18F-APN-1607 Tau PET in Progressive Supranuclear Palsy-Like Symptoms Caused by TBK1 Mutations

Background Pathogenic mutations in the TANK-binding kinase 1 (TBK1) gene have been associated with progressive supranuclear palsy (PSP)-like extrapyramidal symptoms, amyotrophic lateral sclerosis (ALS), as well as cognitive and behavioral alterations. However, the question as to whether TBK1 mutations may be associated with tau burden remains unanswered. Methods To investigate whether patients presenting with PSP-like extrapyramidal symptoms caused by TBK1 mutations have evidence of tau deposition as reflected by positive 18F-APN-1607 tau PET imaging findings. Four patients who showed PSP-like extrapyramidal symptoms, ALS, and cognitive/behavioral alterations were consecutively enrolled between August 2019 and August 2020. Patients underwent TBK1 gene sequencing and 18F-APN-1607 tau PET imaging. All PET images were interpreted in a blinded fashion with respect to genetic results. Brain structural changes were investigated with MRI, whereas 11C-CFT or 18F-DTBZ PET imaging was performed to identify dopaminergic degeneration. Results Pathogenic TBK1 mutations were identified in three of the four study patients. The three mutation carriers – but not the case without – showed positive 18F-APN-1607 binding in PSP-related regions, suggesting the presence of tau pathology. Mesencephalic atrophy (hummingbird sign) was observed in all TBK1 mutation carriers, and two of them also had evidence of frontotemporal atrophy. Dopaminergic degeneration was evident in all cases, regardless of TBK1 mutations. Conclusions Pathogenic TBK1 mutations in patients with PSP-like extrapyramidal symptoms are associated with positive 18F-APN-1607 tau PET imaging findings. Our data should prompt additional investigations on the potential role of tau accumulation in the pathogenesis of disease conditions associated with TBK1 mutations.

Paraquat-induced intracellular Zn2+ dysregulation causes dopaminergic degeneration in the substantia nigra, but not in the striatum

Parkinson's disease (PD) is characterized by a selective death of nigrostriatal dopaminergic neurons, while the difference in the vulnerability to the death between the substantia nigra pars compacta (SNpc) and the striatum is poorly understood. Here we tested the difference focused on paraquat (PQ)-induced intracellular Zn2+ toxicity via extracellular glutamate accumulation. When PQ was locally injected into the SNpc and the striatum, dopaminergic degeneration was observed in the SNpc, but not in the striatum. Intracellular hydrogen peroxide (H2O2) produced by PQ was increased in both the SNpc and the striatum. In contrast, extracellular glutamate accumulation was observed only in the SNpc and rescued in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) cation channels. PQ increased intracellular Zn2+ level in the SNpc, but not in the striatum. The increase was rescued by 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors. PQ-induced dopaminergic degeneration in the SNpc was rescued by ACA, NASPM, and GBR, a dopamine reuptake inhibitor. The present study indicates intracellular H2O2 produced by PQ, which is taken up through dopamine transporters, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptor activation, resulting in dopaminergic degeneration in the SNpc. However, H2O2 signaling is not the case in the striatum. Paraquat-induced Zn2+ dysregulation plays a key role for neurodegeneration in the SNpc, but not in the striatum.

The Relationship between Plasma Hypocretin Levels and Sleep Disorders in Patients with Parkinson's Disease

Introduction: There are many areas of brain degeneration in people with Parkinson's disease. The dopaminergic degeneration process in the midbrain causes early symptoms of sleep disturbances. Hypocretin produced by the hypothalamus is involved in the pathophysiology of Parkinson's disease. Some research results regarding the relationship between plasma hypocretin levels and sleep disorders in patients with Parkinson's disease are still controversial. Method: This research is a cross sectional study in Neurology Polyclinic Dr. M. Djamil Padang and Network Hospital. All research subjects measured hypocretin levels and sleep disorders using the Epworth Sleepiness Scale. Statistical analysis was performed on a computerized basis using IBM SPSS statistics version 23.0 for windows. Result: A total of 60 patients with Parkinson's disease were included in this study, 30 subjects experienced sleep disorders and 30 others had no sleep disorders. There was a significant difference in lower plasma hypocretin levels in the Parkinson's group with sleep disorders, namely 81.817 ± 22.770 and in the group without sleep disorders, plasma hypocretin levels were found to be 255.416 ± 226.590 (p = 0.000). There was no statistical difference in clinical degree, age, duration of illness between the Parkinson's group with sleep disorders and the group without sleep disorders p > 0.05. Conclusion: There is a significant difference in hypocretin levels against the sleep disorder group in people with Parkinson's disease. In this study, there was no association between age, clinical degree of Parkinson's disease, and duration of Parkinson's disease and sleep disturbances. Degeneration in the olfactory bulb area, hypothalamus, and brainstem can precede dopaminergic degeneration in the midbrain and cause sleep disturbance symptoms.

The Relationship between Plasma Hypocretin Levels and Sleep Disorders in Patients with Parkinson's Disease

Introduction: There are many areas of brain degeneration in people with Parkinson's disease. The dopaminergic degeneration process in the midbrain causes early symptoms of sleep disturbances. Hypocretin produced by the hypothalamus is involved in the pathophysiology of Parkinson's disease. Some research results regarding the relationship between plasma hypocretin levels and sleep disorders in patients with Parkinson's disease are still controversial. Method: This research is a cross sectional study in Neurology Polyclinic Dr. M. Djamil Padang and Network Hospital. All research subjects measured hypocretin levels and sleep disorders using the Epworth Sleepiness Scale. Statistical analysis was performed on a computerized basis using IBM SPSS statistics version 23.0 for windows. Result: A total of 60 patients with Parkinson's disease were included in this study, 30 subjects experienced sleep disorders and 30 others had no sleep disorders. There was a significant difference in lower plasma hypocretin levels in the Parkinson's group with sleep disorders, namely 81.817 ± 22.770 and in the group without sleep disorders, plasma hypocretin levels were found to be 255.416 ± 226.590 (p = 0.000). There was no statistical difference in clinical degree, age, duration of illness between the Parkinson's group with sleep disorders and the group without sleep disorders p > 0.05. Conclusion: There is a significant difference in hypocretin levels against the sleep disorder group in people with Parkinson's disease. In this study, there was no association between age, clinical degree of Parkinson's disease, and duration of Parkinson's disease and sleep disturbances. Degeneration in the olfactory bulb area, hypothalamus, and brainstem can precede dopaminergic degeneration in the midbrain and cause sleep disturbance symptoms.

Intracellular Hydrogen Peroxide Produced by 6-Hydroxydopamine is a Trigger for Nigral Dopaminergic Degeneration Via Rapid Influx of Extracellular Zn2+

To elucidate the mechanism of 6-hydroxydopamine (6-OHDA)-induced Zn2+ toxicity, which is involved in neurodegeneration in the substantia nigra pars compacta (SNpc) of rats, we postulated that intracellular hydrogen peroxide (H2O2) produced by 6-OHDA is a trigger for intracellular Zn2+ dysregulation in the SNpc. Intracellular H2O2 level in the SNpc elevated by 6-OHDA was completely inhibited by co-injection of GBR 13069 dihydrochloride (GBR), a dopamine reuptake inhibitor, suggesting that 6-OHDA taken up through dopamine transporters produces H2O2 in the intercellular compartment of dopaminergic neurons. When the SNpc was perfused with H2O2, H2O2 accumulated glutamate in the extracellular compartment and the accumulation was inhibited in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) channels. In addition to 6-OHDA, H2O2 also induced intracellular Zn2+ dysregulation via AMPA receptor activation followed by nigral dopaminergic degeneration. Furthermore, 6-OHDA-induced nigral dopaminergic degeneration was completely inhibited by co-injection of HYDROP, an intracellular H2O2 scavenger or GBR into the SNpc. The present study indicates that H2O2 is produced by 6-OHDA taken up through dopamine transporters in the SNpc, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via AMPA receptor activation, resulting in nigral dopaminergic degeneration. It is likely that intracellular H2O2, but not extracellular H2O2, is a key trigger for nigral dopaminergic degeneration via intracellular Zn2+ dysregulation.

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.

The α-Synuclein Origin and Connectome Model (SOC Model) of Parkinson’s Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline

A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of α-synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial α-synuclein inclusion, and α-synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial α-synuclein pathology occurs within the CNS, leading to a brain-first subtype of PD. In others, pathology begins in the peripheral autonomic nervous system, leading to a body-first subtype. In brain-first cases, it is proposed that the first pathology appears unilaterally, often in the amygdala. If α-synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, α-synuclein spreads mainly to ipsilateral structures including the substantia nigra. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. In body-first cases, the α-synuclein pathology ascends via the vagus to both the left and right dorsal motor nuclei of the vagus owing to the overlapping parasympathetic innervation of the gut. Consequently, the initial α-synuclein pathology inside the CNS is more symmetric, which promotes more symmetric propagation in the brainstem, leading to more symmetric dopaminergic degeneration and less motor asymmetry. At diagnosis, body-first patients already have a larger, more symmetric burden of α-synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power.