PET-based brain molecular connectivity in neurodegenerative disease.

PURPOSE OF REVIEW: Molecular imaging has traditionally been used and interpreted primarily in the context of localized and relatively static neurochemical processes. New understanding of brain function and development of novel molecular imaging protocols and analysis methods highlights the relevance of molecular networks that co-exist and interact with functional and structural networks. Although the concept and evidence of disease-specific metabolic brain patterns has existed for some time, only recently has such an approach been applied in the neurotransmitter domain and in the context of multitracer and multimodal studies. This review briefly summarizes initial findings and highlights emerging applications enabled by this new approach. RECENT FINDINGS: Connectivity based approaches applied to molecular and multimodal imaging have uncovered molecular networks with neurodegeneration-related alterations to metabolism and neurotransmission that uniquely relate to clinical findings; better disease stratification paradigms; an improved understanding of the relationships between neurochemical and functional networks and their related alterations, although the directionality of these relationships are still unresolved; and a new understanding of the molecular underpinning of disease-related alteration in resting-state brain activity. SUMMARY: Connectivity approaches are poised to greatly enhance the information that can be extracted from molecular imaging. While currently mostly contributing to enhancing understanding of brain function, they are highly likely to contribute to the identification of specific biomarkers that will improve disease management and clinical care.

Misfolded protein deposits in Parkinson's disease and Parkinson's disease-related cognitive impairment, a [11C]PBB3 study.

Parkinson's disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of [11C]PBB3 (a ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson's disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent [11C]PBB3 PET. A subset of the PD subjects also underwent PET imaging with [11C](+)DTBZ to assess dopaminergic denervation and [11C]PBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher [11C]PBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between [11C]PBB3 and [11C]PBR28 binding in nigrostriatal regions. [11C]PBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and [11C]PBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies.

Distinct spatial contributions of amyloid pathology and cerebral small vessel disease to hippocampal morphology.

INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aß) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aß, as assessed by 18F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aß were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aß. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aß-vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aß pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.

Multi-tracer PET correlation analysis reveals disease-specific patterns in Parkinson's disease and asymptomatic LRRK2 pathogenic variant carriers compared to healthy controls.

Several genetic pathogenic variants increase the risk of Parkinson's disease (PD) with pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene being among the most common. A joint pattern analysis based on multi-set canonical correlation analysis (MCCA) was utilized to extract PD and LRRK2 pathogenic variant-specific spatial patterns in relation to healthy controls (HCs) from multi-tracer Positron Emission Tomography (PET) data. Spatial patterns were extracted for individual subject cohorts, as well as for pooled subject cohorts, to explore whether complementary spatial patterns of dopaminergic denervation are different in the asymptomatic and symptomatic stages of PD. The MCCA results are also compared to the traditional univariate analysis, which serves as a reference. We identified PD-induced spatial distribution alterations common to DAT and VMAT2 in both asymptomatic LRRK2 pathogenic variant carriers and PD subjects. The inclusion of HCs in the analysis demonstrated that the dominant common PD-induced pattern is related to an overall dopaminergic terminal density denervation, followed by asymmetry and rostro-caudal gradient with deficits in the less affected side still being the best marker of disease progression. The analysis was able to capture a trend towards PD-related patterns in the LRRK2 pathogenic variant carrier cohort with increasing age in line with the known increased risk of this patient cohort to develop PD as they age. The advantage of this method thus resides in its ability to identify not only regional differences in tracer binding between groups, but also common disease-related alterations in the spatial distribution patterns of tracer binding, thus potentially capturing more complex aspects of disease induced alterations.

Novel voxelwise residual analysis of [11C]raclopride PET data improves detection of low-amplitude dopamine release.

Existing methods for voxelwise transient dopamine (DA) release detection rely on explicit kinetic modeling of the [11C]raclopride PET time activity curve, which at the voxel level is typically confounded by noise, leading to poor performance for detection of low-amplitude DA release-induced signals. Here we present a novel data-driven, task-informed method-referred to as Residual Space Detection (RSD)-that transforms PET time activity curves to a residual space where DA release-induced perturbations can be isolated and processed. Using simulations, we demonstrate that this method significantly increases detection performance compared to existing kinetic model-based methods for low-magnitude DA release (simulated +100% peak increase in basal DA concentration). In addition, results from nine healthy controls injected with a single bolus of [11C]raclopride performing a finger tapping motor task are shown as proof-of-concept. The ability to detect relatively low magnitudes of dopamine release in the human brain using a single bolus injection, while achieving higher statistical power than previous methods, may additionally enable more complex analyses of neurotransmitter systems. Moreover, RSD is readily generalizable to multiple tasks performed during a single PET scan, further extending the capabilities of task-based single-bolus protocols.

An update on the use of image-derived input functions for human PET studies: new hopes or old illusions?

BACKGROUND: The need for arterial blood data in quantitative PET research limits the wider usability of this imaging method in clinical research settings. Image-derived input function (IDIF) approaches have been proposed as a cost-effective and non-invasive alternative to gold-standard arterial sampling. However, this approach comes with its own limitations-partial volume effects and radiometabolite correction among the most important-and varying rates of success, and the use of IDIF for brain PET has been particularly troublesome. MAIN BODY: This paper summarizes the limitations of IDIF methods for quantitative PET imaging and discusses some of the advances that may make IDIF extraction more reliable. The introduction of automated pipelines (both commercial and open-source) for clinical PET scanners is discussed as a way to improve the reliability of IDIF approaches and their utility for quantitative purposes. Survey data gathered from the PET community are then presented to understand whether the field's opinion of the usefulness and validity of IDIF is improving. Finally, as the introduction of next-generation PET scanners with long axial fields of view, ultra-high sensitivity, and improved spatial and temporal resolution, has also brought IDIF methods back into the spotlight, a discussion of the possibilities offered by these state-of-the-art scanners-inclusion of large vessels, less partial volume in small vessels, better description of the full IDIF kinetics, whole-body modeling of radiometabolite production-is included, providing a pathway for future use of IDIF. CONCLUSION: Improvements in PET scanner technology and software for automated IDIF extraction may allow to solve some of the major limitations associated with IDIF, such as partial volume effects and poor temporal sampling, with the exciting potential for accurate estimation of single kinetic rates. Nevertheless, until individualized radiometabolite correction can be performed effectively, IDIF approaches remain confined at best to a few tracers.

Prediction of Parkinson's disease pathogenic variants using hybrid Machine learning systems and radiomic features.

PURPOSE: In Parkinson's disease (PD), 5-10% of cases are of genetic origin with mutations identified in several genes such as leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA). We aim to predict these two gene mutations using hybrid machine learning systems (HMLS), via imaging and non-imaging data, with the long-term goal to predict conversion to active disease. METHODS: We studied 264 and 129 patients with known LRRK2 and GBA mutations status from PPMI database. Each dataset includes 513 features such as clinical features (CFs), conventional imaging features (CIFs) and radiomic features (RFs) extracted from DAT-SPECT images. Features, normalized by Z-score, were univariately analyzed for statistical significance by the t-test and chi-square test, adjusted by Benjamini-Hochberg correction. Multiple HMLSs, including 11 features extraction (FEA) or 10 features selection algorithms (FSA) linked with 21 classifiers were utilized. We also employed Ensemble Voting (EV) to classify the genes. RESULTS: For prediction of LRRK2 mutation status, a number of HMLSs resulted in accuracies of 0.98 ± 0.02 and 1.00 in 5-fold cross-validation (80% out of total data points) and external testing (remaining 20%), respectively. For predicting GBA mutation status, multiple HMLSs resulted in high accuracies of 0.90 ± 0.08 and 0.96 in 5-fold cross-validation and external testing, respectively. We additionally showed that SPECT-based RFs added value to the specific prediction of of GBA mutation status. CONCLUSION: We demonstrated that combining medical information with SPECT-based imaging features, and optimal utilization of HMLS can produce excellent prediction of the mutations status in PD patients.

Multimodal Imaging of Substantia Nigra in Parkinson's Disease with Levodopa-Induced Dyskinesia.

BACKGROUND: Degeneration of the substantia nigra (SN) may contribute to levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), but the exact characteristics of SN in LID remain unclear. OBJECTIVE: To further understand the pathogenesis of patients with PD with LID (PD-LID), we explored the structural and functional characteristics of SN in PD-LID using multimodal magnetic resonance imaging (MRI). METHODS: Twenty-nine patients with PD-LID, 37 patients with PD without LID (PD-nLID), and 28 healthy control subjects underwent T1-weighted MRI, quantitative susceptibility mapping, neuromelanin-sensitive MRI, multishell diffusion MRI, and resting-state functional MRI. Different measures characterizing the SN were obtained using a region of interest-based approach. RESULTS: Compared with patients with PD-nLID and healthy control subjects, the quantitative susceptibility mapping values of SN pars compacta (SNpc) were significantly higher (P = 0.049 and P = 0.00002), and the neuromelanin contrast-to-noise ratio values in SNpc were significantly lower (P = 0.012 and P = 0.000002) in PD-LID. The intracellular volume fraction of the posterior SN in PD-LID was significantly higher compared with PD-nLID (P = 0.037). Resting-state fMRI indicated that PD-LID in the medication off state showed higher functional connectivity between the SNpc and putamen compared with PD-nLID (P = 0.031), and the functional connectivity changes in PD-LID were positively correlated with Unified Dyskinesia Rating Scale total scores (R = 0.427, P = 0.042). CONCLUSIONS: Our multimodal imaging findings highlight greater neurodegeneration in SN and the altered nigrostriatal connectivity in PD-LID. These characteristics provide a new perspective into the role of SN in the pathophysiological mechanisms underlying PD-LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease.

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aß-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aß-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aß-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aß-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aß-PET related more closely to higher cortical Aß (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aß-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

Brain Imaging Abnormalities in Mixed Alzheimer's and Subcortical Vascular Dementia.

BACKGROUND: A large proportion of Alzheimer's disease (AD) patients have coexisting subcortical vascular dementia (SVaD), a condition referred to as mixed dementia (MixD). Brain imaging features of MixD presumably include those of cerebrovascular disease and AD pathology, but are difficult to characterize due to their heterogeneity. OBJECTIVE: To perform an exploratory analysis of conventional and non-conventional structural magnetic resonance imaging (MRI) abnormalities in MixD and to compare them to those observed in AD and SVaD. METHODS: We conducted a cross-sectional, region-of-interest-based analysis of 1) hyperintense white-matter signal abnormalities (WMSA) on T2-FLAIR and hypointense WMSA on T1-weighted MRI; 2) diffusion tensor imaging; 3) quantitative susceptibility mapping; and 4) effective transverse relaxation rate (R2*) in N = 17 participants (AD:5, SVaD:5, MixD:7). General linear model was used to explore group differences in these brain imaging measures. RESULTS: Model findings suggested imaging characteristics specific to our MixD group, including 1) higher burden of WMSAs on T1-weighted MRI (versus both AD and SVaD); 2) frontal lobar preponderance of WMSAs on both T2-FLAIR and T1-weighted MRI; 3) higher fractional anisotropy values within normal-appear white-matter tissues (versus SVaD, but not AD); and 4) lower R2* values within the T2-FLAIR WMSA areas (versus both AD and SVaD). CONCLUSION: These findings suggest a preliminary picture of the location and type of brain imaging characteristics associated with MixD. Future imaging studies may employ region-specific hypotheses to distinguish MixD more rigorously from AD or SVaD.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Spatiotemporal patterns of putaminal dopamine processing in Parkinson's disease: A multi-tracer positron emission tomography study.

Alterations in different aspects of dopamine processing may exhibit different progressive behaviours throughout the course of Parkinson's disease. We used a novel data-driven multivariate approach to quantify and compare spatiotemporal patterns related to different aspects of dopamine processing from cross-sectional Parkinson's subjects obtained with: 1) 69 [11C]±dihydrotetrabenazine (DTBZ) scans, most closely related to dopaminergic denervation; 2) 73 [11C]d-threo-methylphenidate (MP) scans, marker of dopamine transporter density; 3) 50 6-[18F]fluoro-l-DOPA (FD) scans, marker of dopamine synthesis and storage. The anterior-posterior gradient in the putamen was identified as the most salient feature associated with disease progression, however the temporal progression of the spatial gradient was different for the three tracers. The expression of the anterior-posterior gradient was the highest for FD at disease onset compared to that of DTBZ and MP (P = 0.018 and P = 0.047 respectively), but decreased faster (P = 0.006) compared to that of DTBZ. The gradient expression for MP was initially similar but decreased faster (P = 0.015) compared to that for DTBZ. These results reflected unique temporal behaviours of regulatory mechanisms related to dopamine synthesis (FD) and reuptake (MP). While the relative early disease upregulation of dopamine synthesis in the anterior putamen prevalent likely extends to approximately 10 years after symptom onset, the presumed downregulation of dopamine transporter density may play a compensatory role in the prodromal/earliest disease stages only.

A Positron Emission Tomography Study of Dopamine Transporter Density in Patients With Bipolar Disorder With Current Mania and Those With Recently Remitted Mania.

Importance: Although dopamine is implicated in the pathophysiology of bipolar disorder (BD), the precise alterations in the dopaminergic system remain unknown. Objective: To assess dopamine transporter (DAT) density in the striatum in patients with BD with current and recently remitted mania in comparison to healthy control individuals and its correlation with severity of manic symptoms. Design, Setting, and Participants: This cross-sectional study conducted in a tertiary care referral center for mood disorders in Vancouver, British Columbia, Canada, recruited 26 patients with BD (9 with current mania; 17 with recently remitted mania) and 21 matched healthy control individuals. DAT density was measured using positron emission tomography with [11C]d-threo-methylphenidate (MP). The differences between the groups in nondisplaceable binding potential (BPND) for DAT was assessed using statistical parametric mapping. The study was conducted from November 2001 to February 2007 and the data were analyzed from November 2020 to December 2021. Main Outcomes and Measures: DAT density as indexed by BPND for MP across groups; manic symptom severity as measured with the Young Mania Rating Scale (YMRS) and correlated with BPND values in patients with BD. Results: Of 47 total participants (mean [SD] age, 37.8 [14.4] years), 27 (57.4%) were female; 26 individuals had BD (9 with current mania and 17 with recently remitted mania) and there were 21 healthy control individuals. MP BPND was significantly lower in patients with BD in the right putamen and nucleus accumbens (mean reduction [MR] = 22%; cluster level familywise error [FWE]-corrected P < .001) as well as left putamen and caudate (MR = 24%; cluster level FWE-corrected P < .001). The reduction in BPND was more extensive and pronounced in patients with current mania, while patients with recently remitted mania had lower BPND in the left striatum but not the right. There was a significant negative correlation between YMRS scores and MP BPND in the right striatum in patients with current mania (ρ = -0.93; 95% CI, -0.99 to -0.69; P < .001) and those with recently remitted mania (ρ = 0.64; 95% CI, -0.86 to -0.23; P = .005) but not in the left striatum in either group. Conclusions and Relevance: These findings indicate that mania was associated with reduced DAT density and remitted mania was associated with DAT levels that approximated those present in individuals without BD. These results have potential implications for drug development for mania.

HYPR4D kernel method on TOF PET data with validations including image-derived input function.

BACKGROUND: Positron emission tomography (PET) images are typically noisy especially in dynamic imaging where the PET data are divided into a number of short temporal frames often with a low number of counts. As a result, image features such as contrast and time-activity curves are highly variable. Noise reduction in PET is thus essential. Typical noise reduction methods tend to not preserve image features/patterns (e.g. contrast and size dependent) accurately. In this work, we report the first application of our HYPR4D kernel method on time-of-flight (TOF) PET data (i.e. PSF-HYPR4D-K-TOFOSEM). The proposed HYPR4D kernel method makes use of the mean 4D high frequency features and inconsistent noise patterns over OSEM subsets as well as the low noise property of the early reconstruction updates to achieve prior-free de-noising. The method was implemented and tested on the GE SIGNA PET/MR and was compared to the TOF reconstructions with PSF resolution modeling available on the system, namely PSF-TOFOSEM with and without standard post filter and PSF-TOFBSREM (TOF Q.Clear) with various beta values (regularization strengths). RESULTS: Results from experimental contrast phantom and human subject data with various PET tracers showed that the proposed method provides more robust and accurate image features compared to other regularization methods. The preservation of contrast for the PSF-HYPR4D-K-TOFOSEM was observed to be better and less dependent on the contrast and size of the target structures as compared to TOF Q.Clear and PSF-TOFOSEM with filter. At the same contrast level, PSF-HYPR4D-K-TOFOSEM achieved better 4D noise suppression than other methods (e.g. >2 times lower noise than TOF Q.Clear at the highest contrast). We also present a novel voxel search method to obtain an image-derived input function (IDIF) and demonstrate that the obtained IDIF is the most quantitative w.r.t. the measured blood samples when the acquired data are reconstructed with PSF-HYPR4D-K-TOFOSEM. CONCLUSIONS: The overall results support superior performance of the PSF-HYPR4D-K-TOFOSEM for TOF PET data and demonstrate that the proposed method is likely suitable for all imaging tasks including the generation of IDIF without requiring any prior information as well as further improving the effective sensitivity of the imaging system.

A pilot study comparing myelin measurements from myelin water imaging and 11C-PIB PET in multiple sclerosis.

MRI-based myelin water fraction (MWF) and PET-based Pittsburgh compound B (PiB) imaging both have potential to measure myelin in multiple sclerosis (MS). We characterised the differences in MWF and PiB binding in MS lesions relative to normal-appearing white matter and assessed the correlation between MWF and PiB binding in 11 MS participants and 3 healthy controls within 14 white matter regions of interest. Both PiB binding and MWF were reduced in MS lesions relative to NAWM, and a modest within subject correlation between MWF and PiB binding was found. This pilot study shows that MWF and PET-PiB provide different information about myelin loss in MS.

Brain microglia activation and peripheral adaptive immunity in Parkinson's disease: a multimodal PET study.

BACKGROUND: Abnormal activation of immune system is an important pathogenesis of Parkinson's disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear. OBJECTIVES: To evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity. METHODS: In this case-control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson's disease. 18F-PBR06 PET/MR for microglia activation, 18F-FP-DTBZ for dopaminergic denervation, total account of T cells and subpopulations of T helper (Th1/Th2/Th17) cells, and the levels of serum inflammatory cytokines were assessed. Sanger sequencing was used to exclude the mix-affinity binders of 18F-PBR06-PET. RESULTS: Compared to healthy controls, patients with Parkinson's disease had an increased 18F-PBR06-PET standardized uptake value ratio (SUVR) in the putamen, particularly in the ipsilateral side of the motor onset. 18F-PBR06-PET SUVR was positively associated with 18F-FP-DTBZ-PET SUVR in the brainstem and not associated with disease severity measured by Hoehn and Yahr stage, MDS-UPDRS III scores. Patients with Parkinson's disease had elevated frequencies of Th1 cells and serum levels of IL10 and IL17A as compared to healthy controls. No significant association between peripheral inflammation markers and microglia activation in the brain of PD was observed. CONCLUSION: Parkinson's disease is associated with early putaminal microglial activation and peripheral phenotypic Th1 bias. Peripheral adaptive immunity might be involved in microglia activation in the process of neurodegeneration in PD indirectly, which may be a potential biomarker for the early detection and the target for immunomodulating therapy.

Dopaminergic Positron Emission Tomography Imaging in the Alpha-Synuclein Preformed Fibril Model Reveals Similarities to Early Parkinson's Disease.

BACKGROUND: Positron emission tomography (PET) imaging in early Parkinson's disease (PD) subjects reveals that increased dopamine (DA) turnover and reduced dopamine transporter (DAT) density precede decreases in DA synthesis and storage. The rat α-synuclein preformed fibril (α-syn PFF) model provides a platform to investigate DA dynamics during multiple stages of α-syn inclusion-triggered nigrostriatal degeneration. OBJECTIVES: We investigated multiple aspects of in vivo dopaminergic deficits longitudinally and similarities to human PD using translational PET imaging readouts. METHODS: Longitudinal imaging was performed every 2 months in PFF and control rats for 7 months. [18 F]-Fluoro-3,4-dihydroxyphenyl-L-alanine (FDOPA) imaging was performed to investigate DA synthesis and storage (Kocc ) and DA turnover, estimated by its inverse, the effective distribution volume ratio (EDVR). 11 C-Methylphenidate (MP) was used to estimate DAT density (BPND ). RESULTS: Early DA turnover increases and DAT binding decreases were observed in the ipsilateral striatum of PFF rats, progressing longitudinally. EDVR decreased 26%, 38%, and 47%, and BPND decreased 36%, 50%, and 65% at the 2-, 4-, and 6-month time points, respectively, compared to ipsilateral control striatum. In contrast, deficits in DA synthesis and storage were not observed in the ipsilateral striatum of PFF rats compared to control injections and were relatively preserved up to 6 months (Kocc decreased 20% at 6 months). CONCLUSIONS: The relative preservation of DA synthesis and storage compared to robust progressive deficits in DAT density and increases in DA turnover in the rat α-syn PFF model display remarkable face validity to dopaminergic alterations in human PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cortical morphology predicts placebo response in multiple sclerosis.

Despite significant insights into the neural mechanisms of acute placebo responses, less is known about longer-term placebo responses, such as those seen in clinical trials, or their interactions with brain disease. We examined brain correlates of placebo responses in a randomized trial of a then controversial and now disproved endovascular treatment for multiple sclerosis. Patients received either balloon or sham extracranial venoplasty and were followed for 48 weeks. Venoplasty had no therapeutic effect, but a subset of both venoplasty- and sham-treated patients reported a transient improvement in health-related quality of life, suggesting a placebo response. Placebo responders did not differ from non-responders in total MRI T2 lesion load, count or location, nor were there differences in normalized brain volume, regional grey or white matter volume or cortical thickness (CT). However, responders had higher lesion activity. Graph theoretical analysis of CT covariance showed that non-responders had a more small-world-like CT architecture. In non-responders, lesion load was inversely associated with CT in somatosensory, motor and association areas, precuneus, and insula, primarily in the right hemisphere. In responders, lesion load was unrelated to CT. The neuropathological process in MS may produce in some a cortical configuration less capable of generating sustained placebo responses.

Comparison of Invasive and Non-invasive Estimation of [11C]PBR28 Binding in Non-human Primates.

PURPOSE: To identify a reliable alternative to the full blood [11C]PBR28 quantification method that would be easily replicated in multiple research and clinical settings. PROCEDURES: Ten [11C]PBR28 scans were acquired from 7 healthy non-human primates (NHP). Arterial input functions (AIFs) were averaged to create a population template input function (TIF). Population-based input functions were created by scaling the TIF with injected activity per body weight (PBIF) or unmetabolized tracer activity in blood at 15-,30-, and 60-min post-injection (PBIF15, PBIF30, and PBIF60). Two additional input functions were used: the native unmetabolized total plasma activity (Totals) and the Totals curve metabolite corrected by a scaled template parent fraction from a 30-min sample (TPF30-IF). Total distribution volumes (VTs) were calculated using PBIF, PBIF30, PBIF15, PBIF60, Totals, TPF30-IF, and the individual AIF (VTAIF). Distribution volume ratios (DVR) were computed using the cerebellum and the centrum semiovale (CSO), as pseudo-reference regions (DVRCereb, DVRCSO). Results obtained with each method were compared to VTAIF. Applicability of these alternative methods was tested on an independent pharmacological challenge dataset of microglial activation and depletion. Evaluation was carried at baseline, immediately after intervention (acute), and weeks post-intervention (post-recovery). RESULTS: VTs computed using PBIF15 and PBIF30 showed the best correlation to VTAIF (r > 0.90), while VT derived from the blood-free-scaled PBIF showed poor correlation (r = 0.46) and DVRCSO correlated the least (r = 0.26). In the pharmacological challenge study, most population-derived VT values were comparable to VTAIF at baseline and showed varied sensitivity to challenges at acute and post-recovery evaluation. DVR values did not detect relevant changes. CONCLUSIONS: Population-based input functions scaled with a single blood sample might be a useful alternative to using AIF to compute [11C]PBR28 binding in healthy NHPs or animals with comparable metabolism and overall perform better than pseudo-reference regions approaches.

Dopamine release during psychological stress in euthymic bipolar I disorder: a Positron Emission Tomography study with [11C]raclopride.

BACKGROUND: Neurochemical mechanisms underlying stress induced relapse of mood episodes in Bipolar I Disorder (BD) remain unknown. This study investigated whether euthymic BD patients have a greater dopamine release in ventral striatum, caudate and putamen in response to psychological stress using Positron Emission Tomography (PET) scanning with the radiotracer [11C]raclopride. METHODS: Euthymic patients with BD (n = 10) and 10 matched healthy controls underwent two [11C]raclopride PET scans, one during a "stress" and the other in a "no stress" condition separated by at least 24 h. Montreal Imaging Stress Test (MIST) was used to induce stress during stress condition. Participants received an injection of [11C]raclopride over one minute followed by PET scan for 60 min. Participants were assessed for mood symptom severity at baseline, and before and after each scan. The reduction in [11C]raclopride binding in stress condition compared with non-stress rest condition for each subject provided an estimate of dopamine release due to stress. RESULTS: There was a significant effect of stress in reducing the [11C]raclopride binding in the ventral striatum, caudate and putamen; however, no significant effects of group or condition x group interaction were found. LIMITATIONS: Small sample size and recruitment of euthymic patients who may be less vulnerable to stress may limit the generalizability of findings. CONCLUSIONS: Our findings showed that psychological stress led to dopamine release in the basal ganglia for all participants but the magnitude of dopamine release during a stress task was not different between euthymic BD patients and healthy controls.