hypometabolism, and atrophy. In addition, repeat neuropsychological testing was performed, including memory, attention, language, and executive tasks (mean follow-up 2.2 ± 0.7 years). Cross-sectional and longitudinal relationships between imaging markers and cognition were assessed using linear mixed models, including terms for the imaging markers, time, sex, age, diagnosis, and interactions for imaging marker × time and imaging marker × time × diagnosis. Results: Linear mixed models showed that baseline hypometabolism and atrophy were associated with poorer baseline performance on attention and executive functions (p < 0.05), whereas amyloid was not related to baseline cognition. Hypometabolism and amyloid were strongly associated with longitudinal decline in essentially all cognitive domains (pinteraction < 0.05), whereas atrophy was related specifically to future decline in Mini-Mental State Examination and memory (pinteraction < 0.05). Conclusion: Glucose hypometabolism and brain atrophy were associated with concurrent cognitive function, whereas brain amyloid was not. Amyloid deposition and glucose hypometabolism were predictors for decline of a wide variety of cognitive functions, while brain atrophy specifically predicted memory deterioration.

Use of amyloid-PET to determine cutpoints for CSF markers: A multicenter study.

Objectives: To define CSF β-amyloid 1–42 (Aβ42) cutpoints to detect cortical amyloid deposition as assessed by 11C-Pittsburgh compound B ([11C]PiB)-PET and to compare these calculated cutpoints with cutpoints currently used in clinical practice. Methods: We included 433 participants (57 controls, 99 with mild cognitive impairment, 195 with Alzheimer disease [AD] dementia, and 82 with non-AD dementia) from 5 European centers. We calculated for each center and for the pooled cohort CSF Aβ42 and Aβ42/tau ratio cutpoints for cortical amyloid deposition based on visual interpretation of [11C]PiB-PET images. Results: Amyloid-PET–based calculated CSF Aβ42 cutpoints ranged from 521 to 616 pg/mL, whereas existing clinical-based cutpoints ranged from 400 to 550 pg/mL. Using the calculated cutpoint from the pooled sample (557 pg/mL), concordance between CSF Aβ42 and amyloid-PET was 84%. Similar concordance was found when using a dichotomized Aβ42/tau ratio. Exploratory analysis showed that participants with a positive amyloid-PET and normal CSF Aβ42 levels had higher CSF tau and phosphorylated tau levels and more often had mild cognitive impairment or AD dementia compared with participants who had negative amyloid-PET and abnormal CSF Aβ42 levels. Conclusions: Amyloid-PET–based CSF Aβ42 cutpoints were higher and tended to reduce intercenter variability compared with clinical-based cutpoints. Discordant participants with normal CSF Aβ42 and a positive amyloid-PET may be more likely to have AD-related amyloid pathology than participants with abnormal CSF Aβ42 and a negative amyloid-PET. Classification of evidence: This study provides Class II evidence that an amyloid-PET–based CSF Aβ42 cutpoint identifies individuals with amyloid deposition with a sensitivity of 87% and specificity of 80%.

Subjective Memory Complaints in APOEɛ4 Carriers are Associated with High Amyloid-β Burden.

BACKGROUND APOEɛ4 genotype and aging have been identified as risk factors for Alzheimers disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning. OBJECTIVE To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly. METHODS 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aβ pathology. RESULTS Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01). CONCLUSION Aging, APOEɛ4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.

Alzheimer's biomarkers in daily practice (ABIDE) project: Rationale and design

The Alzheimers biomarkers in daily practice (ABIDE) project is designed to translate knowledge on diagnostic tests (magnetic resonance imaging [MRI], cerebrospinal fluid [CSF], and amyloid positron emission tomography [PET]) to daily clinical practice with a focus on mild cognitive impairment (MCI)

Interpreting Biomarker Results in Individual Patients With Mild Cognitive Impairment in the Alzheimer's Biomarkers in Daily Practice (ABIDE) Project.

Importance Biomarkers do not determine conversion to Alzheimer disease (AD) perfectly, and criteria do not specify how to take patient characteristics into account. Consequently, biomarker use may be challenging for clinicians, especially in patients with mild cognitive impairment (MCI). Objective To construct biomarker-based prognostic models that enable determination of future AD dementia in patients with MCI. Design, Setting, and Participants This study is part of the Alzheimer’s Biomarkers in Daily Practice (ABIDE) project. A total of 525 patients with MCI from the Amsterdam Dementia Cohort (longitudinal cohort, tertiary referral center) were studied. All patients had their baseline visit to a memory clinic from September 1, 1997, through August 31, 2014. Prognostic models were constructed by Cox proportional hazards regression with patient characteristics (age, sex, and Mini-Mental State Examination [MMSE] score), magnetic resonance imaging (MRI) biomarkers (hippocampal volume, normalized whole-brain volume), cerebrospinal fluid (CSF) biomarkers (amyloid-&bgr;1-42, tau), and combined biomarkers. Data were analyzed from November 1, 2015, to October 1, 2016. Main Outcomes and Measures Clinical end points were AD dementia and any type of dementia after 1 and 3 years. Results Of the 525 patients, 210 (40.0%) were female, and the mean (SD) age was 67.3 (8.4) years. On the basis of age, sex, and MMSE score only, the 3-year progression risk to AD dementia ranged from 26% (95% CI, 19%-34%) in younger men with MMSE scores of 29 to 76% (95% CI, 65%-84%) in older women with MMSE scores of 24 (1-year risk: 6% [95% CI, 4%-9%] to 24% [95% CI, 18%-32%]). Three- and 1-year progression risks were 86% (95% CI, 71%-95%) and 27% (95% CI, 17%-41%) when MRI results were abnormal, 82% (95% CI, 73%-89%) and 26% (95% CI, 20%-33%) when CSF test results were abnormal, and 89% (95% CI, 79%-95%) and 26% (95% CI, 18%-36%) when the results of both tests were abnormal. Conversely, 3- and 1-year progression risks were 18% (95% CI, 13%-27%) and 3% (95% CI, 2%-5%) after normal MRI results, 6% (95% CI, 3%-9%) and 1% (95% CI, 0.5%-2%) after normal CSF test results, and 4% (95% CI, 2%-7%) and 0.5% (95% CI, 0.2%-1%) after combined normal MRI and CSF test results. The prognostic value of models determining any type of dementia were in the same order of magnitude although somewhat lower. External validation in Alzheimer’s Disease Neuroimaging Initiative 2 showed that our models were highly robust. Conclusions and Relevance This study provides biomarker-based prognostic models that may help determine AD dementia and any type of dementia in patients with MCI at the individual level. This finding supports clinical decision making and application of biomarkers in daily practice.

Diagnostic impact of [18F]flutemetamol amyloid imaging in young onset dementia

grees of atrophy, hypermetabolism and amyloid deposition in diagnostic groups with 1A. Mild Cognitive Impairment (MCI), 1B. Subjective Memory Decline (SCD), 1C. CN APOE4 carriers as well as 0. AD patients (for visual comparison). Contrast maps were displayed on the left hemisphere thresholded at t -values of p < 0.001 uncorrected, k 1⁄4 20. Alzheimer’s Imaging Consortium (IC): IC-01: Molecular Imaging P3

Association of Amyloid Positron Emission Tomography With Changes in Diagnosis and Patient Treatment in an Unselected Memory Clinic Cohort: The ABIDE Project

Importance Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PET) in selected research cohorts. However, these research populations do not reflect daily practice, thus hampering clinical implementation of amyloid imaging. Objective To evaluate the association of amyloid PET with changes in diagnosis, diagnostic confidence, treatment, and patients’ experiences in an unselected memory clinic cohort. Design, Setting, and Participants Amyloid PET using fluoride-18 florbetaben was offered to 866 patients who visited the tertiary memory clinic at the VU University Medical Center between January 2015 and December 2016 as part of their routine diagnostic dementia workup. Of these patients, 476 (55%) were included, 32 (4%) were excluded, and 358 (41%) did not participate. To enrich this sample, 31 patients with mild cognitive impairment from the University Medical Center Utrecht memory clinic were included. For each patient, neurologists determined a preamyloid and postamyloid PET diagnosis that existed of both a clinical syndrome (dementia, mild cognitive impairment, or subjective cognitive decline) and a suspected etiology (Alzheimer disease [AD] or non-AD), with a confidence level ranging from 0% to 100%. In addition, the neurologist determined patient treatment in terms of ancillary investigations, medication, and care. Each patient received a clinical follow-up 1 year after being scanned. Main Outcomes and Measures Primary outcome measures were post-PET changes in diagnosis, diagnostic confidence, and patient treatment. Results Of the 507 patients (mean [SD] age, 65 (8) years; 201 women [39%]; mean [SD] Mini-Mental State Examination score, 25 [4]), 164 (32%) had AD dementia, 70 (14%) non-AD dementia, 114 (23%) mild cognitive impairment, and 159 (31%) subjective cognitive decline. Amyloid PET results were positive for 242 patients (48%). The suspected etiology changed for 125 patients (25%) after undergoing amyloid PET, more often due to a negative (82 of 265 [31%]) than a positive (43 of 242 [18%]) PET result (P < .01). Post-PET changes in suspected etiology occurred more frequently in patients older (>65 years) than younger (<65 years) than the typical age at onset of 65 years (74 of 257 [29%] vs 51 of 250 [20%]; P < .05). Mean diagnostic confidence (SD) increased from 80 (13) to 89 (13%) (P < .001). In 123 patients (24%), there was a change in patient treatment post-PET, mostly related to additional investigations and therapy. Conclusions and Relevance This prospective diagnostic study provides a bridge between validating amyloid PET in a research setting and implementing this diagnostic tool in daily clinical practice. Both amyloid-positive and amyloid-negative results had substantial associations with changes in diagnosis and treatment, both in patients with and without dementia.