Siobhan McCormick

Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study

Parkinsons disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinsons disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses, using random effects, of the form BP(ND)(t) or K(occ)(t) = a*e((-)(bt)(-d)(A) + c, where BP(ND) = tracer binding potential (nondispaceable), K(OCC) = tracer uptake constant a, b, c and d are regression parameters, t is the symptom duration and A is the age at onset, were utilized to model the longitudinal progression of radiotracer binding/uptake. We found that the initial tracer binding/uptake was significantly different in anterior versus posterior striatal subregions, indicating that the degree of denervation at disease onset was different between regions. However, the relative rate of decline in tracer binding/uptake was similar between the striatal subregions. While an antero-posterior gradient of severity was maintained for dopamine synthesis, storage and reuptake, the asymmetry between the more and less affected striatum became less prominent over the disease course. Our study suggests that the mechanisms underlying Parkinsons disease initiation and progression are probably different. Whereas factors responsible for disease initiation affect striatal subregions differently, those factors contributing to disease progression affect all striatal subregions to a similar degree and may therefore reflect non-specific mechanisms such as oxidative stress, inflammation or excitotoxicity.

Age-specific progression of nigrostriatal dysfunction in Parkinson's disease

To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinsons disease (PD).

Toward [18F]-labeled aryltrifluoroborate radiotracers: in vivo positron emission tomography imaging of stable aryltrifluoroborate clearance in mice.

The use of a boronic ester as a captor of aqueous [(18)F]-fluoride has been previously suggested as a means of labeling biomolecules in one step for positron emission tomography (PET) imaging. For this approach to be seriously considered, the [(18)F]-labeled trifluoroborate should be humorally stable such that it neither leaches free [(18)F]-fluoride to the bone nor accumulates therein. Herein, we have synthesized a biotinylated boronic ester that is converted to the corresponding trifluoroborate salt in the presence of aqueous [(18)F]-fluoride. In keeping with its in vitro aqueous kinetic stability at pH 7.5, the trifluoroborate appears to clear in vivo quite rapidly to the bladder as the stable trifluoroborate salt with no detectable leaching of free [(18)F]-fluoride to the bone. When this labeled biotin is preincubated with avidin, the pharmacokinetic clearance of the resulting complex is visibly altered. This work validates initial claims that boronic esters are potentially useful as readily labeled precursors to [(18)F]-PET reagents.

Progression of dopaminergic dysfunction in a LRRK2 kindred A multitracer PET study

Objective: Little is known about the progression of dopaminergic dysfunction in LRRK2-associated Parkinson disease (PD). We sought to characterize the neurochemical progression with multitracer PET in asymptomatic members of parkinsonian kindred (family D, Western Nebraska) carrying LRRK2 (R1441C) mutation. Method: Thirteen family D subjects underwent PET scans of presynaptic dopaminergic integrity and five subjects were rescanned 2 to 3 years later. Results: In subjects 8, 9 (mutation carriers), and 13 (genealogically at risk subject), there was a decline in PET markers over the course of the study that was significantly greater than the expected rate of decline in healthy controls. Reduced dopamine transporter binding was the earliest indication of subclinical dopaminergic dysfunction and progression to clinical disease was generally associated with the emergence of abnormal fluorodopa uptake. Conclusion: PET study of presymptomatic members of our LRRK2 kindred revealed dopaminergic dysfunction that progressed over time. This represents an ideal group to study the natural history of early disease and the potential effects of neuroprotective interventions. GLOSSARY: DAT = dopamine transporter; DTBZ = 11C-(±)-α-dihydrotetrabenazine; FD = 18F-6-fluoro-l-dopa; MP = 11C-d-threo-methylphenidate; PD = Parkinson disease; ROI = region of interest; sPD = sporadic PD.

Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson's disease

Parkinsons disease is a relentlessly progressive neurodegenerative disease. Breakdown of compensatory mechanisms influencing putaminal dopamine processing could contribute to the progressive motor symptoms. We studied a cohort of 78 subjects (at baseline) with sporadic Parkinsons disease and 35 healthy controls with multi-tracer positron emission tomography scans to investigate the evolution of adaptive mechanisms influencing striatal dopamine processing in Parkinsons disease progression. Presynaptic dopaminergic integrity was assessed with three radioligands: (i) [(11)C](±)dihydrotetrabenazine, to estimate the density of vesicular monoamine transporter type 2; (ii) [(11)C]d-threo-methylphenidate, to label the dopamine transporter; and (iii) 6-[(18)F]fluoro-L-DOPA, to assess the activity of aromatic amino acid decarboxylase and storage of 6-[(18)F]-fluorodopamine in synaptic vesicles. The subjects with Parkinsons disease and the healthy controls underwent positron emission tomography scans at the initial visit and after 4 and 8 years of follow-up. Non-linear multivariate regression analyses with random effects were utilized to model the longitudinal changes in tracer values in the putamen standardized relative to normal controls. We found evidence for possible upregulation of dopamine synthesis and downregulation of dopamine transporter in the more severely affected putamen in the early stage of Parkinsons disease. The standardized 6-[(18)F]fluoro-L-DOPA and [(11)C]d-threo-methylphenidate values tended to approach [(11)C](±)dihydrotetrabenazine values in the putamen in later stages of disease (i.e. for [(11)C](±)dihydrotetrabenazine values <25% of normal), when the rates of decline in the positron emission tomography measurements were similar for all the markers. Our data suggest that compensatory mechanisms decline as Parkinsons disease progresses. This breakdown of compensatory strategies in the putamen could contribute to the progression of motor symptoms in advanced disease.

Visualizing vesicular dopamine dynamics in Parkinson's disease

It has been suggested that dopamine derived from exogenous levodopa may not follow vesicular dynamics in Parkinsons disease (PD). Using a novel PET method based on the sensitivity of [11C]‐dihydrotetrabenazine (DTBZ) binding to changes in vesicular dopamine levels, we show here that striatal [11C]‐DTBZ binding decreases after levodopa administration in advanced PD, likely reflecting an increase in vesicular dopamine levels. Endogenous dopamine and exogenously derived dopamine seem to follow the same vesicular dynamics. Synapse 63:713–716, 2009.

In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD

This is the first in vivo determination of the vesicular monoamine transporter (VMAT2) density (Bmax) and ligand–transporter affinity (Kdapp) in six unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats using micro-positron emission tomography (PET) imaging with [11C]-(+)-α-dihydrotetrabenazine (DTBZ). A multiple ligand concentration transporter assay (MLCTA) was used to determine a Bmax value of 178 ± 32 pmol/mL and a Kdapp of 47.7 ± 9.3 pmol/mL for the non-lesioned side and 30.52 ± 5.84 and 43.4 ± 15.52 pmol/mL for the lesioned side, respectively. While Bmax was significantly different between the two sides, no significant difference was observed for the Kdapp. In addition to demonstrating the feasibility of in vivo Scatchard analysis in rats, these data confirm the expectation that a 6-OHDA lesion does not affect the affinity; a much simpler binding potential (BP) measure can thus be used as a marker of lesion severity (LS) in this rat model of Parkinsons disease. A transporter occupancy curve demonstrated negligible transporter occupancy (∼1%) at a specific activity (SA) of 1100 nCi/pmol (assuming an injected dose of 100 μCi/100 g), while 10% occupancy was estimated at 100 nCi/pmol. An indirect measurement indicated that the degree of occupancy as a function of SA is independent of LS. Finally, BP measurement reproducibility was assessed and found to be 11% ± 7% for the healthy and 8% ± 12% for the lesioned side. Quantitative PET results can thus be obtained even for severely lesioned animals with the striatum on one side not clearly visible provided accurate image analysis methods are used.

Dopamine transporter PET in normal aging: Dopamine transporter decline and its possible role in preservation of motor function

Objectives: To determine the impact of age‐related decline in dopamine transporter (DAT) expression on motor function in the elderly. Methods: About 33 normal individuals of a wide age range were scanned with PET employing d‐threo‐[11C]‐methylphenidate (MP, a marker of DAT) and [11C]‐dihydrotetrabenazine (DTBZ, that binds to the vesicular monoamine transporter Type 2). Motor function was assessed using the Purdue Pegboard Test (PPB). We analyzed the relationship between [11C]‐MP and motor performance. Results: Age ranged from 27‐ to 77‐year old (mean ± SD, 54.75 ± 14.14). There was no age‐related decline in binding potentials (BP) for [11C]‐DTBZ. In contrast, [11C]‐MP BP was inversely related to age in all striatal regions analyzed (caudate: reduction of 11.2% per decade, P < 0.0001, r = −0.86; putamen: reduction of 10.5% per decade, P < 0.0001, r = −0.80). A differential effect of [11C]‐MP on PPB could be observed according to age group. There was a positive relation between the PPB and [11C]‐MP in young individuals (coefficient = 13.56), whereas in individuals greater than 57 years this relationship was negative (coefficient = −19.53, P = 0.031). Conclusions: Our findings confirm prior observations of age‐related DAT decline and suggest that this phenomenon is independent of changes in VMAT2. After the fifth decade of life, this reduction in DAT binding is associated with a motor performance comparable to mid‐adult life. These findings imply that biochemical processes associated with healthy aging may offset the naturaldecline in motor function observed in the elderly. Synapse 64:146–151, 2010.

Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers.

Objective: In this prospective cohort study, we investigated cerebral glucose metabolism reductions on [18F]-fluorodeoxyglucose (FDG)-PET in progranulin (GRN) mutation carriers prior to frontotemporal dementia (FTD) onset. Methods: Nine mutation carriers (age 51.5 ± 13.5 years) and 11 noncarriers (age 52.7 ± 9.5 years) from 5 families with FTD due to GRN mutations underwent brain scanning with FDG-PET and MRI and clinical evaluation. Normalized FDG uptake values were calculated with reference to the pons. PET images were analyzed with regions of interest (ROI) and statistical parametric mapping (SPM) approaches. Results: Compared with noncarriers, GRN mutation carriers had a lowered anterior-to-posterior (AP) ratio of FDG uptake (0.86 ± 0.09 vs 0.92 ± 0.05) and less left-right asymmetry, consistent with an overall pattern of right anterior cerebral hypometabolism. This pattern was observed regardless of whether they were deemed clinically symptomatic no dementia or asymptomatic. Individual ROIs with lowered FDG uptake included right anterior cingulate, insula, and gyrus rectus. SPM analysis supported and extended these findings, demonstrating abnormalities in the right and left medial frontal regions, right insular cortex, right precentral and middle frontal gyri, and right cerebellum. Right AP ratio was correlated with cognitive and clinical scores (modified Mini-Mental State Examination r = 0.74; Functional Rating Scale r = −0.73) but not age and years to estimated onset in mutation carriers. Conclusion: The frontotemporal lobar degenerative process associated with GRN mutations appears to begin many years prior to the average age at FTD onset (late 50s–early 60s). Right medial and ventral frontal cortex and insula may be affected in this process but the specific regional patterns associated with specific clinical variants remain to be elucidated.

Positron emission tomography kinetic modeling algorithms for small animal dopaminergic system imaging

Small animal positron emission tomography (PET) imaging allows in vivo quantification of lesion‐ or treatment‐induced neurochemical changes in animal models of disease. Important for quantification are the kinetic modeling methods used to determine biologically‐relevant parameters of tracer‐tissue interaction. In this work, we evaluate modeling algorithms for the dopaminergic tracers 11C‐dihydrotetrabenazine (DTBZ), 11C‐methylphenidate (MP), and 11C‐raclopride (RAC), used to image the dopaminergic system in the unilateral 6‐hydroxydopamine lesioned rat model of Parkinsons disease. For the presynaptic tracers, PET measures are compared with autoradiographic binding measurements using DTBZ and [3H]WIN 35,428 (WIN). We independently developed a new variant of the tissue‐input Logan graphical modeling method, and compared its performance with the simplified Logan graphical method and the simplified reference tissue with basis functions method (SRTM), for region of interest (ROI) averaged time activity curves (TACs) and parametric imaging. The modified graphical method was found to be effectively unbiased by target tissue noise and has advantages for parametric imaging, while all tested methods were equivalent for ROI‐averaged data. Synapse 64:200–208, 2010.