Clinicopathological Correlation: Dopamine and Amyloid PET Imaging with Neuropathology in Three Subjects Clinically Diagnosed with Alzheimer's Disease or Dementia with Lewy Bodies.

BACKGROUND: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer's disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker. OBJECTIVE: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). METHODS: Three subjects who had PET imaging with both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared. RESULTS: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD. CONCLUSION: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed.

Instrumented Trail-Making Task to Differentiate Persons with No Cognitive Impairment, Amnestic Mild Cognitive Impairment, and Alzheimer Disease: A Proof of Concept Study.

BACKGROUND: Objective and time-effective tools are needed to identify motor-cognitive impairment and facilitate early intervention. OBJECTIVE: We examined the feasibility, accuracy, and reliability of an instrumented trail-making task (iTMT) using a wearable sensor to identify motor-cognitive impairment among older adults. METHODS: Thirty subjects (age = 82.2 + 6.1 years, body mass index = 25.7 + 4.8, female = 43.3%) in 3 age-matched groups, 11 healthy, 10 with amnestic mild cognitive impairment (aMCI), and 9 with Alzheimer disease (AD), were recruited. Subjects completed iTMT, using a wearable sensor attached to the leg, which translates the motion of the ankle into a human-machine interface. iTMT tests included reaching to 5 indexed circles on a computer screen by moving the ankle-joint while standing. iTMT was quantified by the time required to reach all circles in the correct sequence. Three iTMT tests were designed, including numbers (1-5) positioned in a fixed (iTMTfixed) or random (iTMTrandom) order, or numbers (1-3) and letters (A and B) positioned in random order (iTMTnumber-letter). Each test was repeated twice to examine test-retest reliability. In addition, the conventional trail-making task (TMT A and B), Montreal Cognitive Assessment (MoCA), and dual-task cost (DTC: gait-speed difference between walking alone and walking while counting backward) were used as references. Re sults: Good-to-excellent reliability was achieved for all iTMT tests (intraclass correlation [ICC] = 0.742-0.836). Between-group difference was more pronounced, when using iTMTnumber-letter, with average completion time of 26.3 ± 12.4, 37.8 ± 14.1, and 61.8 ± 34.1 s, respectively, for healthy, aMCI, and AD groups (p = 0.006). Pairwise comparison suggested strong effect sizes between AD and healthy (Cohen's d = 1.384, p = 0.001) and between aMCI and AD (d = 0.923, p = 0.028). Significant correlation was observed when comparing iTMTnumber-letter with MoCA (r = -0.598, p = 0.001), TMT A (r = 0.519, p = 0.006), TMT B (r = 0.666, p < 0.001), and DTC (r = 0.713, p < 0.001). CONCLUSION: This study demonstrated proof of concept of a simple, safe, and practical iTMT system with promising results to identify cognitive and dual-task ability impairment among older adults, including those with aMCI and AD. Future studies need to confirm these observations in larger samples, as well as iTMT's ability to track motor-cognitive decline over time.

Florbetapir PET, FDG PET, and MRI in Down syndrome individuals with and without Alzheimer's dementia.

INTRODUCTION: Down syndrome (DS) is associated with amyloid b (Ab) deposition. METHODS: We characterized imaging measurements of regional fibrillar Ab burden, cerebral metabolic rate for glucose (rCMRgl), gray matter volumes (rGMVs), and age associations in 5 DS with dementia (DS/AD1), 12 DS without dementia (DS/AD2), and 9 normal controls (NCs). RESULTS: There were significant group differences in mean standard uptake value ratios (SUVRs) for florbetapir with DS/AD1 having the highest, followed by DS/AD2, followed by NC. For [18F]-fluorodeoxyglucose positron emission tomography, posterior cingulate rCMRgl in DS/AD1 was significantly reduced compared with DS/AD2 and NC. For volumetric magnetic resonance imaging (vMRI), hippocampal volumes were significantly reduced for the DS/AD1 compared with DS/AD2 and NC. Age-related SUVR increases and rCMRgl reductions were greater in DS participants than in NCs. DISCUSSION: DS is associated with fibrillar Ab, rCMRgl, and rGMV alterations in the dementia stage and before the presence of clinical decline. This study provides a foundation for the studies needed to inform treatment and prevention in DS.

PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer's disease and Lewy body disorders.

BACKGROUND: Biomarkers based on the underlying pathology of Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson's disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2). METHODS: Patients with DLB and AD, Parkinson's disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism. RESULTS: 11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011). CONCLUSIONS: The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients (ClinicalTrials.gov identifier: NCT00857506, registered March 5, 2009).

Neuropathological and biochemical assessments of an Alzheimer's disease patient treated with the γ-secretase inhibitor semagacestat.

Amyloid deposition has been implicated as the key determinant of Alzheimer's disease (AD) pathogenesis. Interventions to antagonize amyloid accumulation and mitigate dementia are now under active investigation. We conducted a combined clinical, biochemical and neuropathological assessment of a participant in a clinical trial of the γ-secretase inhibitor, semagacestat. This patient received a daily oral dose of 140 mg of semagacestat for approximately 76 weeks. Levels of brain amyloid-ß (Aß) peptides were quantified using enzyme-linked immunosorbent assays (ELISA). Western blot/scanning densitometry was performed to reveal BACE1, presenilin1, amyloid precursor protein (APP) and its proteolysis-produced C-terminal peptides APP-CT99 and APP-CT83 as well as several γ-secretase substrates. To serve as a frame of reference, the ELISA and Western analyses were performed in parallel on samples from neuropathologically confirmed non-demented control (NDC) and AD subjects who did not receive semagacestat. Neuropathology findings confirmed a diagnosis of AD with frequent amyloid deposits and neurofibrillary tangles in most areas of the cortex and subcortical nuclei as well as cerebellar amyloid plaques. Mean levels of Tris-soluble Aß40 and glass-distilled formic acid (GDFA)/guanidine hydrochloride (GHCl)-extractable Aß40 in the frontal lobe and GDFA/GHCl-soluble Aß40 in the temporal lobe were increased 4.2, 9.5 and 7.7-fold, respectively, in the semagacestat-treated subject compared to those observed in the non-treated AD group. In addition, GDFA/GHCl-extracted Aß42 was increased 2-fold in the temporal lobe relative to non-treated AD cases. No major changes in APP, ß- and γ-secretase and CT99/CT83 were observed between the semagacestat-treated subject compared to either NDC or AD cases. Furthermore, the levels of γ-secretase substrates in the semagacestat-treated subject and the reference groups were also similar. Interestingly, there were significant alterations in the levels of several γ-secretase substrates between the NDC and non-treated AD subjects. This is the first reported case study of an individual enrolled in the semagacestat clinical trial. The subject of this study remained alive for ~7 months after treatment termination, therefore it is difficult to conclude whether the outcomes observed represent a consequence of semagacestat therapy. Additional evaluations of trial participants, including several who expired during the course of treatment, may provide vital clarification regarding the impacts and aftermath of γ-secretase inhibition.

Bapineuzumab alters aß composition: implications for the amyloid cascade hypothesis and anti-amyloid immunotherapy.

The characteristic neuropathological changes associated with Alzheimer's disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA). Amyloid-ß (Aß) species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-ß precursor protein (AßPP) and its C-terminal (CT) fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD) subjects were compared to non-immunized age-matched subjects with AD (NI-AD) and non-demented control (NDC) cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aß peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aß42 levels as well as an increase in Aß40 which led to a corresponding significant decrease in Aß42:Aß40 ratio in comparison to NI-AD subjects. There were no differences in the levels of AßPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aß profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline.

Tau is reduced in AD plasma and validation of employed ELISA methods.

OBJECTIVE: Measure total tau levels in the circulation of living humans, validate the methods employed and determine if there are consistent differences in total tau levels between normal controls and individuals with mild cognitive impairment (MCI) and/or Alzheimer's disease (AD). METHODS: Employing ELISA methods, validated by Western bolts using three separate tau antibodies, we quantified total tau levels in serially collected serum and plasma samples from individuals longitudinally evaluated for cognitive performance. RESULTS: We identified substantial levels of tau in human circulation using plasma, but not serum. The measurement of authentic tau protein was verified by Western blots using a C-terminal specific antibody, an N-terminal specific antibody and antibody used in the commercially available ELISA kit. We revealed a significant decrease in plasma levels of total tau among subjects with MCI compared to cognitively normal controls, with a further highly significant reduction in AD patients compared to both MCI and normal controls. We also found a significant positive correlation between changing levels of plasma tau and cognitive performance within the entire population and among AD patients. CONCLUSIONS: The data suggest that changes in circulating tau levels quantified in plasma samples, but not serum samples, may represent a viable biomarker for tracking the progression of AD and the efficacy of medications in its treatment.

Positron emission tomography and neuropathologic estimates of fibrillar amyloid-ß in a patient with Down syndrome and Alzheimer disease.

BACKGROUND: Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-ß (Aß) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aß in the living human brain and to provide a close correlation with subsequent Aß neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aß in patients with Down syndrome remains to be determined. OBJECTIVES: To characterize PET estimates of fibrillar Aß burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death. Design/ METHODS: With the family's informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient's diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient's diagnosis or PET measurements. RESULTS: Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aß burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan. CONCLUSIONS: Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aß burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aß and to evaluate investigational Aß-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.

Probable early-onset Alzheimer's disease in an apolipoprotein E2 homozygote.

OBJECTIVE: To describe a case of early-onset Alzheimer's disease (AD) in an apolipoprotein (Apo) ε2/ε2 homozygote. BACKGROUND: Apo ε2/ε2 is the rarest of the ApoE genotypes, representing only 1.4% of the population. Cognitive decline in ApoE ε2 homozygotes has rarely been reported. CASE REPORT/METHODS: We report a 58-year-old Apo ε2/ε2 female who meets clinical criteria for probable AD as confirmed by neuropsychological testing, positron emission/computed tomography scan, CSF analysis and genetic screening for known mutations. RESULTS: The clinical course is typical of AD, with progressive cognitive and functional decline. CONCLUSION: Clinically confirmed early-onset AD is atypical in ApoE2 homozygotes but can occur.

Cholesterol and cognitive performance in normal controls and the influence of elective statin use after conversion to mild cognitive impairment: results in a clinical trial cohort.

BACKGROUND: We reported a significant 67% reduction in the hazard risk of incident Alzheimer's disease (AD) with elective statin use in the AD Anti-inflammatory Prevention Trial (ADAPT), without a reduction in risk of incident mild cognitive impairment (MCI). OBJECTIVE: To assess if cholesterol levels are associated with cognitive performance and determine if statin use alters cognitive performance after onset of MCI. DESIGN: Fractionated cholesterol levels, neurological and cognitive status were evaluated annually. Comparisons of non-LLA (lipid-lowering agent) users or statin-LLA users were performed blind to the ADAPT medication randomization. Pearson's correlations were validated using a time-dependent linear mixed model. RESULTS: The MMSE performance significantly declined over time in non-LLA users, and, after adjusting for this, a significant positive correlation between MMSE and HDL was identified (p = 0.0002). A negative correlation between total and LDL cholesterol, and immediate and delayed recall of the Rivermead paragraph was significant (total cholesterol, p < 0.003; LDL, p < 0.02). Pilot data suggest a positive signal on delayed recall of both the Hopkins word list and Rivermead paragraph with deterioration in the non-LLA users and improvement in the statin users after conversion to MCI. CONCLUSION: Cholesterol levels may be associated with differential performance on the MMSE and measures of learning or memory. The trend for improved delayed recall in statin users with MCI compared to non-LLA users with MCI may have contributed to the reduced hazards risk of incident AD without reducing the risk of MCI.

Reduced risk of incident AD with elective statin use in a clinical trial cohort.

Statins have been reported to reduce the risk and be of benefit in the treatment of Alzheimer's disease (AD). Individuals enrolling in the randomized controlled trial testing two anti-inflammatory agents for primary prevention of AD (Alzheimer's Disease Anti-inflammatory Prevention Trial; ADAPT) were allowed the elective use of statins. Our objective was to assess whether statin use is associated with reduced risk of incident AD among ADAPT participants. In primary ADAPT study , participants were assessed annually for cholesterol levels and cognitive status. If impairment in cognition was noted, a dementia evaluation was performed. Onset of mild cognitive impairment (MCI) or AD was taken as the date of this evaluation. Time-to-onset was analyzed in six-month intervals following enrollment. Without knowledge of primary treatment assignment in ADAPT, participants were grouped by their self-reported use of lipid-lowering agents (LLA). In the current ancillary ADAPT study we found that elective statin use was associated with significantly reduced risk of incident AD after adjustment for age, gender, education and Apolipoprotein E (ApoE) genotype. The findings were similar when comparing all LLA use (statin and non-statin LLA) to non-LLA use. Cholesterol levels were lower among statin users compared with non-LLA users, but the MMSE scores were equivalent. The data suggest that statin therapy may be of benefit in reducing the risk of AD.