Jessamyn McKenzie

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.

Dopamine turnover increases in asymptomatic LRRK2 mutations carriers

Increase in dopamine (DA) turnover was found to occur early in symptomatic Parkinsons disease (PD) and to be functionally related to the dopamine transporter (DAT). The objectives of this study were to examine changes in DA turnover in the asymptomatic PD phase; to compare them with changes in other dopaminergic markers, and to investigate a possible relationship between DAT and DA turnover. Eight subjects from families at increased risk of PD due to LRRK2 mutation were investigated. Positron emission tomography imaging was performed with: 18F‐fluorodopa to determine the effective DA distribution volume (EDV), the inverse of DA turnover, and the DA uptake rate Kocc, a marker of DA synthesis and storage; 11C‐methylphenidate (MP, a DAT marker) and 11C‐dihydrotetrabenazine (DTBZ, a VMAT2 marker) to estimate the binding potentials BPND_MP and BPND_DTBZ. On average, EDV showed the largest reduction from age‐matched control values (42%) followed by BPND _ MP (23%) and BPND _ DTBZ (17%), whereas Kocc remained in the normal range for all subjects. No correlation was found between EDV and any other marker. DA turnover was found to be elevated in asymptomatic mutation carriers at increased risk of PD. Such change was determined to be larger than and statistically independent from changes observed with the other markers. These results support a compensatory role of increased DA turnover in presymptomatic disease and indicate that at this stage, in contrast to the symptomatic PD phase, increased turnover is not related to DAT.

Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies

BACKGROUND People with Parkinsons disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinsons disease and individuals with sporadic Parkinsons disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. METHODS We did two cross-sectional PET studies at the Pacific Parkinsons Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinsons disease, people with sporadic Parkinsons disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinsons disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinsons Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinsons disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (18F-6-fluoro-L-dopa; 18F-FDOPA). We compared findings with those in people with sporadic Parkinsons disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinsons disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. FINDINGS Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinsons disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and 18F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinsons disease (n=15) had reduced striatal dopamine transporter binding and 18F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinsons disease of similar duration. LRRK2 mutation carriers without manifest Parkinsons disease (n=25) had greater 18F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinsons disease, with 18F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinsons disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinsons disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinsons disease, and people with sporadic Parkinsons disease, p<0·0001), striatum (compared with people with sporadic Parkinsons disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinsons disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinsons disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease. INTERPRETATION Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinsons disease and individuals with sporadic Parkinsons disease, but LRRK2 mutation carriers without manifest Parkinsons disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinsons disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinsons disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. FUNDING Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinsons Research Institute, National Research Council of Canada.Summary Background Patients with Parkinson’s Disease (PD) may exhibit premotor neurochemical changes in dopaminergic (DA) and nondopaminergic systems. Using positron emission tomography (PET), we studied participants with leucine-rich repeat kinase 2 (LRRK2) mutations and with sporadic PD to assess whether DA and serotonin transporter (SERT) changes were similar in LRRK2 PD and sporadic PD, and whether asymptomatic LRRK2 mutation carriers exhibited PET changes in the absence of motor symptoms. Methods Between July 1999 and May 2016, we did two cross sectional PET studies at the Pacific Parkinson’s Research Centre (Vancouver, Canada) with LRRK2 mutation carriers with or without manifest PD, patients with sporadic PD, and age-matched healthy controls, all aged 18 years or older. Patients with PD were diagnosed by a neurologist with movement disorder training in accordance with the UK Parkinson’s Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bi-directional Sanger sequencing. First, affected and unaffected LRRK2 carriers seen from July 1999 to January 2012 were imaged with PET tracers for the membrane dopamine transporter (DAT) and dopamine synthesis and storage (18F-6-fluoro-L-dopa; FDOPA) and compared with sporadic PD and age-matched healthy controls. Second, distinct groups of LRRK2 mutation carriers, sporadic PD patients, and age-matched healthy controls seen from November 2012 to May 2016 were studied with tracers for the SERT and vesicular monoamine transporter 2 (VMAT2). Striatal DAT binding, DTBZ binding, FDOPA uptake and SERT binding in multiple brain regions were compared using analysis of covariance adjusted for age. Findings Using data from 40 LRRK2 mutation carriers, 63 patients with sporadic PD, and 35 controls, we identified significant group differences in striatal DAT binding (all age ranges p<0·0001 in caudate and putamen) and FDOPA uptake (age 50 or lower in caudate, p=0·0002; all other age ranges p<0·0001; in putamen, all age ranges p<0·0001). Affected LRRK2 mutation carriers (n=15) had reduced striatal DAT binding and FDOPA uptake, comparable to sporadic PD of similar duration. Unaffected carriers (n=25) had greater FDOPA uptake and DAT binding than sporadic PD (n=63), with FDOPA uptake comparable to and DAT binding lower than healthy controls. Unaffected LRRK2 carriers (n=9) had significantly elevated SERT binding in hypothalamus (greater than healthy controls, 7 LRRK2 PD and 13 sporadic PD subjects; p<0·0001), striatum (greater than sporadic PD; p=0·02) and brainstem (greater than affected LRRK2 carriers; p=0·01) after adjustment for age. SERT binding in cortex was not significantly different between groups after age adjustment. Striatal DTBZ binding was reduced in all affected patients and asymmetrically reduced in one unaffected carrier. Interpretation Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 PD and sporadic PD, but unaffected LRRK2 mutation carriers exhibit increased SERT binding in striatum, brainstem and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of PD. Funding Canada Research Chairs, Michael J. Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson’s Research Institute, National Research Council of Canada

PBB3 imaging in Parkinsonian disorders: Evidence for binding to tau and other proteins

Background and Objectives: To study selective regional binding for tau pathology in vivo, using PET with [11C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy.

Clinical, positron emission tomography, and pathological studies of DNAJC13 p.N855S Parkinsonism

Families of Dutch‐German‐Russian Mennonite descent with multi‐incident parkinsonism have been identified as harboring a pathogenic DNAJC13 p.N855S mutation and are awaiting clinical and pathophysiological characterization.

A scan without evidence is not evidence of absence: Scans without evidence of dopaminergic deficit in a symptomatic leucine‐rich repeat kinase 2 mutation carrier

The basis for SWEDD is unclear, with most cases representing PD mimics but some later developing PD with a dopaminergic deficit.

In vivo dopaminergic and serotonergic dysfunction in DCTN1 gene mutation carriers.

We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome.

Investigation of serotonergic Parkinson's disease-related covariance pattern using [11C]-DASB/PET

We used positron emission tomography imaging with [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)- benzonitrile (DASB) and principal component analysis to investigate whether a specific Parkinsons disease (PD)-related spatial covariance pattern could be identified for the serotonergic system. We also explored if non-manifesting leucine-rich repeat kinase 2 (LRRK2) mutation carriers, with normal striatal dopaminergic innervation as measured with [11C]-dihydrotetrabenazine (DTBZ), exhibit a distinct spatial covariance pattern compared to healthy controls and subjects with manifest PD. 15 subjects with sporadic PD, eight subjects with LRRK2 mutation-associated PD, nine LRRK2 non-manifesting mutation carriers, and nine healthy controls participated in the study. The analysis was applied to the DASB non-displaceable binding potential values evaluated in 42 pre-defined regions of interest. PD was found to be associated with a specific spatial covariance pattern, comprising relatively decreased DASB binding in the caudate, putamen and substantia nigra and relatively preserved binding in the hypothalamus and hippocampus; the expression of this pattern in PD subjects was significantly higher than in healthy controls (P < 0.001) and correlated significantly with disease duration (P < 0.01) and with DTBZ binding in the more affected putamen (P < 0.01). The LRRK2 non-manifesting mutation carriers expressed a different pattern, also significantly different from healthy controls (P < 0.001), comprising relatively decreased DASB binding in the pons, pedunculopontine nucleus, thalamus and rostral raphe nucleus, and with relatively preserved binding in the hypothalamus, amygdala, hippocampus and substantia nigra. This pattern was not present in either sporadic or LRRK2 mutation-associated PD subjects. These findings, although obtained with a relatively limited number of subjects, suggest that specific and overall distinct spatial serotonergic patterns may be associated with PD and LRRK2 mutations. Alterations in regions where relative upregulation is observed in both patterns may be indicative of compensatory mechanisms preceding or protecting from disease manifestation.

Imaging striatal dopaminergic function in phospholipase A2 group VI-related parkinsonism.

Mutations in the phospholipase A2 group VI gene (PLA2G6) have recently been shown to cause adult-onset parkinsonism-dystonia (PARK14). We performed multitracer dopaminergic positron emission tomography (PET) in an individual with phospholipase A–associated neurodegeneration to gain insight into the mechanism of parkinsonism in this syndrome. A 24-year-old Scandinavian man presented with a 5-year history of progressive parkinsonism. Although early developmental milestones were normal, he had been prone to anxiety since his school years, later developing obsessivecompulsive traits. He had depression since age 14 and was on escitalopram. Family history was negative. Examination revealed mild cognitive deficit characterized by frontal-executive dysfunction. There was moderate supranuclear gaze palsy, worse vertically, and lid-opening apraxia. Myoclonus was present in hands. Parkinsonism was mild-moderate, largely symmetric (Video). Pyramidal signs were present in the lower limbs. Dystonia and ataxia were absent. Normal/negative results included gene testing for Parkin, PINK, DJ-1, Huntington’s disease, and SCAs 1, 2, 3, 6, and 7; serum ceruloplasmin, iron, ferritin, sphingomyelinase; and a peripheral blood smear for acanthocytes. Neuro-ophthalmologic examination excluded Kayser-Fleischer rings and retinopathy. Magnetic resonance imaging (MRI) revealed changes consistent with abnormal pallidal iron deposition (Fig. 1A). PANK2 gene mutation was absent, but a single, known pathogenic mutation, Ala80Thr (c.238G>A), was detected in the PLA2G6 gene. PET performed before levodopa (LD) treatment with F-6-fluoroL-dopa (FD) to estimate dopamine synthesis and storage (Fig. 1C), C-d-threo-methylphenidate (MP, dopamine transporter [DAT] marker), C-dihydrotetrabenazine (DTBZ; vesicular monoamine transporter marker; Fig. 1D) to assess presynaptic nigrostriatal dopaminergic integrity, and C-raclopride (RAC) for postsynaptic receptor function (Fig. 1B) showed reduced uptake of all 3 presynaptic tracers, with increased RAC signal, similar to that seen in idiopathic PD (iPD). Parkinsonism responded dramatically to initial LD treatment. After a year of treatment, LD response was still present but was somewhat less marked. A month before the last follow-up, an intruder entered their home and attacked his mother with a knife. At this time, the patient jumped out of his chair, fought with and stabbed the attacker himself, keeping him at bay until help arrived. This was clearly out of proportion to his mobility—he otherwise would need help to get up at that particular time—a ‘‘paradoxical kinesia.’’ Parkinsonism from striatal or pallidal lesions is largely unresponsive to LD. Interestingly, in our patient, although the pallidal MRI abnormality implied a deficit downstream to the striatum, both the positive LD response and increased RAC uptake indicated a largely presynaptic DA abnormality as seen in iPD, with largely intact striatal and poststriatal pathways, suggesting that despite significant structural changes in the pallidi, functional pallidal activity was maintained for at least a year. Further, kinesia paradoxica is well described in PD and may be seen in atypical parkinsonism,