Statistical estimation with Kronecker products in positron emission tomography

AbstractA method for linear statistical analysis of multidimensional imaging data is presented. It is applicable for a class of design and covariance matrices which involve Kronecker products. An efficient algorithm which allows for application of the method to large multidimensional data volumes is given. This has direct application to neuroimaging, and here the technique is applied to positron emission tomography (PET) data. PET is an in vivo functional imaging technique that measures biological processes such as blood flow and receptor concentrations. Here, the algorithm is used to correct for resolution degradation in these images. This process is typically referred to as PET partial volume correction. Examples involving both measured phantom and human data are given. This rapid algorithm leads to advances in the types of quantitative brain imaging studies that can be performed

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) [FP7-242003], from the Medical Research Council (MRC) [MR/P025870/1] and from Parkinson’s UK [J-1204]. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) and NIHR Imperial CRF at Imperial College healthcare NHS trust. The views expressed are those of the authors and not necessarily those of the funder, the NHS, the NIHR, or the Department of Health. This work was also supported financially by a PhD studentship awarded to N.P.L-K from Parkinson’s UK

DREADD activation of pedunculopontine cholinergic neurons reverses motor deficits and restores striatal dopamine signaling in parkinsonian rats

The brainstem-based pedunculopontine nucleus (PPN) traditionally associates with motor function, but undergoes extensive degeneration during Parkinson’s disease (PD), which correlates with axial motor deficits. PPN-Deep Brain Stimulation (DBS) can alleviate certain symptoms, but its mecha-nism(s) of action remains unknown. We previously characterized rats hemi-intranigrally injected with the proteasomal inhibitor lactacystin, as an accurate preclinical model of PD. Here we used a combination of chemogenetics with Positron Emission Tomography (PET) imaging for in vivo in-terrogation of discrete neural networks in this rat model of PD. Stimulation of excitatory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) expressed within PPN cholinergic neurons activated residual nigrostriatal dopaminergic neurons to produce pro-found motor recovery, which correlated with striatal dopamine efflux as well as restored dopamine receptor (DR) 1- and DR2-based medium spiny neuron (MSN) activity, as was ascertained with c-Fos-based immunohistochemistry and stereological cell counts. By revealing that the improved axi-al-related motor functions seen in PD patients receiving PPN-DBS may be due to stimulation of remaining PPN cholinergic neurons interacting with dopaminergic ones in both the Substantia Nigra pars compacta (SNpc) and the striatum, our data strongly favor the PPN cholinergic-midbrain dopaminergic connectome as mechanism for PPN-DBS’s therapeutic effects. These findings have implications for refining PPD-DBS as a promising treatment modality available to PD patients

Comparison of phosphodiesterase 10A and dopamine transporter levels as markers of disease burden in early Parkinson's disease

BACKGROUND: Recent work has shown loss of phosphodiesterase 10A levels in middle-stage and advanced treated patients with PD, which was associated with motor symptom severity. OBJECTIVES: To assess phosphodiesterase 10A levels in early PD and compare with loss of dopamine transporter as markers of disease burden. METHODS: Seventy-eight subjects were included in this study (17 early de novo, 15 early l-dopa-treated, 24 moderate-advanced l-dopa-treated patients with PD, and 22 healthy controls). All participants underwent [11 C]IMA107 PET, [11 C]PE2I PET, and 3-Tesla MRI scan. RESULTS: Early de novo PD patients showed loss of [11 C]IMA107 and of [11 C]PE2I binding in caudate and putamen (P < 0.001); early l-dopa-treated PD patients showed additional loss of [11 C]IMA107 in the caudate (P < 0.001; annual decline 3.6%) and putamen (P < 0.001; annual decline 2.8%), but loss of [11 C]PE2I only in the putamen (P < 0.001; annual decline 6.8%). Lower [11 C]IMA107 correlated with lower [11 C]PE2I in the caudate (rho = 0.51; P < 0.01) and putamen (rho = 0.53; P < 0.01). Longer disease duration correlated with lower [11 C]IMA107 in the caudate (rho = -0.72; P < 0.001) and putamen (rho = -0.48; P < 0.01), and with lower [11 C]PE2I only in the putamen (rho = -0.65; P < 0.001). Higher burden of motor symptoms correlated with lower [11 C]IMA107 in the caudate (rho = -0.42; P < 0.05) and putamen (rho = -0.41; P < 0.05), and with lower [11 C]PE2I only in the putamen (rho = -0.69; P < 0.001). CONCLUSION: Our findings demonstrate loss of phosphodiesterase 10A levels very early in the course of PD and is associated with the gradual and progressive increase of motor symptoms. Phosphodiesterase 10A imaging shows similar potential with dopamine transporter imaging to follow disease progression. © 2019 International Parkinson and Movement Disorder Society

In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF β amyloid 1–42 (Aβ42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI

Norovirus Transmission on Cruise Ship

We documented transmission by food and person-to-person contact; persistence of virus despite sanitization onboard, including introductions of new strains; and seeding of an outbreak on land