Interrelation of striatal dopamine, brain metabolism and cognition in dementia with Lewy bodies

Abstract

Dementia with Lewy bodies, the second most common neurodegenerative dementia, is characterized by cognitive decline, fluctuation of cognition and alertness, visual hallucinations, rapid eye movement sleep behavior disorder, and parkinsonism. Imaging biomarkers are of great importance in diagnosing patients with DLB and associated with characteristic clinical features including cognitive decline. In this study, we investigate interrelation between nigrostriatal dopamine depletion, brain metabolism, and cognition in dementia with Lewy bodies. We enrolled 55 patients with probable dementia with Lewy bodies (15 prodromal dementia with Lewy bodies and 40 dementia with Lewy bodies) and 13 healthy controls. All subjects underwent N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography/computed tomography, 18F-fluorodeoxyglucose positron emission tomography/computed tomography, 18F-florbetaben positron emission tomography/computed tomography, and detailed neuropsychological testing. The relationship between striatal dopamine transporter availability and regional brain metabolism was assessed by general linear models, and the effect of striatal dopamine transporter availability and brain metabolism on specific cognitive function was evaluated by multivariate linear regression analysis. Path analyses were used to evaluate the relationship between striatal dopamine transporter availability, fluorodeoxyglucose uptake, and cognitive function scores. Additionally, a linear mixed model was used to investigate the association between baseline dopamine transporter availability or brain metabolism and cognitive decline. Independent of amyloid deposition, caudate and putamen dopamine transporter availabilities were positively correlated with brain metabolism in the dementia with Lewy bodies-specific hypometabolic regions, most prominently in the occipital and lateral parietal cortices. Both reduced caudate dopamine and brain hypometabolism were associated with low z-scores of Rey-Osterrieth Complex Figure Test copy, Seoul Verbal Learning Test immediate recall, and Controlled Oral Word Association Test Animal. Path analyses showed that the effect of reduced caudate dopamine on Rey-Osterrieth Complex Figure Test copy z-score was completely mediated by brain hypometabolism, whereas it affected Seoul Verbal Learning Test immediate recall z-score both directly and via the mediation of brain hypometabolism. Caudate dopamine depletion was directly associated with COWAT animal z-score, not mediated by brain hypometabolism. Both baseline caudate dopamine transporter availability and brain hypometabolism were associated with longitudinal cognitive decline, with brain hypometabolism being more relevant. Our findings suggest that in dementia with Lewy bodies, striatal dopaminergic depletion and brain hypometabolism are closely related, and they differentially affect cognitive dysfunction in an item-specific manner. Additionally, brain hypometabolism would be more relevant to longitudinal cognitive outcomes than striatal dopaminergic degeneration.

Differential Effects of Tau Stage, Lewy Body Pathology, and Substantia Nigra Degeneration on18F-FDG PET Patterns in Clinical Alzheimer Disease

“…To the best of our knowledge, our study is the first report demonstrating these associations. A very recent multimodal neuroimaging study (n=55) has pointed to an association between nigrostriatal degeneration (as assessed by dopamine transporter SPECT) and cortical hypometabolism in clinical DLB (44). However, such associations had neither been assessed using neuropathologic evaluations nor in the context of clinical AD.…”

“…However, such associations had neither been assessed using neuropathologic evaluations nor in the context of clinical AD. Additional studies combining FDG-PET with imaging modalities aimed to evaluate SN degeneration in-vivo (44)(45)(46)(47) would be of great interest for replicating and studying these associations in larger observational cohorts.…”

Differential Implications of Cerebral Hypoperfusion and Hyperperfusion in Parkinson's Disease

“…Generally, regional cerebral hypoperfusion or hypometabolism in neurodegenerative disorders reflects the underlying neuronal dysfunction and can potentially be used as diagnostic and predictive biomarkers 23‐26 . Our recent previous study also showed that hypometabolism associated with nigrostriatal degeneration was significantly associated with cognitive dysfunction in patients with dementia with Lewy bodies 27 . Conversely, the role of hyperperfusion or hypermetabolism in neurodegenerative disorders remains unclear.…”

“…[23][24][25][26] Our recent previous study also showed that hypometabolism associated with nigrostriatal degeneration was significantly associated with cognitive dysfunction in patients with dementia with Lewy bodies. 27 Conversely, the role of hyperperfusion or hypermetabolism in neurodegenerative disorders remains unclear. Moreover, previous studies reported that dopamine deficiency in dopaminergic inhibitory neurocircuits would result in enhanced oscillatory burst activity of the basal ganglia, 28,29 leading to increased brain metabolism in areas exhibiting PDRP activity, which was ameliorated after levodopa infusion.…”

Effects of amyloid beta and dopaminergic depletion on perfusion and clinical symptoms

“…In specific, decreased brain function mediates the effects of Aβ or tau uptake on cognition 22,23 . Similarly, metabolic or perfusion changes are associated with progression, 24 clinical symptoms, 25 and cognitive dysfunction in DLB 26 . However, increased brain function may be associated with worse cognition in DLB 27,28 .…”