Neuroinflammation and myelin status in Alzheimer’s disease, Parkinson’s disease, and normal aging brains: A small sample study

Microglia and astrocytes play important roles in mediating the immune processes and nutritional support in the central nervous system (CNS). Neuroinflammation has been indicated in the progression of neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD). Chronic neuroinflammation with sustained activation of microglia and astrocytes may affect white matter tracts and disrupt communication between neurons. Recent studies indicate astrogliosis may inhibit remyelination in demyelinating disorders such as multiple sclerosis. In this study, we investigated the relationship between neuroinflammation and myelin status in postmortem human brain tissue (n = 15 including 6 AD, 5 PD, and 4 age-matched, neurologically normal controls (NC)). We conducted systematic and quantitative immunohistochemistry for glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), amyloid beta, and highly phosphorylated tau (tauopathy). White matter intactness was evaluated by myelin and axon staining in adjacent brain tissue sections. Eight of 15 cases (4 AD, 3 PD, and 1 NC) showed increased immunoreactivity for microglia and astrocytes in the white matter that connects striatum and cortex. Quantitative analysis of these 8 cases showed a significant negative correlation between GFAP (but not Iba-1) and myelin (but not axon) staining in white matter (r2 = 0.78, p<0.005). Tau, but not amyloid beta plaques, is significantly higher in AD vs. PD and NC. Tau burden increases with age in AD cases. These observations indicate that astrocytosis in white matter is associated with loss of myelin in AD, PD, and normal aging and that tau is a potent biomarker for AD

Absorbed radiation dosimetry of the D3-specific PET radioligand [18F]FluorTriopride estimated using rodent and nonhuman primate

[(18)F]FluorTriopride ([(18)F]FTP) is a dopamine D(3)-receptor preferring radioligand with potential for investigation of neuropsychiatric disorders including Parkinson disease, dystonia and schizophrenia. Here we estimate human radiation dosimetry for [(18)F]FTP based on the ex-vivo biodistribution in rodents and in vivo distribution in nonhuman primates. Biodistribution data were generated using male and female Sprague-Dawley rats injected with ~370 KBq of [(18)F]FTP and euthanized at 5, 30, 60, 120, and 240 min. Organs of interest were dissected, weighed and assayed for radioactivity content. PET imaging studies were performed in two male and one female macaque fascicularis administered 143-190 MBq of [(18)F]FTP and scanned whole-body in sequential sections. Organ residence times were calculated based on organ time activity curves (TAC) created from regions of Interest. OLINDA/EXM 1.1 was used to estimate human radiation dosimetry based on scaled organ residence times. In the rodent, the highest absorbed radiation dose was the upper large intestines (0.32-0.49 mGy/MBq), with an effective dose of 0.07 mSv/MBq in males and 0.1 mSv/MBq in females. For the nonhuman primate, however, the gallbladder wall was the critical organ (1.81 mGy/MBq), and the effective dose was 0.02 mSv/MBq. The species discrepancy in dosimetry estimates for [(18)F]FTP based on rat and primate data can be attributed to the slower transit of tracer through the hepatobiliary track of the primate compared to the rat, which lacks a gallbladder. Out findings demonstrate that the nonhuman primate model is more appropriate model for estimating human absorbed radiation dosimetry when hepatobiliary excretion plays a major role in radiotracer elimination

Translocator protein in late stage Alzheimer\u27s disease and Dementia with Lewy bodies brains

OBJECTIVE: Increased translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), in glial cells of the brain has been used as a neuroinflammation marker in the early and middle stages of neurodegenerative diseases, such as Alzheimer\u27s disease (AD) and Dementia with Lewy Bodies (DLB). In this study, we investigated the changes in TSPO density with respect to late stage AD and DLB. METHODS: TSPO density was measured in multiple regions of postmortem human brains in 20 different cases: seven late stage AD cases (Braak amyloid average: C; Braak tangle average: VI; Aged 74-88, mean: 83 ± 5 years), five DLB cases (Braak amyloid average: C; Braak tangle average: V; Aged 79-91, mean: 84 ± 4 years), and eight age-matched normal control cases (3 males, 5 females: aged 77-92 years; mean: 87 ± 6 years). Measurements were taken by quantitative autoradiography using [ RESULTS: No significant changes were found in TSPO density of the frontal cortex, striatum, thalamus, or red nucleus of the AD and DLB brains. A significant reduction in TSPO density was found in the substantia nigra (SN) of the AD and DLB brains compared to that of age-matched healthy controls. INTERPRETATION: This distinct pattern of TSPO density change in late stage AD and DLB cases may imply the occurrence of microglia dystrophy in late stage neurodegeneration. Furthermore, TSPO may not only be a microglia activation marker in early stage AD and DLB, but TSPO may also be used to monitor microglia dysfunction in the late stage of these diseases

Binding of the radioligand SIL23 to alpha-synuclein fibrils in Parkinson disease brain tissue establishes feasibility and screening approaches for developing a Parkinson disease imaging agent

Accumulation of α-synuclein (α-syn) fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson disease (PD). Ligands that bind α-syn fibrils could be utilized as imaging agents to improve the diagnosis of PD and to monitor disease progression. However, ligands for α-syn fibrils in PD brain tissue have not been previously identified and the feasibility of quantifying α-syn fibrils in brain tissue is unknown. We report the identification of the (125)I-labeled α-syn radioligand SIL23. [(125)I]SIL23 binds α-syn fibrils in postmortem brain tissue from PD patients as well as an α-syn transgenic mouse model for PD. The density of SIL23 binding sites correlates with the level of fibrillar α-syn in PD brain tissue, and [(125)I]SIL23 binding site densities in brain tissue are sufficiently high to enable in vivo imaging with high affinity ligands. These results identify a SIL23 binding site on α-syn fibrils that is a feasible target for development of an α-syn imaging agent. The affinity of SIL23 for α-syn and its selectivity for α-syn versus Aβ and tau fibrils is not optimal for imaging fibrillar α-syn in vivo, but we show that SIL23 competitive binding assays can be used to screen additional ligands for suitable affinity and selectivity, which will accelerate the development of an α-syn imaging agent for PD

Neuropathic pain: Biomolecular intervention and imaging via targeting microglia activation

Many diseases, including cancer, can lead to neuropathic pain (NP). NP is one of the accompanying symptoms of suffering in many conditions and the life quality of NP patient is seriously affected. Due to complex causes, the effects of clinical treatments have been very unsatisfactory. Many experts have found that neuron-microglia interaction plays an essential role in NP occurrence and development. Therefore, the activation of microglia, related inflammatory mediators and molecular and cellular signaling pathways have become the focus of NP research. With the help of modern functional imaging technology, advanced pre-and clinical studies have been carried out and NP interventions have been attempted by using the different pharmaceuticals and the extracted active components of various traditional herbal medicines. In this communication, we review the mechanism of microglia on NP formation and treatment and molecular imaging technology\u27s role in the clinical diagnosis and evaluation of NP therapies

PET imaging of in vivo caspase-3/7 activity following myocardial ischemia-reperfusion injury with the radiolabeled isatin sulfonamide analogue [(18)F]WC-4-116

The utility of [(18)F]WC-4-116, a PET tracer for imaging caspase-3 activation, was evaluated in an animal model of myocardial apoptosis. [(18)F]WC-4-116 was injected into rats at 3 hours after a 30 min period of ischemia induced by temporary occlusion of the left anterior descending coronary artery in Sprague-Dawley rats. [(18)F]WC-4-116 uptake was quantified by 1) autoradiography, 2) microPET imaging studies, and 3) post-PET biodistribution studies. MicroPET imaging also assessed uptake of the non-caspase-3-targeted tracer [(18)F]ICMT-18 at 3 hours postischemia. Enzyme assays and Western blotting assessed caspase-3 activation in both at-risk and not-at-risk regions. Caspase-3 enzyme activity increased in the at-risk but not in the not-at-risk myocardium. Quantitative autoradiographic analysis of [(18)F]WC-4-116 demonstrated nearly 2-fold higher uptake in the ischemia-reperfusion (IR) versus sham animals. [(18)F]WC-4-116 microPET imaging studies demonstrated that the IR animals was similarly elevated in relation to sham. [(18)F]ICMT-18 uptake did not increase in at-risk myocardium despite evidence of caspase-3 activation. Biodistribution studies with [(18)F]WC-4-116 confirmed the microPET findings. These data indicate that the caspase-3-PET tracer [(18)F]WC-4-116 can noninvasively image in vivo caspase activity during myocardial apoptosis and may be useful for clinical imaging in humans

The Striatal DNA Damage and Neurodegenerations

Reactive oxygen species (ROS) are produced during normal metabolic reactions in living cells. ROS causes oxidative damage to many types of biomolecules. An age-related increase in oxidative damage to DNA and RNA has been described in the human neurons, which play a vital role in the progression of age-associated neurodegeneration. As dopamine metabolism is believed to be the primary source of ROS, oxidative insults correlate with dopamine levels in the striatum during the progression of neurodegenerative diseases. Parallel changes in dopamine concentrations and vesicular monoamine transporter 2 (VMAT2) binding densities in the striatum were observed. Besides Fenton oxidation taking place, the packing of cytosolic dopamine into synaptic vesicles by VMAT2 inhibits its autoxidation and subsequent decay of dopaminergic neurons. The female bias in the DNA damage in the late-stage Parkinson disease (PD) patients suggests that the sex-determining region of the Y chromosome (SRY) genes are critically involved. ROS are involved in regulating the rate of the aging procession in healthy cohorts and an increased life span of patients with neurodegenerative diseases via stimulation of protective stress responses. Moreover, the DNA repair pathway’s mechanism, as genetic modifiers determine the age at onset through a ROS-inducing mutation

[18F]Tosyl fluoride as a versatile [18F]fluoride source for the preparation of 18F-labeled radiopharmaceuticals

Positron emission tomography (PET) is an in vivo imaging technology that utilizes positron-emitting radioisotope-labeled compounds as PET radiotracers that are commonly used in clinic and in various research areas, including oncology, cardiology, and neurology. Fluorine-18 is the most widely used PET-radionuclide and commonly produced by proton bombardment o