Elham Shahinfard

Myelin Water Fraction Is Transiently Reduced after a Single Mild Traumatic Brain Injury – A Prospective Cohort Study in Collegiate Hockey Players

Impact-related mild traumatic brain injuries (mTBI) are a major public health concern, and remain as one of the most poorly understood injuries in the field of neuroscience. Currently, the diagnosis and management of such injuries are based largely on patient-reported symptoms. An improved understanding of the underlying pathophysiology of mTBI is urgently needed in order to develop better diagnostic and management protocols. Specifically, dynamic post-injury changes to the myelin sheath in the human brain have not been examined, despite ‘compromised white matter integrity’ often being described as a consequence of mTBI. In this preliminary cohort study, myelin water imaging was used to prospectively evaluate changes in myelin water fraction, derived from the T2 decay signal, in two varsity hockey teams (45 players) over one season of athletic competition. 11 players sustained a concussion during competition, and were scanned at 72 hours, 2 weeks, and 2 months post-injury. Results demonstrated a reduction in myelin water fraction at 2 weeks post-injury in several brain areas relative to preseason scans, including the splenium of the corpus callosum, right posterior thalamic radiation, left superior corona radiata, left superior longitudinal fasciculus, and left posterior limb of the internal capsule. Myelin water fraction recovered to pre-season values by 2 months post-injury. These results may indicate transient myelin disruption following a single mTBI, with subsequent remyelination of affected neurons. Myelin disruption was not apparent in the athletes who did not experience a concussion, despite exposure to repetitive subconcussive trauma over a season of collegiate hockey. These findings may help to explain many of the metabolic and neurological deficits observed clinically following mTBI.

A Prospective Pilot Investigation of Brain Volume, White Matter Hyperintensities, and Hemorrhagic Lesions after Mild Traumatic Brain Injury

Traumatic brain injury (TBI) is among the most common neurological disorders. Hemorrhagic lesions and white matter hyperintensities (WMH) are radiological features associated with moderate and severe TBI. Brain volume reductions have also been observed during the months following injury. In concussion, no signs of injury are observed on conventional magnetic resonance imaging (MRI), which may be a true feature of concussion or merely due to the limited sensitivity of imaging techniques used so far. Moreover, it is not known whether volume reductions are due to the resolution of trauma-related edema or a true volume loss. Forty-five collegiate-level ice hockey players (20 females) and 15 controls (9 females), 40 players underwent 3-T MRI for hemorrhages [multi-echo susceptibility-weighted imaging (SWI)], WMH (three-dimensional fluid-attenuated inversion recovery), and brain volume at the beginning and the end of the hockey season. Concussed athletes underwent additional imaging and neuropsychological testing at 3 days, 2 weeks, and 2 months after injury. At the end of the hockey season, brain volume was reduced compared to controls by 0.32% (p < 0.034) in the whole cohort and by 0.26% (p < 0.09) in the concussed athletes. Two weeks and 2 months after concussion, brain volume was reduced by −0.08% (p = 0.027) and −0.23% (p = 0.035), respectively. In athletes, the WMH were significantly closer to the interface between gray matter and white matter compared to controls. No significant changes in the number of WMH over the duration of the study were found in athletes. No microhemorrhages were detected as a result of concussion or playing a season of ice hockey. We conclude that mild TBI does not lead to transient increases in brain volume and no new microbleeds or WMH are detectable after concussion. Brain volume reductions appear by 2 weeks after concussion and persist until at least 2 months after concussion. Brain volume is reduced between the beginning and the end of the ice hockey season.

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.

Exploring the use of shape and texture descriptors of positron emission tomography tracer distribution in imaging studies of neurodegenerative disease

Positron emission tomography (PET) data related to neurodegeneration are most often quantified using methods based on tracer kinetic modeling. In contrast, here we investigate the ability of geometry and texture-based metrics that are independent of kinetic modeling to convey useful information on disease state. The study was performed using data from Parkinson’s disease subjects imaged with 11C-dihydrotetrabenazine and 11C-raclopride. The pattern of the radiotracer distribution in the striatum was quantified using image-based metrics evaluated over multiple regions of interest that were defined on co-registered PET and MRI images. Regression analysis showed a significant degree of correlation between several investigated metrics and clinical evaluations of the disease (p < 0.01). The best results were obtained with the first-order moment invariant of the radioactivity concentration values estimated over the full structural extent of the region as defined by MRI (R2 = 0.94). These results demonstrate that there is clinically relevant quantitative information in the tracer distribution pattern that can be captured using geometric and texture descriptors. Such metrics may provide an alternate and complementary data analysis approach to traditional kinetic modeling.

The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study

BACKGROUND Markers of neuroinflammation are increased in some patients with LRRK2 Parkinsons disease compared with individuals with idiopathic Parkinsons disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinsons disease. METHODS Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinsons disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinsons Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N-11C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis. FINDINGS We recruited 14 patients with LRRK2 Parkinsons disease, 16 LRRK2 mutation carriers without Parkinsons disease, eight patients with idiopathic Parkinsons disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinsons disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinsons disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age. INTERPRETATION LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinsons disease compared with healthy controls and in LRRK2 mutation carriers with Parkinsons disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells. FUNDING Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation.

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.

PBB3 binding in a patient with corticobasal syndrome: PBB3 Binding in CBD

Corticobasal degeneration (CBD) is a rapidly progressive parkinsonism typically associated with highly asymmetric cortical signs including apraxia, language impairment, cortical sensory deficit, and myoclonus. Pathologically there are straight filaments of tau associated with ballooned neurons in cortical gray matter and striatum, as well as astrocytic plaques, threads, and tangles. These filaments are predominantly formed by 4-repeat (4R) tau isoforms. Premortem diagnostic accuracy is lower than for other types of parkinsonism, with a differential that includes Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and progressive supranuclear palsy. PET imaging, by demonstrating the specific deposition and distribution of abnormal tau, may help with diagnosis, but findings from tau imaging are variable. We report a case of corticobasal syndrome (CBS) with specific uptake of the tau tracer C-phenyl/pyridinyl-butadienyl-benzothiazole/benzothiazolium 3 (C-PBB3) (Fig 1a). This man presented at age 67 with a 3-year history of motor dysfunction. Initial examination revealed left side rigidity, stimulus-evoked myoclonus and apraxia, and mild cognitive dysfunction (MoCA 21). During the next year prior to his PET study, he developed increasing cognitive difficulty and impulsivity, cortical sensory deficit, and alien limb phenomenon. His MoCA and Dementia Rating Scale-2 (DRS-2) at time of scan were 14 and 62, respectively. He continued to deteriorate, became wheelchair bound with limited verbal output, asymmetric rigidity and dystonia, and died 2 years following PET. Neither amyloid imaging nor autopsy was performed. C-PBB3 PET performed approximately 4 years after symptom onset and quantified with nondisplaceable binding potential and cerebellar white matter as reference region revealed asymmetric bilateral binding, greater on the right, in frontal, parietal, temporal, and occipital cortex, caudate, thalamus, globus pallidus, and ventral striatum. In comparison to controls (n = 7) of similar age (mean = 65 years, SD = 10.8), C-PBB3 binding was increased by ≥2 SD in the bilateral globus pallidus, right insula, and right temporal lobe (Fig 1b). Binding was bilaterally increased in the motor cortex of the CBS subject, more on the right. This increase was < 2 SD of healthy control values, likely reflecting the small sample size and cortical atrophy in the CBS subject. Prior studies with F-AV-1451 in pathologically confirmed CBD reported uptake in cortex and basal ganglia, which correlated with postmortem 4R tau burden, but not with postmortem autoradiography, and concluded that F-AV-1451 probably binds to a small fraction of 4R tau burden. Smith and colleagues found F-AV-1451 imaging differentiated CBD from Alzheimer Disease (AD) and Progressive Supranuclear Palsy (PSP); however, cortical uptake did not correlate with atrophy on MRI or hypometabolism on fluoro-2-deoxyglucose (FDG) PET. Cho and colleagues reported asymmetric uptake in subcortical regions including precentral white matter in 6 CBS cases versus 20 controls. Uptake in precentral white matter correlated with motor symptoms, but overlapped with control values. Our findings are consistent with those of Maruyama and colleagues. Ono and colleagues compared postmortem binding of C-PBB3 and F-AV-1451 using autoradiography. They found strong binding of C-PBB3 to astrocytic plaques, coiled bodies, and argyrophilic threads in CBD, supporting reactivity with 4R aggregates. In contrast, weaker binding with only faint fluorescence was found with F-AV-1451. To date, results from F-AV-1451 appear inconsistent, with low sensitivity for the 4R aggregates found in CBD in vitro and variable results in vivo. C-PBB3 in PSP showed specific binding in areas where the highest tau burden is expected and was higher in more advanced cases. However, binding was also observed in synucleinopathies, questioning its specificity for tau. In CBD, C-PBB3 may show specific binding that correlates with the clinical manifestations and asymmetric characteristics of CBS, but further studies are needed.

Hematopoietic Stem Cell Transplantation in Late-Onset Krabbe Disease: No Evidence of Worsening Demyelination and Axonal Loss 4 Years Post-allograft: Hematopoietic Stem Cell Transplantation in Late-Onset Krabbe Disease

Late‐onset adult Krabbe disease is a very rare demyelinating leukodystrophy, affecting less than 1 in a million people. Hematopoietic stem cell transplantation (HSCT) strategies can stop the accumulation of toxic metabolites that damage myelin‐producing cells. We used quantitative advanced imaging metrics to longitudinally assess the impact of HSCT on brain abnormalities in adult‐onset Krabbe disease.

PBB3 Imaging in Parkinsonian disorders: Evidence for binding to abnormally aggregated proteins in addition to tau proteins

Objective: The aim of this work is to evaluate clinimetric properties of a method for measuring Parkinson’s disease (PD) upper limb temporal irregularities during spiral drawing tasks.Background: B ...Basic Science Abstracts - Session Title: Parkinsons Disease: Pathophysiology: abstract no. 518