Citations

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.

AbstractBackgroundIt is important to determine the natural history of sporadic and familial frontotemporal lobar degeneration (FTLD) and generate clinical, neuropsychological, neuroimaging and biofluid data for planning disease‐modifying trials.MethodAs part of the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD; U19 AG063911) protocol, investigators at 19 centers in North America will enroll 2100 participants with FTLD over the next 5 years beginning in early 2020.ResultAs of 1/20/20, the ARTFL/LEFFTDS (A/L) Consortium had enrolled 1832 participants, including 850 in kindreds with familial FTLD (239 associated with mutations in MAPT, 192 in GRN, 370 in C9orf72, 4 with mutations in both GRN and C9orf72, and 45 with a mutation in a different gene or no mutation in any known FTLD‐associated gene). Over 500 participants have undergone 2 or more annual visits to date. MRI has been performed in 1105. Biofluid samples have also been collected, with blood (DNA, plasma, serum, mRNA, PBMC) in 1413 and CSF in 303. Over 60 manuscripts using A/L data or samples have been published to date. Five clinical trials involving A/L and ALLFTD participants are in progress or planned. The longitudinal arm in ALLFTD will enroll 500 of existing A/L and 600 future participants for annual assessments with similar methodology to A/L. An additional 1000 FTLD patients will undergo focused one‐time clinical evaluations and biofluid collection.ConclusionThe data/samples from already‐enrolled and planned participants in ALLFTD and findings published to date underscore the utility of evaluating FTLD subjects. The absence of identifiable mutations in some with familial FTLD suggests that other genes are yet to be discovered. ALLFTD data will inform clinical trial design, and many participants will be eligible for future trials. The key data and samples in ALLFTD are available to interested investigators worldwide. Supported by: AG063911, AG045390, NS092089, AG016976, AG21886.

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease that affects aging populations. Current MRI techniques are often limited in their sensitivity to underlying neuropathological changes.PurposeTo characterize differences in voxel‐based morphometry (VBM), apparent diffusion coefficient (ADC), and intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) metrics in aging populations. Additionally, to investigate the connection between cognitive assessments and neuroimaging metrics.Study TypeProspective/cross‐sectional.PopulationIn all, 49 subjects, including 13 with AD dementia, 12 with mild cognitive impairment (MCI), and 24 healthy controls (HC).Field Strength/Sequence3T/magnetization‐prepared rapid acquisition gradient echo (MP‐RAGE) and IVIM‐DWIAssessmentAll participants completed a cognitive screening battery prior to MRI. IVIM‐DWI maps (pure diffusion coefficient [D], pseudodiffusion coefficient [D*], and perfusion fraction [f]) were generated from a biexponential fit of diffusion MRI data. VBM was performed on the standard T1‐weighted MP‐RAGE structural images. Group‐wise templates were used to compare across groups.Statistical TestsAnalysis of covariance (ANCOVA) with gender and age as covariates (familywise error [FWE] corrected, post‐hoc comparisons using Bonferroni correction) for group comparisons. Partial‐η2 and Hedges' g were used for effect‐size analysis. Spearman's correlations (false discovery rate [FDR]‐corrected) for the relationship between cognitive scores and imaging.ResultsClusters of significant group‐wise differences were found mainly in the temporal lobe, hippocampus, and amygdala using all VBM and IVIM methods (P < 0.05 FWE). While VBM showed significant changes between MCI and AD groups and between HC and AD groups, no significant clusters were observed between HC and MCI using VBM. ADC and IVIM‐D demonstrated significant changes, at P < 0.05 FWE, between HC and MCI, notably in the amygdala and hippocampus. Several voxel‐based correlations were observed between neuroimaging metrics and cognitive tests within the cognitively impaired groups (P < 0.05 FDR).Data ConclusionThese findings suggest that IVIM‐DWI metrics may be earlier biomarkers for AD‐related changes than VBM. The use of these techniques may provide novel insight into subvoxel neurodegenerative processes.Level of Evidence2Technical Efficacy Stage2 J. MAGN. RESON. IMAGING 2020;52:1811–1826.

Twelve cases (6 M, 6F; mean age 87.9) with incidental Lewy bodies (no clinical diagnosis of parkinsonism or dementia) had medical histories of supraventricular arrhythmia (6/12), dysphagia (5/12), depression (5/12) and falls (4/12). Standardized movement disorder assessments were performed antemortem on 6 cases. The mean Part III UPDRS score was 7 (range 2–14). Motor findings included kinetic tremor (5/6), rest tremor (3/6), postural instability (3/6), postural tremor (2/6), and voice tremor (2/6). Of these 6 cases one was considered to have a normal movement exam, 2 were diagnosed as essential tremor, and 3 as nonspecific tremor disorder. Mean MMSE score in 7 cases was 26.6 (range 23–30). Medical records review revealed 4/12 cases had cognitive impairment not meeting criteria for dementia. Of these 12 cases, 5 had received standardized cognitive assessments: 3 were categorized as cognitively normal and 2 as mild cognitive impairment. Our series of incidental Lewy body disease cases reveal a range of neurologic findings including tremor and cognitive impairment. Antemortem standardized evaluations suggest there may be early clinical markers for Lewy body disorders. Supported by the State of AZ Department of Health Services, NIA P30 AG19610 and the Prescott Family Parkinson's Initiative: a Partnership of the Michael J. Fox Foundation and the Arizona Parkinson's Disease Consortium.

AbstractObjectiveThere are few neuropathological studies on Parkinson's disease with mild cognitive impairment (PD‐MCI). Those published reveal coexisting Lewy body and Alzheimer's disease pathology. Our objective is to determine the pathology that underlies PD‐MCI.MethodsWe used data from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study. Of 736 autopsied subjects with standardized movement and cognitive assessments, 25 had PD‐MCI. Neuropathological findings, including Lewy body and Alzheimer's disease pathology, were compared in PD subjects with amnestic MCI (A‐MCI) and nonamnestic MCI (NA‐MCI).ResultsSignificant pathological heterogeneity within PD‐MCI was found. This included varying Lewy body stages, Alzheimer's disease pathology, and cerebral amyloid angiopathy. There was a significant increase in the severity of Lewy body pathology (meeting The Unified Staging System for Lewy Body disorders neocortical stage) in nonamnestic MCI (7/1, 63%) when compared with amnestic MCI (3/14, 21%, P = 0.032).ConclusionAlthough a small study, distinct pathological changes may contribute to PD‐MCI phenotype. © 2020 International Parkinson and Movement Disorder Society

Background: QEEG could provide physiological biomarkers for changes over time in Parkinson's disease (PD) cognitive decline if they track with longitudinal neuropsychological performance. Objective: Our aim was to correlate longitudinal changes in frequency domain quantitative electroencephalography (QEEG) measures with change in neuropsychological performance testing in PD. Methods: 71 PD subjects, not demented at baseline, were studied from the Arizona Study of Aging and Neurodegenerative Disorders cohort. Baseline and follow-up digital EEG from PD subjects were analyzed for QEEG measures of background rhythm frequency and global relative power in delta (2.5–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), and beta (13–30 Hz) bands. Baseline and subsequent evaluation included Mini Mental Status Examination and five other neuropsychological tests that load on cognitive domains known to decline in PD. Pearson coefficient was used to assess correlations. Multiple linear regression modeling was used to assess the effect of variable combinations of QEEG and other measures, including age and PD duration. Results: Changes in delta bandpower showed the highest and most consistent pattern of correlations with longitudinal changes in neuropsychological testing. The highest correlation was between delta bandpower increase and decline in the Rey Auditory-Verbal Learning Test (−0.59:p < 0.001). Delta bandpower was also increased in the incident dementia group compared to non-dementia at followup. Conclusions: 1) Longitudinal change in the QEEG frequency domain measure of delta bandpower correlated best with longitudinal neuropsychological performance change in PD; 2) These results constitute preliminary evidence that delta bandpower may be a suitable biomarker for evaluating PD cognitive deterioration longitudinally.

Dementia is a frequent complication of Parkinson's disease (PD). About half of PD dementia (PDD) is hypothesized to be due to progression of the underlying Lewy body pathology into limbic regions and the cerebral cortex while the other half is thought to be due to coexistent Alzheimer's disease (AD). Clinically, however, these are indistinguishable. The spread of amyloid plaques to the striatum has been reported to be a sensitive and specific indicator of dementia due to AD. The purpose of the present study was to determine if the presence of striatal plaques might also be a useful indicator of the presence of diagnostic levels of AD pathology within PD subjects. We analyzed neuropathologically-confirmed cases of PD without dementia (PDND, N = 31), PDD without AD (PDD, N = 31) and PD with dementia meeting clinicopathological criteria for AD (PDAD, N = 40). The minimum diagnostic criterion for AD was defined as including a clinical history of dementia, moderate or frequent CERAD cortical neuritic plaque density and Braak neurofibrillary stage III-VI. Striatal amyloid plaque densities were determined using Campbell-Switzer and Thioflavine S stains. Striatal plaque densities were significantly higher in PDAD compared to PDD (p < 0.001). The presence of striatal plaques was approximately 80% sensitive and 80% specific for predicting AD. In comparison, the presence of cerebral cortex plaques alone was highly sensitive (100%) but had poor specificity (48% to 55%). The results suggest that striatal amyloid imaging may be clinically useful for making the distinction between PDD and PDAD.

Abstract This study was designed to correlate clinical findings with the extent of pathologic a-synuclein (aSyn) in the brain using the Unified Staging System for Lewy Body disorders (USSLB). Data from 280 cases from the Arizona Study of Aging and Neurodegenerative Disorders are presented. Each case had a complete USSLB staging and at least 1 full research clinical assessment, including subspecialty neurologist-administered movement and cognitive evaluation. Of the 280, 25.7% were cognitively normal, 8.6% had mild cognitive impairment, and 65.7% had dementia. All cases could be categorized into 1 of 5 USSLB stages (8.6% stage I—olfactory bulb only; 15.4% IIa—brainstem predominant; 13.6% IIb—limbic predominant; 31.8% III—brainstem and limbic; and 30.7% IV—neocortical) yet using the Braak staging system 70 cases (25.3%) could not be classified. Those with USSLB stages III and IV died at a younger age. Multiple measures of motor parkinsonism, cognitive impairment, hyposmia, and probable RBD were significantly correlated with increasing USSLB stage. We conclude that the USSLB is the most comprehensive staging system for all Lewy body disorders and allows for categorization and ranking of all brains with significant correlations to many motor and nonmotor clinical signs and symptoms.