Impact of molecular imaging on the diagnostic process in a memory clinic.

BACKGROUND: [(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET measure fibrillar amyloid-ß load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population. METHODS: One hundred fifty-four patients underwent paired dynamic [(11)C]PIB and static [(18)F]FDG PET scans shortly after completing a standard dementia screening. Two-year clinical follow-up data were available for 39 patients. Parametric PET images were assessed visually and results were reported to the neurologists responsible for the initial diagnosis. Outcome measures were (change in) clinical diagnosis and confidence in that diagnosis before and after disclosing PET results. RESULTS: [(11)C]PIB scans were positive in 40 of 66 (61%) patients with a clinical diagnosis of Alzheimer's disease (AD), 5 of 18 (28%) patients with frontotemporal dementia (FTD), 4 of 5 (80%) patients with Lewy body dementia, and 3 of 10 (30%) patients with other dementias. [(18)F]FDG uptake patterns matched the clinical diagnosis in 38 of 66 (58%) of AD patients, and in 6 of 18 (33%) FTD patients. PET results led to a change in diagnosis in 35 (23%) patients. This only occurred when prior diagnostic certainty was <90%. Diagnostic confidence increased from 71 ± 17% before to 87 ± 16% after PET (p < .001). Two-year clinical follow-up (n = 39) showed that [(11)C]PIB and [(18)F]FDG predicted progression to AD for patients with mild cognitive impairment, and that the diagnosis of dementia established after PET remained unchanged in 96% of patients. CONCLUSIONS: In a memory clinic setting, combined [(11)C]PIB and [(18)F]FDG PET are of additional value on top of the standard diagnostic work-up, especially when prior diagnostic confidence is low.

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

OBJECTIVE: To examine the relationships between apolipoprotein E (APOE) ε4 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 ε4 negative, 40 heterozygous, and 22 homozygous Alzheimer disease dementia patients underwent dynamic (90 minutes) [(11)C]Pittsburgh compound B (PIB) and static [(18)F]fluorodeoxyglucose (FDG) PET scans. Parametric nondisplaceable binding potential images of [(11)C]PIB and standardized uptake value ratio images of [(18)F]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 ε4 dose on distributions of both [(11)C]PIB (p for trend <0.05) and [(18)F]FDG (p for trend <0.01). More specifically, a univariate general linear model of individual regions showed increased [(11)C]PIB binding in frontal cortex of APOE ε4 noncarriers compared with APOE ε4 carriers (p < 0.05). In contrast, APOE ε4 carriers had reduced [(18)F]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 ε4 dose effect for amyloid deposition in the frontal lobe, whereas APOE ε4 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.

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

Alzheimer's 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 Alzheimer's disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimer's 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 ß: -0.37) and between visuo-spatial functioning and occipital binding for older patients (standardized ß: -0.39). For [(18)F]fluorodeoxyglucose, associations were found between parietal uptake with visuo-spatial (standardized ß: 0.55), attention (standardized ß: 0.39) and executive functioning (standardized ß: 0.37) in younger patients, and between posterior cingulate uptake and memory in older patients (standardized ß: 0.41, all P<0.05). These in vivo findings suggest that clinical differences between younger and older patients with Alzheimer's 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 Alzheimer's disease may contribute to the distinct cognitive profile in these patients.

Longitudinal imaging of Alzheimer pathology using [11C]PIB, [18F]FDDNP and [18F]FDG PET.

PURPOSE: [(11)C]PIB and [(18)F]FDDNP are PET tracers for in vivo detection of the neuropathology underlying Alzheimer's disease (AD). [(18)F]FDG is a glucose analogue and its uptake reflects metabolic activity. The purpose of this study was to examine longitudinal changes in these tracers in patients with AD or mild cognitive impairment (MCI) and in healthy controls. METHODS: Longitudinal, paired, dynamic [(11)C]PIB and [(18)F]FDDNP (90 min each) and static [(18)F]FDG (15 min) PET scans were obtained in 11 controls, 12 MCI patients and 8 AD patients. The mean interval between baseline and follow-up was 2.5 years (range 2.0-4.0 years). Parametric [(11)C]PIB and [(18)F]FDDNP images of binding potential (BP(ND)) and [(18)F]FDG standardized uptake value ratio (SUVr) images were generated. RESULTS: A significant increase in global cortical [(11)C]PIB BP(ND) was found in MCI patients, but no changes were observed in AD patients or controls. Subsequent regional analysis revealed that this increase in [(11)C]PIB BP(ND) in MCI patients was most prominent in the lateral temporal lobe (p < 0.05). For [(18)F]FDDNP, no changes in global BP(ND) were found. [(18)F]FDG uptake was reduced at follow-up in the AD group only, especially in frontal, parietal and lateral temporal lobes (all p < 0.01). Changes in global [(11)C]PIB binding (ρ = -0.42, p < 0.05) and posterior cingulate [(18)F]FDG uptake (ρ = 0.54, p < 0.01) were correlated with changes in Mini-Mental-State Examination score over time across groups, whilst changes in [(18)F]FDDNP binding (ρ = -0.18, p = 0.35) were not. CONCLUSION: [(11)C]PIB and [(18)F]FDG track molecular changes in different stages of AD. We found increased amyloid load in MCI patients and progressive metabolic impairment in AD patients. [(18)F]FDDNP seems to be less useful for examining disease progression.