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1.  Striatal and cortical β-amyloidopathy and cognition in Parkinson disease 
Background
Although most prior cognitive studies of β-amyloidopathy in Parkinson disease (PD) focused on cortical plaque deposition, recent post-mortem studies point to an important role of striatal β-amyloid plaque deposition.
Objective
To investigate the relative contributions of striatal and cortical β-amyloidopathy to cognitive impairment in PD.
Methods
Patients with PD (n=62; age 68.9±6.4 years, Hoehn and Yahr stage 2.7±0.5, Montreal Cognitive Assessment score 25.2±3.0) underwent [11C]Pittsburgh compound B β-amyloid, [11C]dihydrotetrabenazine monoaminergic and [11C]methyl-4-piperidinyl propionate acetylcholinesterase brain positron emission tomography imaging and neuropsychological assessment. [11C]Pittsburgh compound B β-amyloid data from young to middle-aged healthy subjects were used to define elevated [11C]Pittsburgh compound B binding in the patients.
Results
Elevated cortical and striatal β-amyloid deposition were present in 38% and 16%, respectively, of this predominantly non-demented cohort of patients with PD. Increased striatal β-amyloid deposition occurred in half of all subjects with increased cortical β-amyloid deposition. In contrast, increased striatal β-amyloid deposition did not occur in the absence of increased cortical β-amyloid deposition. Analysis of covariance using global composite cognitive z-scores as the outcome parameter showed significant regressor effects for combined striatal and cortical β-amyloidopathy (F=4.18, P=0.02) after adjusting for covariate effects of cortical cholinergic activity (F=5.67, P=0.02), caudate nucleus monoaminergic binding, duration of disease and age (total model: F=3.55, P=0.0048). Post-hoc analysis showed significantly lower cognitive z-score for combined striatal and cortical β-amyloidopathy compared to cortical-only β-amyloidopathy and non-β-amyloidopathy subgroups.
Conclusions
The combined presence of striatal and cortical β-amyloidopathy is associated with greater cognitive impairment than cortical β-amyloidopathy alone in PD.
doi:10.1002/mds.26369
PMCID: PMC4724301  PMID: 26380951
Acetylcholinesterase; β-amyloid; cognitive impairment; cortex; dopamine; Parkinson disease; PET; striatum
2.  APOE effect on Alzheimer’s biomarkers in older adults with significant memory concern 
Background
This study assessed APOE ε4 carrier status effects on Alzheimer’s disease (AD) imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC).
Methods
Cognitively normal, SMC, and early mild cognitive impairment participants from ADNI were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [18F]Florbetapir amyloid positivity on CSF biomarkers.
Results
SMC ε4+ showed greater amyloid deposition than SMC ε4−, but no hypometabolism or MTL atrophy. SMC ε4+ showed lower Aβ1–42 and higher tau/p-tau than ε4−, which were most abnormal in APOE ε4+ and cerebral amyloid positive SMC.
Conclusion
SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at-risk nature of the SMC group and the importance of APOE in mediating this risk.
doi:10.1016/j.jalz.2015.03.003
PMCID: PMC4637003  PMID: 25960448
significant memory concern (SMC)/subjective cognitive decline (SCD); apolipoprotein E (APOE); neuroimaging; [18F]Florbetapir PET; [18F]Fluorodeoxyglucose (FDGb) PET; structural magnetic resonance imaging (MRI); cerebrospinal fluid (CSF); Alzheimer’s Disease Neuroimaging Initiative (ADNI)
3.  Non-exercise physical activity attenuates motor symptoms in Parkinson disease independent from nigrostriatal degeneration 
Parkinsonism & related disorders  2015;21(10):1227-1231.
Objective
To investigate the relationship between time spent in non-exercise and exercise physical activity and severity of motor functions in Parkinson disease (PD).
Background
Increasing motor impairments of PD incline many patients to a sedentary lifestyle. We investigated the relationship between duration of both non-exercise and exercise physical activity over a 4-week period using the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire and severity of clinical motor symptoms in PD. We accounted for the magnitude of nigrostriatal degeneration.
Methods
Cross-sectional study. PD subjects, n=48 (40M); 69.4±7.4 (56–84) years old; 8.4±4.2 (2.5–20) years motor disease duration, mean UPDRS motor score 27.5 ± 10.3 (7–53) and mean MMSE score 28.4 ± 1.9 (22–30) underwent [11C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation and completed the CHAMPS questionnaire and clinical assessment.
Results
Bivariate correlations showed an inverse relationship between motor UPDRS severity scores and duration of non-exercise physical activity (R= −0.37, P=0.0099) but not with duration of exercise physical activity (R= −0.05, P= 0.76) over 4 weeks. Multiple regression analysis using UPDRS motor score as outcome variable demonstrated a significant regressor effect for duration of non-exercise physical activity (F=6.15, P=0.017) while accounting for effects of nigrostriatal degeneration (F=4.93, P=0.032), levodopa-equivalent dose (LED; F=1.07, P=0.31), age (F=4.37, P=0.043) and duration of disease (F=1.46, P=0.23; total model (F=5.76, P=0.0004).
Conclusions
Non-exercise physical activity is a correlate of motor symptom severity in PD independent of the magnitude of nigrostriatal degeneration. Non-exercise physical activity may have positive effects on functional performance in PD.
doi:10.1016/j.parkreldis.2015.08.027
PMCID: PMC4587298  PMID: 26330028
dopamine; exercise; Parkinson disease; physical activity; PET; sedentariness
5.  Multiple Testing for Neuroimaging via Hidden Markov Random Field 
Biometrics  2015;71(3):741-750.
Summary
Traditional voxel-level multiple testing procedures in neuroimaging, mostly p-value based, often ignore the spatial correlations among neighboring voxels and thus suffer from substantial loss of power. We extend the local-significance-index based procedure originally developed for the hidden Markov chain models, which aims to minimize the false nondiscovery rate subject to a constraint on the false discovery rate, to three-dimensional neuroimaging data using a hidden Markov random field model. A generalized expectation-maximization algorithm for maximizing the penalized likelihood is proposed for estimating the model parameters. Extensive simulations show that the proposed approach is more powerful than conventional false discovery rate procedures. We apply the method to the comparison between mild cognitive impairment, a disease status with increased risk of developing Alzheimer’s or another dementia, and normal controls in the FDG-PET imaging study of the Alzheimer’s Disease Neuroimaging Initiative.
doi:10.1111/biom.12329
PMCID: PMC4579542  PMID: 26012881
Alzheimer’s disease; False discovery rate; Generalized expectation-maximization algorithm; Ising model; Local significance index; Penalized likelihood
6.  Educational Attainment and Motor Burden in Parkinson disease 
OBJECTIVE
Greater educational attainment is a protective factor for neurodegenerative dementias. If education earlier in life leads to greater cerebral reserve, it may play a similar protective role in Parkinson disease (PD).
METHODS
We conducted a cross-sectional clinical-imaging study of 142 subjects with PD. All subjects underwent [11C]dihydrotetrabenazine PET to confirm nigrostriatal dopaminergic denervation and brain MRI to estimate adjusted cortical grey matter volume.
RESULTS
After adjusting for possible confounders including cognitive and dopaminergic covariates, as well as non-specific neurodegeneration covariates (age, disease duration, and total adjusted cortical gray matter volume), lower years of education remained a significant predictor of higher total MDS-UPDRS motor score (t=−3.28, p=0.001). Education level associated inversely with white matter hyperintensities in a post-hoc analysis (n=83).
CONCLUSIONS
Higher educational attainment is associated with lower severity of motor impairment in PD. This association may reflect an extranigral protective effect upon white matter integrity.
doi:10.1002/mds.26272
PMCID: PMC4504749  PMID: 26096339
Parkinson disease; Education; Gray Matter; Dopamine; Neuroprotection
7.  The ADNI PET Core: 2015 
INTRODUCTION
This paper reviews the work done in the ADNI PET core over the past 5 years, largely concerning techniques, methods, and results related to amyloid imaging in ADNI.
METHODS
The PET Core has utilized [18F]florbetapir routinely on ADNI participants, with over 1600 scans available for download. Four different laboratories are involved in data analysis, and have examined factors such as longitudinal florbetapir analysis, use of FDG-PET in clinical trials, and relationships between different biomarkers and cognition.
RESULTS
Converging evidence from the PET Core has indicated that cross-sectional and longitudinal florbetapir analyses require different reference regions. Studies have also examined the relationship between florbetapir data obtained immediately after injection, which reflects perfusion, and FDG-PET results. Finally, standardization has included the translation of florbetapir PET data to a centiloid scale.
CONCLUSION
The PET Core has demonstrated a variety of methods for standardization of biomarkers such as florbetapir PET in a multicenter setting.
doi:10.1016/j.jalz.2015.05.001
PMCID: PMC4510459  PMID: 26194311
8.  Post-Mortem Evaluation of Amyloid-Dopamine Terminal PET Dementia Classifications 
Annals of neurology  2015;78(5):824-830.
Clinical classification of early dementia and mild cognitive impairment is imprecise. We reported previously that molecular imaging classification of early dementia and mild cognitive impairment with dual amyloid and dopamine terminal positron emission tomography differs significantly from expert clinical classification. We now report pathologic diagnoses in a substantial subset of our previously imaged subjects. Among 36 subjects coming to autopsy, imaging classifications and pathologic diagnosis were concordant in 33 cases (κ=0.85). This approach enhanced specificity of Alzheimer disease diagnosis. The strong concordance of imaging based classifications and pathologic diagnoses suggests that this imaging approach will be useful in establishing more accurate and convenient classification biomarkers for dementia research.
doi:10.1002/ana.24481
PMCID: PMC4836870  PMID: 26183692
9.  Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer’s Disease: Results from the DIAN Study Group 
PLoS ONE  2016;11(3):e0152082.
Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer’s Network (DIAN), an autosomal dominant Alzheimer’s disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer’s disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.
doi:10.1371/journal.pone.0152082
PMCID: PMC4807073  PMID: 27010959
10.  Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials 
Neurology  2015;85(8):692-700.
Objective:
To evaluate the effects of bapineuzumab on brain β-amyloid (Aβ) burden using 11C-Pittsburgh compound B (11C-PiB)-PET.
Methods:
Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aβ over 71 weeks using an 11C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region.
Results:
A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in 11C-PiB-PET GCA between bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = −0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = −0.068; p = 0.027; 1.0 mg/kg vs placebo δ = −0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results.
Conclusions:
The 11C-PiB-PET imaging results demonstrated reduction of fibrillar Aβ accumulation in patients with Alzheimer disease treated with bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aβ species were inadequately targeted.
doi:10.1212/WNL.0000000000001877
PMCID: PMC4553028  PMID: 26208959
11.  Clinical Markers for Identifying Cholinergic Deficits in Parkinson's Disease 
Background
Cholinergic projection systems degeneration is associated with dopamine non-responsive features of Parkinson's disease (PD). Cholinergic deficits are variable in non-demented PD. Identification of cholinergic deficits in PD may help with selection of suitable patients for targeted cholinergic drug treatment in PD. The objective of this retrospective multivariate predictor analysis study was to identify clinical markers indicative of cholinergic deficits in PD patients, as assessed by acetylcholinesterase ([11C]PMP) positron emission tomography.
Methods
One hundred thirty-seven PD patients (34 female) participated; median modified Hoehn and Yahr score was 2.5 (range 1–4), average age of 65.6 ± 7.4 years, and average duration of motor disease symptoms of 6.0 ± 4.2 years. Subjects were dichotomized as “normocholinergic” or “hypocholinergic” based on a 5th percentile cutoff from normal for the basal forebrain-cortical and pedunculopontine nucleus-thalamic cholinergic projection systems. Previously identified clinical indices of cholinergic denervation were used for statistical prediction of cholinergic deficits. Logistic regression determined which risk factors predicted cholinergic deficits. Sensitivity, specificity, and accuracy were determined for the (combinations of) significant predictor variables.
Results
There were 49 (35.8%) hypocholinergic PD subjects. The combination of RBD symptoms and fall history showed highest diagnostic accuracy (81.1%) for predicting combined thalamic and cortical cholinergic deficits. A combined assessment of 8.5 meter walk time and lower score on the Montreal cognitive assessment scale provided diagnostic accuracy of 80.7 % for predicting isolated cortical cholinergic denervation.
Conclusion
Assessment of clinical indices of cholinergic denervation may be useful for identifying suitable subjects for trials of targeted cholinergic drug treatments in PD.
doi:10.1002/mds.26061
PMCID: PMC4318774  PMID: 25393613
Parkinson's disease; acetylcholine; acetylcholinesterase; PET; biomarkers
12.  The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET 
Although amyloid imaging with PiB-PET, and now with F-18-labelled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤45 years) and typical Alzheimer’s disease patients. The units of this scale have been named “Centiloids.” Basically, we describe a “standard” method of analyzing PiB PET data and then a method for scaling any “non-standard” method of PiB PET analysis (or any other tracer) to the Centiloid scale.
doi:10.1016/j.jalz.2014.07.003
PMCID: PMC4300247  PMID: 25443857
13.  Advanced Age, Cardiovascular Risk Burden, and Timed Up and Go Test Performance in Parkinson Disease 
Background.
Cardiovascular comorbidities are a known risk factor for impaired mobility in elderly individuals. Motor impairments in Parkinson disease are conventionally ascribed to nigrostriatal dopaminergic denervation although progressive gait and balance impairments become more common with aging and often show limited response to dopaminergic replacement therapies.
Methods.
We explored the association between elevated cardiovascular risk factors and performance on the Timed Up and Go test in cross-sectional of Parkinson disease subjects (n = 83). Cardiovascular risk factor status was estimated using the Framingham General Cardiovascular Disease risk-scoring algorithm in order to dichotomize the cohort into those with and without elevated modifiable cardiovascular risk compared with normative scores for age and gender. All subjects underwent clinical and neuroimaging evaluations including a 3-m Timed Up and Go test, [11C]dihydrotetrabenazine positron emission tomography imaging to estimate nigrostriatal dopamine terminal loss, and an magnetic resonance imaging assessment of leukoaraiosis. A similar analysis was performed in 49 healthy controls.
Results.
After adjusting for disease duration, leukoaraiosis, and nigrostriatal dopaminergic denervation, Parkinson disease subjects with elevated Framingham risk scores (n = 61) displayed slower Timed Up and Go test performance (β = 1.86, t = 2.41, p = .018) compared with subjects with normal range Framingham risk scores (n = 22). When age ≥65 was added to the model in a post hoc analysis, the strength of effect seen with older age (β = 1.51, t = 2.44, p = .017) was similar to that of elevated Framingham risk scoring (β = 1.87, t = 2.51, p = .014). In a multivariable regression model studying the healthy control population, advanced age (t = 2.15, p = .037) was a significant predictor of Timed Up and Go speed though striatal [11C]dihydrotetrabenazine (t = −1.30, p = .19) and elevated Framingham risk scores (t = 1.32, p = .19) were not.
Conclusions.
Modifiable cardiovascular risk factors and older age may independently exacerbate balance-related disability in Parkinson disease and may exert additive or synergistic pathological effects. The pathophysiology of these impairments cannot be explained completely by nigrostriatal dopaminergic denervation or leukoaraiosis burden and may relate to systemic factors seen with accelerated aging.
doi:10.1093/gerona/glu070
PMCID: PMC4296117  PMID: 24864306
Aging; Parkinson disease; Framingham risk score; Dopamine; Cardiovascular risk factors.
14.  Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease 
Parkinsonism & related disorders  2014;20(12):1394-1398.
Background
There is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.
Objective
To investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.
Methods
Cross-sectional study. Patients with PD (n=148; age 65.6±7.4 years, Hoehn and Yahr stage 2.4±0.6, with (n=15) and without (n=133) comorbid type II DM, underwent [11C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [11C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.
Results
There were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (−0.98±1.01) compared to the non-diabetics (−0.36±0.91; F=7.78, P=0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F=8.39, P<0.0001).
Conclusion
Diabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than diseasespecific neurodegenerations.
doi:10.1016/j.parkreldis.2014.10.008
PMCID: PMC4314515  PMID: 25454317
Acetylcholine; cognitive impairment; diabetes mellitus; dopamine; Parkinson disease; PET
15.  Biomarker Progressions Explain Higher Variability in Stage-Specific Cognitive Decline than Baseline Values in Alzheimer Disease 
Background
It is unknown which commonly employed Alzheimer disease biomarker values-baseline or progression-best predict longitudinal cognitive decline.
Methods
526 subjects from the Alzheimer’s Disease Neuroimaging Initiative. ADNI composite memory (ADNI-Mem) and executive (ADNI-Exe) scores were the primary outcomes. Individual-specific slope of the longitudinal trajectory of each biomarker was first estimated. These estimates and observed baseline biomarker values were used as predictors of cognitive declines. Variability in cognitive declines explained by baseline biomarker values were compared with variability explained by biomarker progression values.
Results
About 40% of variability in memory and executive function declines was explained by ventricular volume progression among MCI. 84% of memory and 65% of executive function declines were explained by FDG-PET score progression and ventricular volume progression, respectively, among AD.
Conclusions
Biomarker progressions explained higher variability in cognitive decline than biomarker baseline values. This has important implications for clinical trials targeted to modify AD biomarkers.
doi:10.1016/j.jalz.2014.04.513
PMCID: PMC4253728  PMID: 25022534
ADNI; Cognitive declines; Biomarker; Biomarker progressions; ADNI-Mem; ADNI-Exe; MCI; FDG-PET; MRI volume
16.  Abnormal MoCA and Normal Range MMSE scores in Parkinson disease without dementia: Cognitive and Neurochemical Correlates 
Parkinsonism & related disorders  2014;20(10):1076-1080.
Background
The Montreal Cognitive Assessment (MoCA) is increasingly being used as a cognitive screening test in Parkinson disease (PD). The MoCA’s popularity likely reflects its ability to detect executive dysfunction, a relative deficiency of the Mini-Mental State Examination (MMSE).
Objective
To compare neurochemical and neuropsychological functions in non-demented PD patients with mild cognitive impairment (PD-MCI) and without, as defined by MoCA (PD-MCI=MoCA<26).
Methods
Non-demented PD subjects underwent combined MoCA and MMSE, detailed cognitive testing and [11C]methyl-4-piperidinyl propionate acetylcholinesterase and [11C]dihydrotetrabenazine monoaminergic PET imaging.
Results
Eighteen subjects met MoCA PD-MCI criteria but had MMSE scores in the normal range, compared to 29 subjects with normal MoCA and MMSE scores. The MoCA-defined PD-MCI group had reduced performance in global cognition (t=2.91, P=0.0056), most significantly in executive function (t=3.18, P=0.002), as well as significant reduction in dorsal caudate nucleus dopaminergic innervation (t=2.72, P=0.009) compared to the PD without MCI group. Both MoCA and MMSE had poor diagnostic accuracy for PD-MCI (65.3%) when using the Level 2 Movement Disorder Society Task Force definition.
Conclusion
PD subjects with normal range MMSE but abnormal MoCA scores had evidence of caudate nucleus dopaminergic denervation and mild cognitive changes, predominantly in executive function. The MoCA may be able to preferentially detect executive dysfunction compared to the MMSE, but the MoCA has limited diagnostic accuracy for PD-MCI, and should not be used alone to make this diagnosis.
doi:10.1016/j.parkreldis.2014.07.008
PMCID: PMC4180768  PMID: 25085750
Assessment of cognitive disorders/dementia; MCI (mild cognitive impairment); PD (Parkinson disease); PET (positron emission tomography)
17.  Extra-nigral pathologies are common in Parkinson disease with freezing of gait: an in vivo PET study 
BACKGROUND
Cholinergic denervation has been associated with falls and slower gait speed and β-amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra-nigral pathologies and freezing of gait (FoG).
METHODS
Patients with PD (n=143; age 65.5±7.4 years, Hoehn and Yahr stage 2.4±0.6, Montreal Cognitive Assessment score 25.9±2.6) underwent [11C]methyl-4-pi-peridinyl propionate acetylcholinesterase and [11C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic “off” state. A subset of subjects (n=61) underwent [11C]Pittsburgh compound-B β-amyloid PET imaging. Normative data were used to dichotomize abnormal β-amyloid uptake or cholinergic deficits.
RESULTS
FoG was present in 20 patients (14.0%). Freezers had longer duration of disease (P=0.009), more severe motor disease (P<0.0001) and lower striatal dopaminergic activity (P=0.013) compared to non-freezers. FoG was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ2=5.56, P=0.018) but not in the thalamic cholinergic denervation group (17.4%, χ2=0.26, P=0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical β-amyloid deposition (30.4%, Fisher Exact test: P = 0.032). FoG frequency was lowest with absence of both pathology (4.8%), intermediate in subjects with single extra-nigral pathology (14.3%) and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran-Armitage trend test Z=2.63, P=0.015). Within the group of freezers, 90% had at least one of the two extra-nigral pathologies studied.
CONCLUSIONS
Extra-nigral pathologies, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology.
doi:10.1002/mds.25929
PMCID: PMC4162130  PMID: 24909584
acetylcholine; β-amyloid; dopamine; gait freezing; Parkinson’s disease; PET
18.  It still hurts: altered opioid activity in the brain during social rejection and acceptance in major depressive disorder 
Molecular psychiatry  2015;20(2):193-200.
The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen “social pain.” We used positron emission tomography scanning with the selective MOR radioligand [11C]carfentanil to test the hypothesis that MOR system activation in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n = 17) compared to healthy controls (HCs, n = 18). During rejection, MDD patients showed reduced MOR activation (e.g., reduced endogenous opioid release) in brain regions regulating stress, mood, and motivation, and slower emotional recovery compared to HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with MOR activation in the nucleus accumbens, a reward structure. Abnormal MOR function in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse, and contribute to poor treatment outcomes.
doi:10.1038/mp.2014.185
PMCID: PMC4469367  PMID: 25600108
depression; mu; opioid; PET; social; rejection; acceptance; stress
19.  4-[18F]fluoro-m-hydroxyphenethylguanidine: A Radiopharmaceutical for Quantifying Regional Cardiac Sympathetic Nerve Density with Positron Emission Tomography 
Journal of medicinal chemistry  2013;56(18):7312-7323.
4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG, [18F]1) is a new cardiac sympathetic nerve radiotracer with kinetic properties favorable for quantifying regional nerve density with PET and tracer kinetic analysis. An automated synthesis of [18F]1 was developed in which the intermediate 4-[18F]fluoro-m-tyramine ([18F]16) was prepared using a diaryliodonium salt precursor for nucleophilic aromatic [18F]fluorination. In PET imaging studies in rhesus macaque monkeys, [18F]1 demonstrated high quality cardiac images with low uptake in lungs and liver. Compartmental modeling of [18F]1 kinetics provided ‘net uptake rate’ constants Ki (mL/min/g wet) and Patlak graphical analysis of [18F]1 kinetics provided Patlak slopes Kp (mL/min/g). In pharmacological blocking studies with the norepinephrine transporter inhibitor desipramine (DMI), each of these quantitative measures declined in a dose-dependent manner with increasing DMI doses. These initial results strongly suggest that [18F]1 can provide quantitative measures of regional cardiac sympathetic nerve density in human hearts using PET.
doi:10.1021/jm400770g
PMCID: PMC4520396  PMID: 23965035
20.  REGULARIZED 3D FUNCTIONAL REGRESSION FOR BRAIN IMAGE DATA VIA HAAR WAVELETS 
The annals of applied statistics  2014;8(2):1045-1064.
The primary motivation and application in this article come from brain imaging studies on cognitive impairment in elderly subjects with brain disorders. We propose a regularized Haar wavelet-based approach for the analysis of three-dimensional brain image data in the framework of functional data analysis, which automatically takes into account the spatial information among neighboring voxels. We conduct extensive simulation studies to evaluate the prediction performance of the proposed approach and its ability to identify related regions to the outcome of interest, with the underlying assumption that only few relatively small subregions are truly predictive of the outcome of interest. We then apply the proposed approach to searching for brain subregions that are associated with cognition using PET images of patients with Alzheimer’s disease, patients with mild cognitive impairment, and normal controls.
doi:10.1214/14-AOAS736
PMCID: PMC4465522  PMID: 26082826
Alzheimer’s disease; Brain imaging; Functional data analysis; Haar wavelet; Lasso; PET image; Variable selection
21.  High Endogenous μ-Opioid Activation in the PAG and Red Nucleus During Migraine Allodynia – Preliminary Report II 
We investigated in vivo the allodynic response of the central μ-opioid system during spontaneous migraine headaches, following a sustained pain threshold challenge on the trigeminal ophthalmic region. Six migraineurs were scanned during the ictal and interictal phases using Positron Emission Tomography (PET) with the selective μ-opioid receptor (μOR) radiotracer [11C]carfentanil. Females were scanned during the mid-late follicular phase of two separate cycles. Patients showed ictal trigeminal allodynia during the thermal challenge that was concurrent and positively correlated with μOR activation in the midbrain, extending from red nucleus to ventrolateral periaqueductal gray matter. These findings demonstrate for the first time in vivo the high μOR activation in the migraineurs’ brains in response to their allodynic experience.
doi:10.1002/acn3.66
PMCID: PMC4184673  PMID: 25328905
22.  Association of μ-Opioid Activation in the Prefrontal Cortex with Spontaneous Migraine Attacks – Brief Report I 
We evaluated in vivo the μ-opioid system during spontaneous episodic migraine headaches. Seven patients were scanned at different phases of their migraine using Positron Emission Tomography with the selective μ-opioid receptor (μOR) radiotracer [11C]carfentanil. In the ictal phase, there was μOR activation in the medial prefrontal cortex, which was strongly associated with the μOR availability level during the interictal phase. Furthermore, μ-opioid binding changes showed moderate negative correlation with the combined extension and severity of the attacks. These results indicate for the first time that there is high μOR activation in the migraineurs’ brains during headache attacks in response to their pain.
doi:10.1002/acn3.65
PMCID: PMC4110741  PMID: 25072055
23.  Modifiable cardiovascular risk factors and axial motor impairments in Parkinson disease 
Neurology  2014;82(17):1514-1520.
Objective:
Cardiovascular comorbidities associate with neurodegeneration in the elderly and may contribute to extranigral pathologies and medically refractory axial motor features in Parkinson disease (PD).
Methods:
We explored differences in the estimated rate of axial motor feature accrual between patients with PD with and without elevated cardiovascular risk factors as estimated by the Framingham General Cardiovascular Disease risk-scoring algorithm in a cross-sectional cohort study. All participants underwent motor evaluations with the Movement Disorders Society revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS), [11C]dihydrotetrabenazine (DTBZ) monoaminergic brain PET imaging, and MRI.
Results:
Participants with PD with elevated Framingham risk (FR) scores (n = 63, 74.1%) showed higher unadjusted rates of total MDS-UPDRS (t = 3.60, p = 0.0006) and axial motor scores (t = 3.98, p = 0.0001) per estimated year of motor symptoms compared to participants with normal-range risk scores (n = 22, 25.9%). After controlling for sex, Montreal Cognitive Assessment score, frontal leukoaraiosis severity, and striatal DTBZ activity, elevated risk factor status was associated with the rate of accrual of axial motor impairments (R2 = 0.206; t = 2.62, p = 0.011) but not with total MDS-UPDRS motor score (R2 = 0.198; t = 1.51, p = 0.135). Frontal leukoaraiosis was associated with the rate of axial and total MDS-UPDRS scores per year of symptoms and also with elevated systolic blood pressure (R2 = 0.291; t = 2.30, p = 0.024) in a separate risk-factor model.
Conclusion:
Cardiovascular risk factors may contribute to axial motor features in PD. Early modification of cardiovascular risk factors, including hypertension, deserves further study as a novel disease-modifying strategy in PD.
doi:10.1212/WNL.0000000000000356
PMCID: PMC4011463  PMID: 24682965
24.  Reducing between scanner differences in multi-center PET studies 
NeuroImage  2009;46(1):154-159.
This work is part of the multi-center Alzheimer's Disease Neuroimaging Initiative (ADNI), a large multi-site study of dementia, including patients having mild cognitive impairment (MCI), probable Alzheimer's disease (AD), as well as healthy elderly controls. A major portion of ADNI involves the use of [18F]-fluorodeoxyglucose (FDG) with positron emission tomography (PET). The objective of this paper is reduction of inter-scanner differences in the FDG-PET scans obtained from the 50 participating PET centers having fifteen different scanner models. In spite of a standardized imaging protocol, systematic inter-scanner variability in PET images from various sites is observed primarily due to differences in scanner resolution, reconstruction techniques, and different implementations of scatter and attenuation corrections. Two correction steps were developed by comparison of 3-D Hoffman brain phantom scans with the ‘gold standard’ digital 3-D Hoffman brain phantom: i) high frequency correction; where a smoothing kernel for each scanner model was estimated to smooth all images to a common resolution and ii) low frequency correction; where smooth affine correction factors were obtained to reduce the attenuation and scatter correction errors. For the phantom data, the high frequency correction reduced the variability by 20%-50% and the low frequency correction further reduced the differences by another 20%-25%. Correction factors obtained from phantom studies were applied to 95 scans from normal control subjects obtained from the participating sites. The high frequency correction reduced differences similar to the phantom studies. However, the low frequency correction did not further reduce differences; hence further refinement of the procedure is necessary.
doi:10.1016/j.neuroimage.2009.01.057
PMCID: PMC4308413  PMID: 19457369
25.  Association of plasma and cortical beta-amyloid is modulated by APOE ε4 status 
Background
APOE ε4’s role as a modulator of the relationship between soluble plasma beta-amyloid (Aβ) and fibrillar brain Aβ measured by Pittsburgh Compound-B positron emission tomography ([11C]PiB PET) has not been assessed.
Methods
Ninety-six Alzheimer’s Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at time of scan were included. Regional and voxel-wise analyses of [11C]PiB data were used to determine the influence of APOE ε4 on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [11C]PiB uptake.
Results
In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [11C]PiB binding compared to using APOE and plasma Aβ1-40/Aβ1-42 as separate terms.
Conclusions
The results suggest that plasma Aβ is a potential Alzheimer’s disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.
doi:10.1016/j.jalz.2013.01.007
PMCID: PMC3750076  PMID: 23541187
Alzheimer’s disease (AD); mild cognitive impairment (MCI); Alzheimer’s Disease Neuroimaging Initiative (ADNI); beta-amyloid (Aβ); plasma beta-amyloid; positron emission tomography (PET); Pittsburgh Compound-B ([11C]PiB); Apolipoprotein E (APOE)

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