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1.  Assessment of the biodistribution of an [18F]FDG-loaded perfluorocarbon double emulsion using dynamic micro-PET in rats 
Perfluorocarbon (PFC) double emulsions loaded with a water-soluble, therapeutic agent can be triggered by ultrasound in a process known as acoustic droplet vaporization (ADV). Elucidating the stability and biodistribution of these sonosensitive vehicles and encapsulated agents are critical in developing targeted drug delivery strategies using ultrasound. [18F]fluorodeoxyglucose (FDG) was encapsulated in a PFC double emulsion and the in vitro diffusion of FDG was assessed using a Franz diffusion cell. Using dynamic micro positron emission tomography (micro-PET) and direct tissue sampling, the biodistribution of FDG administered as a solution (i.e. non-emulsified) or as an emulsion was studied in Fisher 344 rats (n = 6) bearing subcutaneous 9L gliosarcoma. Standardized uptake values (SUVs) and area under the curve of the SUV (AUCSUV) of FDG were calculated for various tissues. The FDG flux from the emulsion decreased by up to a factor of 6.9 compared to the FDG solution. FDG uptake, calculated from the AUCSUV, decreased by 36% and 44% for brain and tumor, respectively, when comparing FDG solution versus FDG emulsion (p < 0.01). Decreases in AUCSUV in highly metabolic tissues such as brain and tumor demonstrated retention of FDG within the double emulsion. No statistically significant differences in lung AUCSUV were observed, suggesting minimal accumulation of the emulsion in the pulmonary capillary bed. The liver AUCSUV increased by 356% for the FDG emulsion, thus indicating significant hepatic retention of the emulsion.
doi:10.1002/cmmi.1532
PMCID: PMC3677228  PMID: 23613440
micro-PET; biodistribution; perfluorocarbon; emulsion; acoustic droplet vaporization; ultrasound; responsive agents
2.  Diabetes is associated with Postural Instability and Gait Difficulty in Parkinson disease 
Parkinsonism & related disorders  2013;19(5):522-526.
Background
Comorbid diabetes may be associated with more severe motor impairment in Parkinson disease. In normal elderly individuals, diabetes is associated with parkinsonian features, including gait difficulty and rigidity, though not tremor. Whether diabetes contributes to increased motor dysfunction in Parkinson disease by exacerbating nigrostriatal dopaminergic denervation or through intensification of extranigral pathology is unknown.
Methods
We performed a case-control study (n=39) involving 13 Parkinson disease subjects (age 66.4 yrs ± 5.5; duration of disease 6.9 yrs ± 4.4) with diabetes and 26 age, gender, and duration-of-disease-matched Parkinson disease controls without diabetes. All subjects underwent [11C]dihydrotetrabenazine vesicular monoamine transporter type-2 positron emission tomography imaging to assess striatal dihydrotetrabenazine distribution volume ratio and Unified Parkinson disease rating scale motor examination to determine rigidity, bradykinesia, tremor, and postural instability and gait difficulty subscores. Magnetic resonance imaging scans were analyzed to assess leukoaraiosis burden.
Results
After controlling for nigrostriatal dopaminergic denervation, Parkinson disease subjects with diabetes displayed greater postural instability and gait difficulty subscores (t=3.81, p=0.0005). There were no differences in bradykinesia, rigidity, or tremor subscores between cases and controls. The association between diabetes and postural instability and gait difficulty persisted after controlling for comorbid hypertension and body mass index. Leukoaraiosis, distal vibratory sense, and levodopa dose equivalents did not differ significantly between cases and controls.
Conclusions
Diabetes may contribute to postural instability and gait difficulty in Parkinson disease through mechanisms other than nigrostriatal dopaminergic denervation.
doi:10.1016/j.parkreldis.2013.01.016
PMCID: PMC3607954  PMID: 23462483
Diabetes; Parkinson disease; PET; Dopamine; Postural Instability; Gait Difficulty (PIGD)
3.  Response of the μ-opioid system to social rejection and acceptance 
Molecular psychiatry  2013;18(11):10.1038/mp.2013.96.
The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n = 18), we used a μ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography (PET) during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus, and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids play a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG, and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula, and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well-being in the social environment.
doi:10.1038/mp.2013.96
PMCID: PMC3814222  PMID: 23958960
opioid; PET; social; rejection; acceptance; depression; mu; stress
4.  β-amyloid and postural instability and gait difficulty in Parkinson disease at risk for dementia 
Background
Although motor impairments in Parkinson disease are attributed to nigrostriatal dopaminergic denervation, postural instability and gait difficulty (PIGD) features are less responsive to dopaminergic medications. PIGD features are a risk factor also for development of dementia in Parkinson disease. These observations suggest that non-dopaminergic mechanisms may contribute to axial motor impairments. The objective was to perform a correlative positron emission tomography study to examine the relationship between neocortical β-amyloid deposition ([11C]-Pittsburgh Compound-B), nigrostriatal dopaminergic denervation ([11C]-dihydrotetrabenazine), and PIGD feature severity in Parkinson disease patients at risk for dementia.
Methods
Cross-sectional study of 44 Parkinson disease patients (11 Female / 33 Male; 69.5 ± 6.6 years; 7.0 ± 4.8 years motor disease duration; mean Hoehn and Yahr stage 2.7 ± 0.5) who underwent positron emission tomography, motor feature severity assessment using the Movement Disorder Society revised Unified Parkinson's Disease Rating Scale, and the Dementia Rating Scale.
Results
Linear regression (R2adj=0.147, F4,39=2.85, p=0.036) showed that increased PIGD feature severity was associated with increased neocortical [11C]-Pittsburgh Compound-B binding (β=0.346, t39=2.13, p=0.039), while controlling for striatal [11C]-dihydrotetrabenazine binding, age, and Dementia Rating Scale total score.
Conclusion
Increased neocortical β-amyloid deposition, even at low range levels, is associated with higher PIGD feature severity in Parkinson disease patients at risk for dementia. This finding may explain why the PIGD motor phenotype is a risk factor for development of dementia in Parkinson disease.
doi:10.1002/mds.25213
PMCID: PMC3680885  PMID: 23239424
Parkinson disease; β-amyloid; dopamine; PET; MDS-UPDRS
5.  Impaired default network functional connectivity in autosomal dominant Alzheimer disease 
Neurology  2013;81(8):736-744.
Objective:
To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.
Methods:
Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).
Results:
We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.
Conclusion:
Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.
doi:10.1212/WNL.0b013e3182a1aafe
PMCID: PMC3776464  PMID: 23884042
6.  Denicotinized Versus Average Nicotine Tobacco Cigarette Smoking Differentially Releases Striatal Dopamine 
Nicotine & Tobacco Research  2012;15(1):11-21.
Introduction:
Nicotine has long been recognized as a necessary but insufficient component of tobacco cigarettes to maintain a psychophysiological need to smoke. This study examined venous plasma concentrations effects of nicotine in cigarette smoking after overnight abstinence to release striatal dopamine (DA).
Methods:
Twenty-two male smokers smoked either denicotinized (denic) or average nicotine (nic) cigarettes under single blind conditions. Each was given [11C]raclopride and scanned in a positron emission tomography (PET) facility.
Results:
Smoking either denic or nic cigarettes released striatal DA. Denic cigarette smoking released DA primarily in the right striatum, whereas nic cigarette smoking released DA in both striata, but especially in the left. Increases in venous plasma nicotine concentrations correlated positively with increased DA release in the left caudate nucleus. Smoking denic cigarettes reduced craving as much as smoking nic cigarettes. Craving reduction after nic tobacco smoking correlated with increases in plasma nicotine.
Conclusions:
Nonnicotine factors in tobacco smoking produce important right brain effects. Nicotine is a pharmacological factor during tobacco smoking that releases bilateral striatal DA, but more in the left brain.
doi:10.1093/ntr/nts029
PMCID: PMC3524055  PMID: 22491891
7.  Assessing Mild Cognitive Impairment with Amyloid and Dopamine Terminal Molecular Imaging 
We evaluated positron emission tomography (PET)-based classification of neurodegenerative pathology in mild cognitive impairment (MCI).
Methods
A cross-sectional and prospective evaluation of a cohort of 27 MCI subjects drawn from a university-based Cognitive Disorders clinic. We compared expert clinical consensus classification of MCI at entry, and possible dementia at follow-up, with molecular imaging-based classification employing [11C]DTBZ-PET measurement of striatal dopamine terminal integrity and [11C]PiB-PET measurement of cerebral amyloid burden.
Results
Eleven subjects were initially classified clinically as amnestic MCI, 7 as multidomain MCI, and 9 as nonamnestic MCI. At mean follow-up of 3 years, 18 subjects converted to dementia. PET imaging evidence of significant cerebral amyloid deposition and/or nigrostriatal denervation were strong predictors of conversion to dementia. There was only moderate concordance between expert clinical classifications and PET-based classifications of dementia subtypes.
Conclusions
Combined PET molecular imaging of cerebral amyloid burden and striatal dopamine terminal integrity may be useful identifying subjects at high risk for progression to dementia and in defining neurochemically differentiated subsets of MCI subjects.
doi:10.2967/jnumed.112.112599
PMCID: PMC3790329  PMID: 23572495
Dementia; Alzheimer disease; Lewy Body dementia; Frontotemporal dementia
8.  Amyloid Deposition, Hypometabolism, and Longitudinal Cognitive Decline 
Annals of neurology  2012;72(4):578-586.
Objective
Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) population, we examined (1) cross-sectional relationships between amyloid deposition, hypometabolism, and cognition, and (2) associations between amyloid and hypometabolism measurements and longitudinal cognitive measurements.
Methods
We examined associations between mean cortical florbetapir uptake, mean 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) within a set of predefined regions, and Alzhiemer’s Disease Assessment Scale (ADAS-cog) performance in 426 ADNI participants (126 normal, 162 early mild cognitive impairment [EMCI], 85 late MCI [LMCI], 53 Alzheimer disease [AD] patients). For a subset of these (76 normal, 81 LMCI) we determined whether florbetapir and FDG-PET were associated with retrospective decline in longitudinal ADAS-cog measurements.
Results
Twenty-nine percent of normal subjects, 43% of EMCI patients, 62% of LMCI patients, and 77% of AD patients were categorized as florbetapir positive. Florbetapir was negatively associated with concurrent FDG and ADAS-cog in both MCI groups. In longitudinal analyses, florbetapir-positive subjects in both normal and LMCI groups had greater ongoing ADAS-cog decline than those who were florbetapir negative. However, in normal subjects, florbetapir positivity was associated with greater ADAS-cog decline than FDG, whereas in LMCI, FDG positivity was associated with greater decline than florbetapir.
Interpretation
Although both hypometabolism and β-amyloid (Aβ) deposition are detectable in normal subjects and all diagnostic groups, Aβ showed greater associations with cognitive decline in normal participants. In view of the minimal cognitive deterioration overall in this group, this suggests that amyloid deposition has an early and subclinical impact on cognition that precedes metabolic changes. At moderate and later stages of disease (LMCI/AD), hypometabolism becomes more pronounced and more closely linked to ongoing cognitive decline.
doi:10.1002/ana.23650
PMCID: PMC3786871  PMID: 23109153
9.  Aβ-amyloid deposition in patients with Parkinson disease at risk for development of dementia 
Neurology  2012;79(11):1161-1167.
Objective:
The aim of our study was to examine the relationship between corticostriatal Aβ-amyloid deposition and cognitive dysfunction in a cohort of patients with Parkinson disease (PD) at risk for dementia.
Methods:
This was a cross-sectional study of 40 patients with PD with mild cognitive impairment (MCI) or other known dementia risk factors. Subjects underwent dynamic Aβ-amyloid and vesicular monoamine transporter 2 PET imaging using [11C] Pittsburgh compound B (PiB) and [11C]dihydrotetrabenazine (DTBZ), respectively, and neuropsychological assessment. PiB and DTBZ PET data were analyzed using the Logan graphical method to determine cerebral PiB deposition relative to the cerebellar hemispheres and striatal DTBZ binding relative to occipital neocortex. Component z scores were calculated for individual cognitive domains (memory, visuospatial processing, working memory/attention, and executive function) and combined linearly for global estimation of cognition. Correlation of cognitive function and cortical PiB binding was investigated.
Results:
Elevated cerebral PiB binding at levels seen in patients with AD was infrequent (6 of 40 subjects). Mean cortical PiB binding in the entire cohort was 1.16 ± 0.16 (distribution volume ratio; range 0.96–1.78). A significant correlation was noted between cortical PiB binding and global composite cognitive function (r = −0.55, p < 0.005) as well as the Wechsler Adult Intelligence Scale score (r = −0.54, p = 0.0004).
Conclusion:
Elevated cerebral Aβ-amyloid deposition at levels seen in Alzheimer disease is uncommon in subjects with PD at risk for dementia. In our sample, the prevalence of markedly elevated PiB binding was significantly lower than that found in prior studies of cognitively normal elderly individuals. Neocortical PiB binding correlated robustly with measures of cognitive impairment in our cohort.
doi:10.1212/WNL.0b013e3182698d4a
PMCID: PMC3525303  PMID: 22933741
10.  Oxytocin Gene Polymorphisms Influence Human Dopaminergic Function in a Sex Dependent Manner 
Biological Psychiatry  2012;72(3):198-206.
Background
Oxytocin, classically involved in social and reproductive activities, is increasingly recognized as an antinociceptive and anxiolytic agent, effects which may be mediated via oxytocin’s interactions with the dopamine system. Thus, genetic variation within the oxytocin gene (OXT) is likely to explain variability in dopamine-related stress responses. As such, we examined how OXT variation is associated with stress-induced dopaminergic neurotransmission in a healthy human sample.
Method
Fifty-five young healthy volunteers were scanned using [11C] raclopride positron emission tomography while they underwent a standardized physical and emotional stressor that consisted of moderate levels of experimental sustained deep muscle pain, and a baseline, control state. Four haplotype tagging single nucleotide polymorphisms located in regions near OXT were genotyped. Measures of pain, affect, anxiety, well-being and interpersonal attachment were also assessed.
Results
Female rs4813625 C allele carriers demonstrated greater stress-induced dopamine release, measured as reductions in receptor availability from baseline to the pain-stress condition relative to female GG homozygotes. No significant differences were detected among males. We also observed that female rs4813625 C allele carriers exhibited higher attachment anxiety, higher trait anxiety and lower emotional well-being scores. In addition, greater stress-induced dopamine release was associated with lower emotional well-being scores in female rs4813625 C allele carriers.
Conclusions
Our results suggest that variability within the oxytocin gene appear to explain interindividual differences in dopaminergic responses to stress, which are shown to be associated with anxiety traits, including those linked to attachment style, as well as emotional well-being in women.
doi:10.1016/j.biopsych.2012.01.033
PMCID: PMC3392442  PMID: 22418012
oxytocin; genetics; dopamine; positron emission tomography; humans; sex differences
11.  Heterogeneity of cholinergic denervation in Parkinson's disease without dementia 
Parkinson's disease (PD) is a multisystem neurodegenerative disorder. Heterogeneous clinical features may reflect heterogeneous changes in different brain regions. In contrast to the pronounced nigrostriatal denervation characteristic of PD, cholinergic changes are less marked. We investigated cholinergic innervation activity in PD subjects relative to normal subjects. Nondemented PD subjects (n=101, age 65.3±7.2 years) and normal subjects (n=29, age 66.8±10.9 years) underwent clinical assessment and [11C]methyl-4-piperidinyl propionate acetylcholinesterase and [11C]dihydrotetrabenazine monoaminergic positron emission tomography (PET) imaging. Cholinergic projection changes were heterogeneous for 65 out of 101 PD subjects who had neocortical and thalamic acetylcholinesterase activity within the normal range. The remainder had combined neocortical and thalamic (13/101), isolated neocortical (18/101), or isolated thalamic (5/101) acetylcholinesterase activity below the normal range. The low neocortical acetylcholinesterase activity subgroup had significantly lower global cognitive performance compared with the normal range subgroup (F=7.64, P=0.0069) with an independent effect for nigrostriatal denervation (F=7.60, P=0.0074). The low thalamic acetylcholinesterase activity subgroup did not differ from the normal thalamic acetylcholinesterase activity subgroup in cognitive performance or motor impairments except for a history of falls (P=0.0023). Cholinergic denervation is heterogeneous with reduced neocortical and/or thalamic acetylcholinesterase activity in 36% of nondemented PD subjects with corresponding clinical phenotypic variation. Results also show independent cognitive effects for both cholinergic and dopaminergic system changes in nondemented PD subjects.
doi:10.1038/jcbfm.2012.60
PMCID: PMC3421100  PMID: 22569194
acetylcholinesterase; cognitive impairment; dopamine; motor; Parkinson's disease; PET
12.  Symptoms of Rapid Eye Movement Sleep Behavior Disorder are Associated with Cholinergic Denervation in Parkinson Disease 
Annals of neurology  2012;71(4):560-568.
Objective
Rapid eye movement sleep behavior disorder (RBD) is common in Parkinson disease (PD), but its relationship to the varied neurotransmitter deficits of PD and prognostic significance remain incompletely understood. RBD and cholinergic system degeneration are identified independently as risk factors for cognitive impairment in PD. We aimed to assess the association between cholinergic denervation and symptoms of RBD in PD patients without dementia.
Methods
Eighty subjects with PD without dementia (age, 64.6 ± 7.0 years; range, 50–82 years; 60 males, 20 females; mean Montreal Cognitive Assessment Test [MoCA] score, 26.2 ± 2.1; range 21–30) underwent clinical assessment, neuropsychological testing, and [11C]methylpiperidyl propionate acetylcholinesterase and [11C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 positron emission tomography (PET) imaging. 11C3-Amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) serotonin transporter PET imaging was performed in a subset of 35 subjects. The presence of RBD symptoms was determined using the Mayo Sleep Questionnaire.
Results
Twenty-seven of 80 subjects (33.8%) indicated a history of RBD symptoms. Subjects with and without RBD symptoms showed no significant differences in age, motor disease duration, MoCA, Unified Parkinson Disease Rating Scale motor scores, or striatal DTBZ binding. Subjects with RBD symptoms, in comparison to those without, exhibited decreased neocortical, limbic cortical, and thalamic cholinergic innervation (0.0213 ± 0.0018 vs 0.0236 ± 0.0022, t = 4.55, p < 0.0001; 0.0388 ± 0.0029 vs 0.0423 ± 0.0058, t = 2.85, p = 0.0056; 0.0388 ± 0.0025 vs 0.0427 ± 0.0042, t = 4.49, p < 0.0001, respectively). Brainstem and striatal DASB binding showed no significant differences between groups.
Interpretation
The presence of RBD symptoms in PD is associated with relative neocortical, limbic cortical, and thalamic cholinergic denervation although not with differential serotoninergic or nigrostriatal dopaminergic denervation. The presence of RBD symptoms may signal cholinergic system degeneration.
doi:10.1002/ana.22691
PMCID: PMC3727906  PMID: 22522445
13.  Cerebral Amyloid Deposition and Serotoninergic Innervation in Parkinson Disease 
Archives of neurology  2012;69(12):1628-1631.
Background
Prior studies suggest that serotoninergic neurotransmission reduces β-amyloid (Aβ) production.
Objective
To determine whether serotoninergic system degeneration in Parkinson disease promotes Aβ deposition, using in vivo positron emission tomographic probes of serotonin system integrity and Aβ deposition.
Design, Setting, and Patients
Cross-sectional study of 13 subjects with Parkinson disease from the movement disorders clinics at the University of Michigan Health System and Veterans Affairs Ann Arbor Healthcare System, with positron emission tomography using the serotonin transporter ligand carbon 11 ([11C])–labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) and the Aβ ligand [11C]Pittsburgh compound B.
Results
Inverse correlations were found between DASB and Pittsburgh compound B distribution volume ratios in the neocortex (ρ=−0.577; P=.04) and striatum (ρ=−0.780; P=.002).
Conclusion
Serotoninergic system degeneration in Parkinson disease may promote the development of cerebral amyloidopathy.
doi:10.1001/archneurol.2012.764
PMCID: PMC3671396  PMID: 22964894
14.  Thalamic cholinergic innervation is spared in Alzheimer disease compared to Parkinsonian disorders 
Neuroscience Letters  2012;514(2):169-172.
OBJECTIVE
There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus-laterodorsal tegmental complex (PPN-LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN-Thalamic (PPN-Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB).
METHODS
AD (n=13; mean age 75.4±5.5), PD (n=11; age 71.4±6.4), PDD (n=6; age 70.8±4.7), DLB (n=6; age 68.0±8.6) and normal controls (NC; n=14; age 69.0±7.5) subjects underwent AChE [11C]-methyl-4-piperidinyl propionate (PMP) PET imaging. PPN-Thal PET data were analyzed using the Nagatsuka method.
RESULTS
There were no significant differences in mean age between the groups (F=1.86, p=0.134). Kruskal-Wallis testing demonstrated a significant group effect for PPN-Thal AChE hydrolysis rates (F=9.62, P<0.0001). Compared to NC, reduced thalamic k3 hydrolysis rate was noted in subjects with PDD (−19.8%; AChE k3 hydrolysis rates 0.1072±0.0143 min−1), DLB (−17.4%; 0.1103±0.0112 min−1) and PD (−12.8%; 0.1165±0.0114 min−1). Each of these 3 subgroups were statistically different from AD subjects (−0.7%; 0.1326±0.0095 min−1) who showed relatively spared thalamic k3 hydrolysis rates which were comparable to NC (0.1336±0.0142 min−1).
CONCLUSIONS
Thalamic cholinergic denervation is present in PD, PDD, and DLB but not in AD. Neurodegenerative involvement of thalamic cholinergic afferent projections may contribute to disease-specific motor and cognitive abnormalities.
doi:10.1016/j.neulet.2012.02.083
PMCID: PMC3320689  PMID: 22414859
Acetylcholine; [11C] PMP PET; Alzheimer disease; Parkinson disease; PPN; Parkinson disease with dementia
15.  The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI) 
Objective: Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Aβ, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort.
Methods: Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Aβ, tau, and p-tau, and cognitive performance and complaints.
Results: E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not E-MCI diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants. Other effects of APOE ε4 status on cognition and CSF tau levels were also observed.
Conclusions: APOE ε4 status is associated with amyloid accumulation and lower CSF Aβ, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease.
doi:10.3389/fnagi.2013.00011
PMCID: PMC3612590  PMID: 23554593
apolipoprotein E (APOE); early mild cognitive impairment (E-MCI); Florbetapir/AV-45/Amyvid; positron emission tomography (PET); magnetic resonance imaging (MRI); cerebrospinal fluid (CSF); Alzheimer's disease neuroimaging initiative (ADNI)
16.  Leucoaraiosis, nigrostriatal denervation and motor symptoms in Parkinson’s disease 
Brain  2011;134(8):2358-2365.
Leucoaraiosis is associated with motor symptoms in otherwise normal older adults. Comorbid leucoaraiosis is predicted to contribute also to motor features in Parkinson’s disease but previous studies of white matter changes in Parkinson’s disease show variable results. No prior studies have compared directly the effects of both leucoaraiosis and the degree of nigrostriatal dopaminergic denervation on motor features. We investigated the effect of leucoaraiosis severity on motor impairment independent of the degree of nigrostriatal dopaminergic denervation in Parkinson’s disease. Seventy-three subjects with Parkinson’s disease (Hoehn and Yahr stages 1–3) underwent brain magnetic resonance and [11C]dihydrotetrabenazine vesicular monoamine transporter type 2 positron emission tomography imaging. Automated assessment of supratentorial fluid-attenuated inversion recovery magnetic resonance hyperintense white matter voxels was performed using cerebellar white matter as the intensity reference. White matter signal hyperintensity burden was log-transformed and normalized for brain volume. Unified Parkinson’s Disease Rating Scale total and subscore ratings were assessed to determine motor impairment. Subjects receiving dopaminergic medications were examined in the clinically defined ‘OFF’ state. Multivariate regression analysis with measures of white matter signal hyperintensity burden and nigrostriatal denervation as independent variables demonstrated a significant overall model for total motor Unified Parkinson's Disease Rating Scale scores (F = 11.4, P < 0.0001) with significant regression effects for both white matter signal hyperintensity burden (t = 2.0, β = 0.22, P = 0.045) and striatal monoaminergic binding (t = −3.5, β = −0.38, P = 0.0008). Axial motor impairment demonstrated a robust association with white matter signal hyperintensity burden (t = 4.0, β = 0.43, P = 0.0001) compared with striatal monoaminergic binding (t = −2.1, β = 0.22, P = 0.043). White matter signal hyperintensity burden regression effects for bradykinesia had borderline significance. No significant white matter signal hyperintensity burden effects were found for rigidity or tremor subscores. White matter signal hyperintensity burden was significantly higher in the subgroup with postural instability and gait difficulties compared with the tremor-predominant subgroup despite no significant differences in age or duration of disease. These findings indicate that increased white matter signal hyperintensity burden is associated with worse motor performance independent of the degree of nigrostriatal dopaminergic denervation in Parkinson’s disease. Comorbid white matter disease is a greater determinant of axial motor impairment than nigrostriatal dopaminergic denervation.
doi:10.1093/brain/awr139
PMCID: PMC3155702  PMID: 21653540
dopamine; motor; Parkinson’s disease; leucoaraiosis; magnetic resonance imaging; white matter hyperintensities
17.  The Role of Serotonin in Sleep Disordered Breathing Associated with Parkinson Disease: A Correlative [11C]DASB PET Imaging Study 
PLoS ONE  2012;7(7):e40166.
Sleep dysfunction and excessive daytime sleepiness are common in Parkinson disease (PD). Several studies suggest that PD patients exhibit high prevalence of sleep-disordered breathing (SDB). PD has a complex profile of neurochemical deficits in which abnormalities of different neurotransmitter systems may play significant and differing roles in the development of non-motor features. In the present study, we investigated whether SDB in PD is related to serotoninergic neuron degeneration. We used a cross-sectional design to assess the correlation between SDB and measures of caudal brainstem serotonin neuron integrity. Fifty one PD participants with mean disease duration of 6.0 (SD 3.7) years and mean age of 63.9 (SD 6.2) years were studied. We measured caudal brainstem serotoninergic innervation with [11C]DASB positron emission tomography (PET) imaging and striatal dopaminergic innervation with [11C]DTBZ PET imaging. SDB was assessed with polysomnography (PSG) and sleepiness with multiple sleep latency tests. Greater than half of participants exhibited PSG evidence of significant SDB; 12 participants had normal PSGs, 6 had mild SDB, 20 had moderate SDB, and 13 had severe SDB. We found no association between severity of SDB and caudal brainstem serotoninergic innervation in PD participants. Striatal dopaminergic denervation did not correlate with severity of SDB. We did find significant correlations between measures of motor function impairment and sleep quantity and quality in PD. Neither serotoninergic nor dopaminergic neuron degeneration is likely to play a major role in SDB observed in PD patients.
doi:10.1371/journal.pone.0040166
PMCID: PMC3390329  PMID: 22792235
18.  Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI 
Neurobiology of aging  2009;32(7):1207-1218.
The Functional Activities Questionnaire (FAQ) and Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog) are frequently-used indices of cognitive decline in Alzheimer’s disease (AD). The goal of this study was to compare FDG-PET and clinical measurements in a large sample of elderly subjects with memory disturbance. We examined relationships between glucose metabolism in FDG-PET regions of interest (FDG-ROIs), and ADAS-cog and FAQ scores in AD and mild cognitive impairment (MCI) patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Low glucose metabolism at baseline predicted subsequent ADAS-cog and FAQ decline. In addition, longitudinal glucose metabolism decline was associated with concurrent ADAS-cog and FAQ decline. Additionally, a power analysis revealed that FDG-ROI values have greater statistical power than ADAS-cog to detect attenuation of cognitive decline in AD and MCI patients. Glucose metabolism is a sensitive measure of change in cognition and functional ability in AD and MCI, and has value in predicting future cognitive decline.
doi:10.1016/j.neurobiolaging.2009.07.002
PMCID: PMC2891865  PMID: 19660834
FDG-PET; Alzheimer’s disease; Mild Cognitive Impairment
19.  Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography 
Brain  2011;134(6):1647-1657.
We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of aβ-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score ≥ 18) underwent a conventional clinical evaluation followed by 11C-dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical aβ-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ∼35% of subjects (Cohen’s κ = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia.
doi:10.1093/brain/awr089
PMCID: PMC3102241  PMID: 21555336
Alzheimer’s disease; Lewy body dementia; frontotemporal dementia; amyloid; dopamine; diagnosis
20.  Characterizing Alzheimer’s Disease using a Hypometabolic Convergence Index 
NeuroImage  2011;56(1):52-60.
This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer’s disease (AD), compares it to other biological, cognitive and clinical measures, and demonstrate its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual’s fluorodeoxyglucose positron emission tomography (FDG PET) image corresponds to that in probable AD patients, and is generated using a fully automated voxel-based image analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18 months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups (p = 9e-17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCI’s or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, have the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms.
doi:10.1016/j.neuroimage.2011.01.049
PMCID: PMC3066300  PMID: 21276856
hypometabolic convergence index; Alzheimer’s disease; FDG; PET; MCI; hippocampal volume
21.  Amyloid pathway-based candidate gene analysis of [11C]PiB-PET in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort 
Brain Imaging and Behavior  2012;6(1):1-15.
Amyloid imaging with [11C]Pittsburgh Compound-B (PiB) provides in vivo data on plaque deposition in those with, or at risk for, Alzheimer’s disease (AD). We performed a gene-based association analysis of 15 quality-controlled amyloid-pathway associated candidate genes in 103 Alzheimer’s Disease Neuroimaging Initiative participants. The mean normalized PiB uptake value across four brain regions known to have amyloid deposition in AD was used as a quantitative phenotype. The minor allele of an intronic SNP within DHCR24 was identified and associated with a lower average PiB uptake. Further investigation at whole-brain voxel-wise level indicated that non-carriers of the minor allele had higher PiB uptake in frontal regions compared to carriers. DHCR24 has been previously shown to confer resistance against beta-amyloid and oxidative stress-induced apoptosis, thus our findings support a neuroprotective role. Pathway-based genetic analysis of targeted molecular imaging phenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets.
doi:10.1007/s11682-011-9136-1
PMCID: PMC3256261  PMID: 21901424
Alzheimer’s disease; ADNI; Pathway-based gene analysis; PiB-PET; Endophenotype; Voxel-based analysis
22.  Temporoparietal hypometabolism is common in FTLD and is associated with imaging diagnostic errors 
Archives of neurology  2010;68(3):329-337.
Objective
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Design
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Setting
Academic medical centers
Patients
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Results
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Conclusions
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
doi:10.1001/archneurol.2010.295
PMCID: PMC3058918  PMID: 21059987
23.  Rhinorrhea: A common non-dopaminergic feature of Parkinson disease 
We compared the frequency of rhinorrhea between 34 Parkinson disease (PD) subjects and 15 normal controls (NC), and explored relationships between rhinorrhea and clinical functions, and degree of nigrostriatal dopaminergic denervation using 11C-dihydrotetrabenazine (DTBZ) brain positron emission tomography (PET) imaging. 68% (23/34) of PD subjects reported rhinorrhea of any cause compared to 27% (4/15) of NC (χ2=7.07, p=0.008). Rhinorrhea frequency remained higher in the PD group after excluding possible rhinitic etiologies: 35% (12/34) PD versus 7% (1/15) of NC (χ2=4.38, p=0.04). There were no differences in demographics, nigrostriatal dopaminergic denervation, and clinical motor or non-motor variables between PD subjects with and without rhinorrhea, except that more PD subjects with rhinorrhea complained of lightheadedness (52% vs. 9%, χ2=5.85, p=0.02). Rhinorrhea is a common non-dopaminergic feature of PD, unrelated to olfactory or motor deficits. Further investigations are needed to determine if rhinorrhea correlates with sympathetic denervation or other autonomic symptoms in PD.
doi:10.1002/mds.23366
PMCID: PMC3010315  PMID: 20842685
Parkinson disease; rhinorrhea; PET; olfaction; dopamine transporter

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