Background-Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain.

Methods:We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death. Results:We observed elevated cortical uptake of [ 11 C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse A␤ plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden. Individuals with Parkinson disease (PD) are nearly 6 times more likely to develop dementia than age-matched controls, and the majority of individuals with PD who survive more than 15 years after diagnosis will develop dementia. Conclusions:1,2 Clinicopathologic investigations have revealed heterogeneous histopathology, with Alzheimer disease (AD) pathology (amyloid plaques and neurofibrillary tangles) present in a subset of individuals with PD dementia (PDD).1 When present, AD pathology is typically found in conjunction with other neuropathologic changes, including limbic and cortical Lewy bodies and degeneration of subcortical monoaminergic and cholinergic pathways. The contribution of AD pathology to the pathogenesis of dementia in the setting of PD is thus uncertain. The presence of AD pathology has been postulated to influence clinical manifestations of dementia, for example masking features of dementia with Lewy bodies (DLB) such as hallucinations and fluctuations 3,4 or influencing the timing of dementia onset in patients with Lewy body disorders. 5Antemortem evaluation of A␤ plaque burden by PET imaging using amyloid-specific radiotracers can potentially clarify the role of these lesions in the pathogenesis of Lewy body-associated dementias (PDD and DLB). The tracer N-methyl-[11 C]2-(4Ј-methylaminophenyl)-6-hydroxybenzothiazole (or [ 11 C]-PIB for Pittsburgh Compound-B) has shown great promise for this purpose, demonstrating rapid diffusion across the blood-brain barrier, high affinity to a From the

Objective Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease (PD) clinical trials raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 PET tracers with in vitro measures of nigral cell counts and striatal dopamine in MPTP treated monkeys. Methods Sixteen macaques had MRI and baseline PETs using 6-[18F]fluorodopa (FD), [11C] dihydrotetrabenazine (DTBZ) and [11C] 2beta-carbomethoxy-3beta-4-fluorophenyltropane (CFT). MPTP (0 to 0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by three weeks. After eight weeks, PETs were repeated and animals euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase stained nigral cells. Results Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss < 50% (r2= 0.84; r2= 0.86; r2= 0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2= 0.95; r2= 0.94; r2= 0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ and CFT correlated strongly with each other (r2=0.98, p<0.001). Interpretation Tracer uptake correlated with nigral neurons only when nigral loss < 50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.

Background: Welding exposes workers to manganese (Mn) fumes, but it is unclear if this exposure

Objectives Manganese exposure leads to diffuse cerebral metal deposition with the highest concentration in the globus pallidus associated with increased T1-weighted MRI signal. T1 signal intensity in extra-pallidal basal ganglia (caudate and putamen) has not been studied in occupationally exposed workers. Diffusion weighted imaging is a non-invasive measure of neuronal damage and may provide a quantification of neurotoxicity associated with welding and manganese exposure. This study investigated extra-pallidal T1 basal ganglia signal intensity as a marker of manganese exposure and basal ganglia diffusion weighted imaging abnormalities as a potential marker of neurotoxicity. Methods A 3T MR case:control imaging study was performed on 18 welders and 18 age- and gender-matched controls. Basal ganglia regions of interest were identified for each subject. T1-weighted intensity indices and apparent diffusion coefficients were generated for each region. Results All regional indices were higher in welders than controls (p≤0.05). Combined basal ganglia (ρ=0.610), caudate (ρ=0.645), anterior (ρ=0.595) and posterior putamen (ρ=0.511) indices were more correlated with exposure than pallidal (ρ=0.484) index. Welder apparent diffusion coefficient values were lower than controls for globus pallidus (p=0.03) and anterior putamen (p=0.004). Conclusions Welders demonstrated elevated T1 indices throughout the basal ganglia. Combined basal ganglia, caudate and putamen indices were more correlated with exposure than pallidal index suggesting more inclusive basal ganglia sampling results in better exposure markers. Elevated indices were associated with diffusion weighted abnormalities in the pallidum and anterior putamen suggesting neurotoxicity in these regions.