Yuhei Takado

AIM: Attention-deficit/hyperactivity disorder (ADHD) is associated with dysregulation of dopamine and norepinephrine neurotransmission. Extended-release methylphenidate (MPH), a first-line treatment for ADHD, modulates these systems. However, its specific effects on the dopamine transporter (DAT) and norepinephrine transporter (NET) are inadequately characterized. This study evaluated the effects of MPH on DAT and NET binding in adults with ADHD and examined the relationship between transporter binding and cognitive improvement. METHODS: This longitudinal dual-tracer positron emission tomography (PET) study used [18F]-FEPE2I for DAT imaging and (S,S)-[18F]- FMeNER-D2 for NET imaging. PET imaging and cognitive assessments were conducted on 21 adults with ADHD before MPH treatment, and 12 of these participants were reevaluated after achieving treatment stabilization. RESULTS: MPH treatment significantly decreased DAT binding in the caudate and putamen and NET binding in the thalamus and pons. Improvements in attention and multitasking abilities were observed. Baseline NET binding in the pons was higher in individuals with ADHD than in controls, and higher baseline DAT binding in the putamen predicted improvement in sustained attention. However, changes in DAT and NET binding did not correlate with cognitive improvement. Blood concentration analysis revealed that even at MPH blood levels that resulted in high DAT occupancy in the striatum, NET occupancy in the thalamus remained moderate. CONCLUSIONS: MPH simultaneously reduced DAT and NET binding in ADHD, enhanced dopamine and norepinephrine transmission, and improved cognitive function. The differential occupancy of DAT and NET suggests distinct contributions to the therapeutic effects of MPH.

Epileptiform discharges and neuronal hyperexcitability are key pathophysiological features of Alzheimer's disease and related tauopathies. We previously identified selective dynfuntion of parvalbumin-positive GABAergic interneurons (PV neurons), which regulate neural network excitability, in a tauopathy mouse model. However, the mechanistic link between PV neuron deficits, tau pathology, and neurodegeneration remains unclear. Here, we demonstrate that pharmacological enhancement of phasic PV neuron activity markedly attenuates tau accumulation and neuronal loss in a tauopathy mouse model. We developed DSR-143630, a novel activator of voltage-gated sodium channel Nav1.1, selectively expressed in PV neurons. Administration of DSR-143630 alleviated febrile seizures in Nav1.1 haploinsufficient mice and suppressed high-frequency oscillations (HFOs), an electrophysiological signature of hyperexcitability associated with cognitive impairments, in rTg4510 tau transgenic mice. Longitudinal tau PET and volumetric MRI demonstrated that DSR-143630 treatment from 4 to 11 months of age profoundly reduced age-dependent tau deposition and atrophy in the neocortex and hippocampus. Postmortem analyses further revealed decreased levels of phosphorylated tau, preservation of neuronal populations, and attenuated neuroinflammatory responses, including reactive gliosis. These findings establish PV neuron dysfunctions and consequent network hyperexcitability as key drivers of tau pathogenesis and highlight pharmacological Nav1.1 activation as a promising disease-modifying strategy for neurodegenerative tauopathies.

BackgroundLewy body disease (LBD) is a neurodegenerative disease characterized by Lewy bodies, and it clinically presents dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Alzheimer's disease (AD) pathologies frequently coexist with LBD, complicating the clinical manifestation.ObjectiveWe evaluated the impact of AD pathologies, including amyloid-β and tau depositions, on cognitive dysfunction and glucose metabolism in LBD using multiple positron emission tomography scans.MethodsOur study cohort consisted of 14 patients diagnosed with LBD, including five from the PD spectrum and nine from the DLB spectrum. In addition, 12 amyloid-negative cognitively healthy controls (HCs) and 13 amyloid-positive AD-spectrum patients were included. We subsequently explored the influence of amyloid and tau deposition on cognitive dysfunction and glucose metabolism among the LBD patients.ResultsIn the LBD group, 44.4% of the DLB patients were amyloid-positive, and all PD patients were amyloid-negative. While tau accumulation was lower than in AD and similar to HCs at the group level, tau accumulation in the AD signature region was correlated with cognitive dysfunction. Among the changes in glucose metabolism, the cingulate island sign (CIS) index was elevated compared to AD. However, as cognitive impairment progressed, the CIS index decreased, reflecting reduced metabolism in the posterior cingulate gyrus, which was closely associated with tau accumulation in the same region.ConclusionsOur findings indicate that AD pathologies, and particularly tau accumulation, significantly impact both cognitive dysfunction and glucose metabolism in LBD. This underscores the importance of addressing AD-related changes in the clinical management of LBD patients.