Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease

Introduction: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. Methods: FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. Results: Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. Discussion: Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure

Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study

BACKGROUND: New research criteria for preclinical Alzheimer’s disease (AD)have been proposed by the National Institute on Aging and Alzheimer’s Association. They include stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and injury markers (stage 2) and abnormal amyloid and injury markers and subtle cognitive changes (stage 3). We investigated the occurrence and long-term outcome of these stages. METHODS: Cerebrospinal fluidamyloid-β1–42 and tau levels and a memory composite score were used to classify 311 cognitively normal(Clinical Dementia Rating [CDR]=0) research participants ≥65 years as normal (both markers normal), preclinical AD stage 1–3, or Suspected Non-Alzheimer Pathophysiology (SNAP, abnormal injury marker without abnormal amyloid marker). Outcome measures were progression to CDR≥0·5 symptomatic AD and mortality up to 15 years after baseline (average=4 years). FINDINGS: 129 (41·5%) of participants were normal, 47 (15%)were in stage 1, 36 (12%) in stage 2, 13 (4%)in stage 3, 72 (23%) had SNAP, and 14 (4·5%) remained unclassified. The proportion of preclinical AD (stage 1–3) in our cohort was higher in individuals older than 72 years and in APOE-ε4 carriers. The 5-year progression rate to CDR≥0·5 symptomatic AD was 2% for normal participants, 11% for stage 1, 26% for stage 2, 56% for stage 3, and 5% for SNAP. Compared with normal individuals, participants with preclinical AD had an increased risk of death (HR=6·2, p=0·0396). INTERPRETATION: Preclinical AD is common in cognitively normal elderly and strongly associated with future cognitive decline and mortality. Preclinical AD thus should be an important target for therapeutic interventions

Diagnostic Value of Subjective Memory Complaints Assessed with a Single Item in Dominantly Inherited Alzheimer’s Disease: Results of the DIAN Study

Objective. We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimer\u27s disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN). Methods. The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: n = 107; NCs: n = 109), early symptomatic (CDR 0.5; MCs: n = 48; NCs: n = 8), and dementia stage (CDR ≥ 1; MCs: n = 28; NCs: n = 0). These groups were subdivided by the presence or absence of SMCs. Results. At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs (P = 0.6). At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs (P = 1.0). At CDR ≥ 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset. Conclusions. The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials

IC‐03‐02: Early frame of PiB and FDG in autosomal dominant Alzheimer’s disease: Similarity, discrepancy, and clinical implication

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153108/1/alzjjalz201506013.pd

P2‐138: Early frame of PiB and FDG in autosomal dominant Alzheimer’s disease: Similarity, discrepancy, and clinical implication

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152890/1/alzjjalz201506676.pd

Neurological manifestations of autosomal dominant familial Alzheimer\u27s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Background Autosomal dominant familial Alzheimer\u27s disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD. Methods We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms. Findings The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer\u27s disease, including visual agnosia (55·1%, 95% CI 45·7–64·6), aphasia (57·9%, 48·6–67·3), and behavioural changes (61·7%, 51·5–70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9–7·2], aphasia [23·0%, 20·0–26·0], and behavioural changes [31·7%, 28·4–35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8–15·0), and seizures (2·8%, 0·5–5·9) and moderate for parkinsonism (11·2%, 5·3–17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6–22·2 and 15·0%, 12·5–17·6, respectively), parkinsonism (12·5%, 10·1–15·0), and seizures (20·3%, 17·4–23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04–1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90–0·97, p=0·0007; seizures 0·95, 0·92–0·98, p=0·0018; corticobulbar deficits 0·91, 0·86–0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74–0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease. Interpretation The non-cognitive clinical manifestations of Alzheimer\u27s disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer\u27s disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms. Funding National Institutes of Health and German Center for Neurodegenerative Diseases. © 2016 Elsevier Lt