Dynamic multi-pinhole collimated brain SPECT of Parkinson's disease by [123I]FP-CIT: a feasibility study of fSPECT.

We investigated the feasibility of using a dopamine transporter (DaT) tracer ligand ([123I]FP-CIT) along with novel multi-pinhole brain collimators for dynamic brain single photon emission computed tomography (SPECT) in suspected Parkinson's disease patients. Thirteen patients underwent dynamic tracer acquisitions before standard imaging. Uptake values were corrected for partial volume effects. Specific binding ratio (SBRcalc) was calculated, reflecting binding potential relative to non-displaceable binding (BPND) in the cortex. Additional pharmacokinetic parameters (BPND, R1, k2) were estimated using the simplified reference tissue model, revealing differences between Kahraman low-score (LS) and high-score (HS) groups. Results showed increasing striatal tracer uptake until 100 min post-injection, with consistent values afterward. Uptake and SBRcalc ratios matched visual assessment. LS patients had lower putamen than caudate nucleus tracer uptake, decreased BPND values, while R1 and k2 values were comparable to HS patients. In conclusion, dynamic multi-pinhole SPECT using DaT tracer with the extraction of pharmacokinetic parameters is feasible and could help enable early differentiation of reduced and normal DaT values.

Uptake of 18F-AV45 in the Putamen Provides Additional Insights into Alzheimer's Disease beyond the Cortex.

Cortical uptake in brain amyloid positron emission tomography (PET) is increasingly used for the biological diagnosis of Alzheimer's disease (AD); however, the clinical and biological relevance of the striatum beyond the cortex in amyloid PET scans remains unclear. A total of 513 amyloid-positive participants having 18F-AV45 amyloid PET scans available were included in the analysis. The associations between cognitive scores and striatal uptake were analyzed. The participants were categorized into three groups based on the residual from the linear fitting between 18F-AV45 uptake in the putamen and the cortex in the order of HighP > MidP > LowP group. We then examined the differences between these three groups in terms of clinical diagnosis, APOE genotype, CSF phosphorylated tau (ptau) concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate to evaluate the additional insights provided by the putamen beyond the cortex. The 18F-AV45 uptake in the putamen was more strongly associated with ADAS-cog13 and MoCA scores (p < 0.001) compared to the uptake in the caudate nucleus. Despite comparable cortical uptakes, the HighP group had a two-fold higher risk of being ε4-homozygous or diagnosed with AD dementia compared to the LowP group. These three groups had significantly different CSF ptau concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate. These findings suggest that the assessment of 18F-AV45 uptake in the putamen is of unique value for evaluating disease severity and predicting disease progression.

Estimating the sequence of biomarker changes in Parkinson's disease.

OBJECTIVE: To estimate the sequence of several common biomarker changes in Parkinson's disease (PD) using a novel data-driven method. METHODS: We included 374 PD patients and 169 healthy controls (HC) from the Parkinson's Progression Markers Initiative (PPMI). Biomarkers, including the left putamen striatal binding ratio (SBR), right putamen SBR, left caudate SBR, right caudate SBR, cerebrospinal fluid (CSF) α-synuclein, and serum neurofilament light chain (NfL), were selected in our study. The discriminative event-based model (DEBM) was utilized to model the sequence of biomarker changes and establish the disease progression timeline. The estimated disease stages for each subject were obtained through cross-validation. The associations between the estimated disease stages and the clinical symptoms of PD were explored using Spearman's correlation. RESULTS: The left putamen is the earliest biomarker to become abnormal among the selected biomarkers, followed by the right putamen, CSF α-synuclein, right caudate, left caudate, and serum NfL. The estimated disease stages are significantly different between PD and HC and yield a high accuracy for distinguishing PD from HC, with an area under the curve (AUC) of 0.98 (95% confidence interval 0.97-0.99), a sensitivity of 0.95, and a specificity of 0.92. Moreover, the estimated disease stages correlate with motor experiences of daily living, motor symptoms, autonomic dysfunction, and anxiety in PD patients. CONCLUSION: We determined the sequence of several common biomarker changes in PD using DEBM, providing data-driven evidence of the disease progression of PD.

A genetic and transcriptomic assessment of the KTN1 gene in Parkinson's disease risk.

Parkinson's disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. An association has been described between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson's Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to unaffected individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

Nigrostriatal tau pathology in parkinsonism and Parkinson's disease.

While Parkinson's disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinson's Disease Rating Scale III but were insufficient in degree to diagnose Parkinson's disease. However, in our past studies, cases in this cohort had a selection bias, as both a clinical syndrome in between no motor deficits and Parkinson's disease, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in the current study, we only based inclusion on the presence of a clinical phenotype with mild motor impairment insufficient to diagnose Parkinson's disease. Then, we divided this group further based upon whether or not subjects had a synucleinopathy in the nigrostriatal system. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation and loss of the tyrosine hydroxylase-phenotype in the substantia nigra and putamen occur equally in mild motor deficit groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8 positive phosphorylated tau, a pathology not seen in the nigrostriatal system of age-matched controls. These findings were confirmed with early (tau Ser208 phosphorylation) and late (tau Ser396/Ser404 phosphorylation) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated.

Osteogenic stimulation of osteoprogenitors by putamen ovi peptides and hyaluronic acid.

Eggshell peptides (EP) majorly contribute to rapid bone building in chicks, wherefore this paper investigated their potential for stimulating osteogenesis in vitro. In this study, the effects of EP, also called putamen ovi peptides and a combination of hyaluronic acid with EP in cell culture medium were tested towards proliferation, differentiation, gene expression and mineralization of bovine osteoprogenitors and primary human osteoblasts. The influence of EP at concentrations of 0.005 g/L, 0.5 g/L and 0.5 g/L with 0.25% hyaluronic acid was analyzed using immunocytochemical staining of bone-specific matrix proteins, namely collagen type I, osteonectin, osteopontin and osteocalcin, to prove osteoblastic differentiation. Additionally, Richardson-staining was performed. All tests revealed a superior osteoblastic differentiation with EP at 0.5 g/L after 5 days of cultivation. Hyaluronic acid alone showed controversial results and partially constrained osteoblastic differentiation in combination with EP to a level as low as for pure EP at 0.005 g/L. Of particular interest is the osteoblast-typical mineralization, as an important indicator of bone formation, which was measured indirectly via the calcium concentration after cultivation over 4 weeks. The mineralization showed an increase by a factor of 286 during the cultivation of primary human osteoblasts with hyaluronic acid and EP. Meanwhile, cell cultures treated with EP (0.5 g/L) only showed an 80-fold increase in calcium concentration.The influence of EP (0.5 g/L) on primary human osteoblasts was investigated by gene expression after 2 weeks of cultivation. Microarray and qRT-PCR analysis showed a strongly increased expression of main important genes in bone formation, bone regeneration and the physiological bone remodelling processes. Namely, BMP 2, osteopontin and the matrix metalloproteinases 1 and 9, were present during in vitro osteoprogenitor culture with EP. By explicitly underlining the potential of eggshell peptides for stimulating osteogenesis, as well as emphasizing complex and controversial interaction with hyaluronan, this manuscript is relevant for developing new functionalized biomaterials for bone regeneration.

Perturbation of serine enantiomers homeostasis in the striatum of MPTP-lesioned monkeys and mice reflects the extent of dopaminergic midbrain degeneration.

Loss of dopaminergic midbrain neurons perturbs l-serine and d-serine homeostasis in the post-mortem caudate putamen (CPu) of Parkinson's disease (PD) patients. However, it is unclear whether the severity of dopaminergic nigrostriatal degeneration plays a role in deregulating serine enantiomers' metabolism. Here, through high-performance liquid chromatography (HPLC), we measured the levels of these amino acids in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and MPTP-plus-probenecid (MPTPp)-treated mice to determine whether and how dopaminergic midbrain degeneration affects the levels of serine enantiomers in various basal ganglia subregions. In addition, in the same brain regions, we measured the levels of key neuroactive amino acids modulating glutamatergic neurotransmission, including l-glutamate, glycine, l-aspartate, d-aspartate, and their precursors l-glutamine, l-asparagine. In monkeys, MPTP treatment produced severe denervation of nigrostriatal dopaminergic fibers (⁓75%) and increased the levels of serine enantiomers in the rostral putamen (rPut), but not in the subthalamic nucleus, and the lateral and medial portion of the globus pallidus. Moreover, this neurotoxin significantly reduced the protein expression of the astrocytic serine transporter ASCT1 and the glycolytic enzyme GAPDH in the rPut of monkeys. Conversely, concentrations of d-serine and l-serine, as well as ASCT1 and GAPDH expression were unaffected in the striatum of MPTPp-treated mice, which showed only mild dopaminergic degeneration (⁓30%). These findings unveil a link between the severity of dopaminergic nigrostriatal degeneration and striatal serine enantiomers concentration, ASCT1 and GAPDH expression. We hypothesize that the up-regulation of d-serine and l-serine levels occurs as a secondary response within a homeostatic loop to support the metabolic and neurotransmission demands imposed by the degeneration of dopaminergic neurons.

Homeostasis of serine enantiomers is disrupted in the post-mortem caudate putamen and cerebrospinal fluid of living Parkinson's disease patients.

L-serine generated in astrocytes plays a pivotal role in modulating essential neurometabolic processes, while its enantiomer, D-serine, specifically regulates NMDA receptor (NMDAR) signalling. Despite their physiological relevance in modulating cerebral activity, serine enantiomers metabolism in Parkinson's disease (PD) remains elusive. Using High-Performance Liquid Chromatography (HPLC), we measured D- and L-serine levels along with other amino acids known to modulate NMDAR function, such as L-glutamate, L-aspartate, D-aspartate, and glycine, in the post-mortem caudate putamen (CPu) and superior frontal gyrus (SFG) of PD patients. Moreover, we examined these amino acids in the cerebrospinal fluid (CSF) of de novo living PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients versus subjects with other neurological disorders (OND), used as control. We found higher D-serine and L-serine levels in the CPu of PD patients but not in the SFG, a cerebral region that, in contrast to the CPu, is not innervated by nigral dopaminergic terminals. We also highlighted a significant elevation of both serine enantiomers in the CSF samples from PD but not in those of AD and ALS patients, compared with control subjects. By contrast, none or only minor changes were found in the amount of other NMDAR modulating amino acids. Our findings identify D-serine and L-serine level upregulation as a biochemical signature associated with nigrostriatal dopaminergic degeneration in PD.

Nigral Pathology Contributes to Microstructural Integrity of Striatal and Frontal Tracts in Parkinson's Disease.

BACKGROUND: Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood. OBJECTIVE: To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD. METHODS: Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively. RESULTS: Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load. CONCLUSIONS: In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Increased Free Water in the Putamen in Idiopathic REM Sleep Behavior Disorder.

BACKGROUND: It has been suggested that the loss of nigrostriatal dopaminergic axon terminals occurs before the loss of dopaminergic neurons in the substantia nigra (SN) in Parkinson's disease (PD). This study aimed to use free-water imaging to evaluate microstructural changes in the dorsoposterior putamen (DPP) of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) patients, which is considered a prodromal stage of synucleinopathies. METHODS: Free water values in the DPP, dorsoanterior putamen (DAP), and posterior SN were compared between the healthy controls (n = 48), iRBD (n = 43) and PD (n = 47) patients. In iRBD patients, the relationships between baseline and longitudinal free water values and clinical manifestations or dopamine transporter (DAT) striatal binding ratio (SBR) were analyzed. RESULTS: Free water values were significantly higher in the DPP and posterior substantia nigra (pSN), but not in the DAP, in the iRBD and PD groups than in controls. In iRBD patients, free water values in the DPP were progressively increased and correlated with the progression of clinical manifestations and the striatal DAT SBR. Baseline free water in the DPP was negatively correlated with striatal DAT SBR and hyposmia and positively correlated with motor deficits. CONCLUSIONS: This study demonstrates that free water values in the DPP are increased cross-sectionally and longitudinally and associated with clinical manifestations and the function of the dopaminergic system in the prodromal stage of synucleinopathies. Our findings indicate that free-water imaging of the DPP has the potential to be a valid marker of early diagnosis and progression of synucleinopathies. © 2023 International Parkinson and Movement Disorder Society.

Intense inhibitory avoidance training increases nuclear-phosphorylated glucocorticoid receptors in neurons of CA1 of hippocampus and ventral caudate putamen.

Corticosterone (CORT), the principal glucocorticoid in rodents, is released after stressful experiences such as training with high foot-shock intensities in the inhibitory avoidance task (IA). CORT reaches the glucocorticoid receptor (GR) located in almost all brain cells; the GR is subsequently phosphorylated at serine 232 (pGRser232). This has been reported as an indicator of ligand-dependent activation of the GR, as well as a requirement for its translocation into the nucleus for its transcription factor activity. The GR is present in the hippocampus with a high concentration in CA1 and dentate gyrus (DG), and a smaller proportion in CA3, and sparsely present in the caudate putamen (CPu); both structures are involved in memory consolidation of IA. To study the participation of CORT in IA, we quantified the ratio of pGR-positive neurons in both dorsal hippocampus (CA1, CA3 and DG) and dorsal and ventral regions of CPu of rats trained in IA, using different foot-shock intensities. Brains were dissected 60 min after training for immunodetection of pGRser232 positive cells. The results show that the groups trained with 1.0 and 2.0 mA had higher retention latencies than the 0.0 mA or 0.5 mA groups. An increase in the ratio of pGR-positive neurons was found in CA1 and ventral region of CPu only for the 2.0 mA trained group. These findings suggest that activation of GRs in CA1 and ventral CPu is involved in the consolidation of a stronger memory of IA, possibly through the modulation of gene expression.

Increased Free Water in the Substantia Nigra in Asymptomatic LRRK2 G2019S Mutation Carriers.

BACKGROUND: The alteration of substantia nigra (SN) degeneration in populations at risk of Parkinson's disease (PD) is unclear. OBJECTIVE: We investigated free water (FW) values in the posterior SN (pSN) in asymptomatic LRRK2 G2019S mutation carriers. METHODS: We analyzed diffusion imaging data from 28 asymptomatic LRRK2 G2019S mutation carriers and 30 healthy controls (HCs), whereas 11 asymptomatic LRRK2 G2019S carriers and 11 HCs were followed up. FW values in the pSN were measured and compared between the groups. The relationship between longitudinal changes in FW in the pSN and dopamine transporter striatal binding ratio (SBR) was analyzed. RESULTS: FW values in the pSN were significantly elevated and kept increasing during follow-up in asymptomatic LRRK2 G2019S carriers. There was a negative correlation between FW changes in the left pSN and SBR changes in the left putamen. CONCLUSION: FW in the pSN has the potential to be a progression imaging marker of early dopaminergic degeneration in the population at risk of PD. © 2022 International Parkinson and Movement Disorder Society.

Association between susceptibility value and cerebral blood flow in the bilateral putamen in patients undergoing hemodialysis.

Hemodialysis (HD) is the most regularly applied replacement therapy for end-stage renal disease, but it may result in brain injuries. The correlation between cerebral blood flow (CBF) alteration and iron deposition has not been investigated in patients undergoing HD. Ferritin level may be a dominant factor in CBF and iron deposition change. We hypothesize that ferritin level might be the key mediator between iron deposition and CBF alteration. The correlation in the putamen was estimated between the susceptibility values and CBF in patients undergoing HD. Compared with healthy controls, patients showed more altered global susceptibility values and CBF. The susceptibility value was negatively correlated with CBF in the putamen in patients. Moreover, the susceptibility value was negatively correlated with ferritin level and positively correlated with serum iron level in the putamen of patients. CBF was positively correlated with ferritin level and negatively correlated with serum iron level in the putamen of patients. These findings indicate that iron dyshomeostasis and vascular damage might exist in the putamen in patients. The results revealed that iron dyshomeostasis and vascular damage in the putamen may be potential neural mechanisms for neurodegenerative processes in patients undergoing HD.

Motor symptoms in Parkinson's disease are related to the interplay between cortical curvature and thickness.

INTRODUCTION: Brain atrophy in Parkinson's disease occurs to varying degrees in different brain regions, even at the early stage of the disease. While cortical morphological features are often considered independently in structural brain imaging studies, research on the co-progression of different cortical morphological measurements could provide new insights regarding the progression of PD. This study's aim was to examine the interplay between cortical curvature and thickness as a function of PD diagnosis, motor symptoms, and cognitive performance. METHODS: A total of 359 de novo PD patients and 159 healthy controls (HC) from the Parkinson's Progression Markers Initiative (PPMI) database were included in this study. Additionally, an independent cohort from four databases (182 PD, 132 HC) with longer disease durations was included to assess the effects of PD diagnosis in more advanced cases. Pearson correlation was used to determine subject-specific associations between cortical curvature and thickness estimated from T1-weighted MRI images. General linear modeling (GLM) was then used to assess the effect of PD diagnosis, motor symptoms, and cognitive performance on the curvature-thickness association. Next, longitudinal changes in the curvature-thickness correlation as well as the predictive effect of the cortical curvature-thickness association on changes in motor symptoms and cognitive performance across four years were investigated. Finally, Akaike information criterion (AIC) was used to build a GLM to model PD motor symptom severity cross-sectionally. RESULTS: A significant interaction effect between PD motor symptoms and age on the curvature-thickness correlation was found (ßstandardized = 0.11; t(350) = 2.12; p = 0.03). This interaction effect showed that motor symptoms in older patients were related to an attenuated curvature-thickness association. No significant effect of PD diagnosis was observed for the PPMI database (ß = 0.03; t(510) = 0.35; p = 0.72). However, in patients with a longer disease duration, a significant effect of diagnosis on the curvature-thickness association was found (ßstandardized = 0.31; t(306.7) = 3.49; p = 0.0006). Moreover, rigidity, but not tremor, in PD was significantly related to the curvature-thickness correlation (ßstandardized = 0.11, t(350) = 2.24, p = 0.03; ßstandardized = -0.03, t(350) = -0.58, p = 0.56, respectively). The curvature-thickness association was attenuated over time in both PD and HC, but the two groups did not show a significantly different effect (ßstandardized = 0.03, t(184.7) = 0.78, p = 0.44). No predictive effects of the CC-CT correlation on longitudinal changes in cognitive performance or motor symptoms were observed (all p-values > 0.05). The best cross-sectional model for PD motor symptoms included the curvature-thickness correlation, cognitive performance, and putamen dopamine transporter (DAT) binding, which together explained 14 % of variance. CONCLUSION: The association between cortical curvature and thickness is related to PD motor symptoms and age. This research shows the potential of modeling the curvature-thickness interplay in PD.

Sleep benefit in patients with Parkinson's disease is associated with the dopamine transporter expression in putamen.

PURPOSE: Sleep benefit (SB) is a well-known phenomenon in patients with Parkinson's disease (PD); however, the mechanisms underlying this phenomenon remain unclear. This study aimed to evaluate whether the SB phenomenon in PD patients is associated with dopamine transporter (DAT) expression levels in the striatum. METHODS: The data of 125 PD patients were collected and divided into SB (n = 61) and non-SB (nSB) groups (n = 54) depending on whether they had SB or not. DAT expression on both sides of the striatum in PD patients was measured using 2b-carbomethoxy-3b-(4-trimethylstannylphenyl) tropane (11C-CFT) positron emission tomography imaging. The clinical variables, sleep scores, and striatum 11C-CFT uptake index of PD patients between the SB and nSB groups were compared. The associations of clinical variables, sleep scores, and striatum 11C-CFT uptake index with the SB variable were analyzed using logistic regression analysis. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of the striatum 11C-CFT uptake index in distinguishing SB patients from nSB patients. RESULTS: The tremor subtype ratio (P = 0.011), levodopa equivalent daily dose (LEDD) (P < 0.001), sleep efficiency score (P = 0.025), habitual sleep efficiency (P = 0.012), and night sleep duration (P = 0.005) in the SB group were significantly different from those in the nSB group. The 11C-CFT uptake index in both the contralateral and ipsilateral striata in the SB group was significantly higher than that in the nSB group (P < 0.05). The binary logistic regression showed that SB variables were significantly and independently associated with tremor subtype (P = 0.048), LEDD (P = 0.021), sleep duration at night (P = 0.035), 11C-CFT uptake index in the contralateral (P = 0.013) and ipsilateral (P = 0.019) putamen in PD patients after correction for important clinical confounders. ROC analysis showed that the 11C-CFT uptake index on the onset side of the putamen had a high capacity (AUC: 0.916) to distinguish SB patients from nSB patients with high sensitivity (83.33 %) and specificity (88.89 %). CONCLUSION: DAT expression in the putamen was associated with the SB phenomenon in PD patients, and the putamen DAT expression level could predict the SB phenomenon in PD patients.

Patterns of striatal dopamine depletion and motor deficits in de novo Parkinson's disease.

The background of this study is to investigate whether striatal dopamine depletion patterns (selective involvement in the sensorimotor striatum or asymmetry) are associated with motor deficits in Parkinson's disease (PD). We enrolled 404 drug-naïve patients with early stage PD who underwent dopamine transporter (DAT) imaging. After quantifying DAT availability in each striatal sub-region, principal component (PC) analysis was conducted to yield PCs representing the spatial patterns of striatal dopamine depletion. Subsequently, multivariate linear regression analysis was conducted to investigate the relationship between striatal dopamine depletion patterns and motor deficits assessed using the Unified PD Rating Scale Part III (UPDRS-III). Mediation analyses were used to evaluate whether dopamine deficiency in the posterior putamen mediated the association between striatal dopamine depletion patterns and parkinsonian motor deficits. Three PCs indicated patterns of striatal dopamine depletion: PC1 (overall striatal dopamine deficiency), PC2 (selective dopamine loss in the sensorimotor striatum), and PC3 (symmetric dopamine loss in the striatum). Multivariate linear regression analysis revealed that PC1 (ß = - 1.605, p < 0.001) and PC2 (ß = 3.201, p < 0.001) were associated with motor deficits (i.e., higher UPDRS-III scores in subjects with severe dopamine depletion throughout the whole striatum or more selective dopamine loss in the sensorimotor striatum), whereas PC3 was not (ß = - 0.016, p = 0.992). Mediation analyses demonstrated that the effects of PC1 and PC2 on UPDRS-III scores were indirectly mediated by DAT availability in the posterior putamen, with a non-significant direct effect. Dopamine deficiency in the posterior putamen was most relevant to the severity of motor deficits in patients with PD, while the spatial patterns of striatal dopamine depletion were not a key determinant.

Novel Allosteric Modulator Southern Research Institute-32743 Reverses HIV-1 Transactivator of Transcription-Induced Increase in Dopamine Release in the Caudate Putamen of Inducible Transactivator of Transcription Transgenic Mice.

Development of neurocognitive disorder in human immunodeficiency virus (HIV)-infected patients has been linked to dysregulation of dopamine by the HIV-1 transactivator of transcription (Tat) protein, a negative allosteric modulator of dopamine transporter (DAT). Using fast scan cyclic voltammetry, the present study determined the effects of in vivo Tat expression on dopamine release in the caudate putamen of inducible Tat transgenic (iTat-tg) mice and the impact of a novel DAT allosteric modulator, Southern Research Institute (SRI)-32743, on the Tat effect. We found that 7- or 14-day doxycycline (Dox)-induced Tat expression in iTat-tg mice resulted in a 2-fold increase in phasic but not tonic stimulated baseline dopamine release relative to saline control mice. To determine whether the Tat-induced increase in dopamine release is mediated by DAT regulation, we examined the effect of an in vitro applied DAT inhibitor, nomifensine, on the dopamine release. Nomifensine (1 nM-10 µM) concentration-dependently enhanced phasic stimulated dopamine release in both saline- and Dox-treated iTat-tg mice, while the magnitude of the nomifensine-mediated dopamine release was unchanged between saline and Dox treatment groups. A single systemic administration of SRI-32743 prior to animal sacrifice reversed the increased dopamine release in the baseline of phasic dopamine release and nomifensine-augmented dopamine levels in Dox-treated iTat-tg mice, while SRI-32743 alone did not alter baseline of dopamine release. These findings suggest that Tat expression induced an increase in extracellular dopamine levels by not only inhibiting DAT-mediated dopamine transport but also stimulating synaptic dopamine release. Thus, DAT allosteric modulators may serve as a potential therapeutic intervention for HIV infection-dysregulated dopamine system observed in HIV-1 positive individuals. SIGNIFICANCE STATEMENT: HIV infection-induced dysregulation of the dopaminergic system has been implicated in the development of neurocognitive impairments observed in HIV positive patients. Understanding the mechanisms underlying HIV-1 Tat protein-induced alteration of extracellular dopamine levels will provide insights into the development of molecules that can attenuate Tat interaction with targets in the dopaminergic system. Here, we determined whether Tat alters dopamine release and how the novel DAT allosteric modulator, SRI-32743, impacts dopamine neurotransmission to attenuate Tat-induced effects on extracellular dopamine dynamics.

Nitric Oxide Linked to mGluR5 Upregulates BDNF Synthesis by Activating MMP2 in the Caudate and Putamen after Challenge Exposure to Nicotine in Rats.

Nitric oxide (NO) linked to glutamate receptors in the caudate and putamen (CPu) regulates neuroadaptation after drug exposure. Matrix-metalloproteinase (MMP), a Ca2+-dependent zinc-containing endopeptidase, increases mature brain-derived neurotrophic factor (BDNF) synthesis after drug exposure in the brain. The present study determined that NO synthesis linked to metabotropic glutamate receptor subtype 5 (mGluR5) stimulation after challenge exposure to nicotine activates MMP, which upregulates BDNF synthesis in the CPu. Subcutaneous injection of challenge nicotine (1.0 mg/kg) after repeated injections of nicotine (1.0 mg/kg/day) for 14 days and 7 days of nicotine withdrawal increased MMP2 activity and BDNF expression in the CPu of rats. These increases were prevented by the bilateral intra-CPu infusion of the mGluR5 antagonist, MPEP (0.1 nmol/side), the IP3 receptor antagonist, xestospongin C (0.004 nmol/side) or the neuronal nitric oxide synthase (nNOS) and NO inhibitor, Nω-propyl (0.1 nmol/side) prior to the challenge nicotine. Furthermore, bilateral intra-CPu infusion of the MMP2 inhibitor, OA-Hy (1 nmol/side) prevented the challenge nicotine-induced increase in the expression of BDNF. These findings suggest that elevation of NO synthesis linked to mGluR5 potentiates BDNF synthesis via activation of MMP2 after challenge exposure to nicotine in the CPu of rats.

18 F-Florzolotau Tau Positron Emission Tomography Imaging in Patients with Multiple System Atrophy-Parkinsonian Subtype.

BACKGROUND: Anecdotal evidence suggests that patients diagnosed with the parkinsonian subtype of multiple system atrophy (MSA-P) may show uptake of the second-generation tau positron emission tomography (PET) tracer 18 F-Florzolotau (previously known as 18 F-APN-1607) in the putamen. OBJECTIVES: This study systematically investigated the localization and magnitude of 18 F-Florzolotau uptake in a relatively large cohort of patients with MSA-P. METHODS: 18 F-Florzolotau PET imaging was performed in 31 patients with MSA-P, 24 patients with Parkinson's disease (PD), and 20 age-matched healthy controls. 18 F-Florzolotau signal in the striatum was analyzed by visual inspection and classified as either positive or negative. Regional 18 F-Florzolotau binding was also expressed as standardized uptake value ratio (SUVR) to assess whether it was associated with core symptoms of MSA-P after adjustment for potential confounders. RESULTS: By visual inspection and semiquantitative SUVR comparisons, patients with MSA-P showed elevated 18 F-Florzolotau uptake in the putamen, globus pallidus, and dentate-a finding that was not observed in PD. This increased signal was significantly associated with the core symptoms of MSA-P. In addition, patients with MSA-P with cerebellar ataxia showed an elevated 18 F-Florzolotau uptake in the cerebellar dentate. CONCLUSIONS: 18 F-Florzolotau tau PET imaging findings may reflect the clinical severity of MSA-P and can potentially discriminate between this condition and PD. © 2022 International Parkinson and Movement Disorder Society.

Widespread alterations in microRNA biogenesis in human Huntington's disease putamen.

Altered microRNA (miRNA) expression is a common feature of Huntington's disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin binds to Ago2, a central component of miRNA biogenesis, and disrupts mature miRNA levels. In this study, we sought to determine if miRNA maturation per se was compromised in HD. Towards this end, we characterized major miRNA biogenesis pathway components and miRNA maturation products (pri-miRNA, pre-miRNA, and mature) in human HD (N = 41, Vonsattel grades HD2-4) and healthy control (N = 25) subjects. Notably, the striatum (putamen) and cortex (BA39) from the same individuals were analyzed in parallel. We show that Ago2, Drosha, and Dicer were strongly downregulated in human HD at the early stages of the disease. Using a panel of HD-related miRNAs (miR-10b, miR-196b, miR-132, miR-212, miR-127, miR-128), we uncovered various types of maturation defects in the HD brain, the most prominent occurring at the pre-miRNA to mature miRNA maturation step. Consistent with earlier findings, we provide evidence that alterations in autophagy could participate in miRNA maturation defects. Notably, most changes occurred in the striatum, which is more prone to HTT aggregation and neurodegeneration. Likewise, we observed no significant alterations in miRNA biogenesis in human HD cortex and blood, strengthening tissue-specific effects. Overall, these data provide important clues into the underlying mechanisms behind miRNA alterations in HD-susceptible tissues. Further investigations are now required to understand the biological, diagnostic, and therapeutic implications of miRNA/RNAi biogenesis defects in HD and related neurodegenerative disorders.