Diabetes, Gray Matter Loss, and Cognition in the Setting of Parkinson Disease.

RATIONALE AND OBJECTIVES: Parkinson disease (PD) is a progressive neurodegenerative disorder affecting motor and cognitive functions. Prior studies showed that patients with PD and diabetes (DM) demonstrate worse clinical outcomes compared to nondiabetic subjects with PD. Our study aimed at defining the relationship between DM, gray matter volume, and cognition in patients with PD. MATERIALS AND METHODS: This study included 36 subjects with PD (12 with DM, 24 without DM, mean age = 66). Subjects underwent high-resolution T1-weighted brain magnetic resonance imaging, [(11)C]dihydrotetrabenazine positron emission tomography imaging to quantify nigrostriatal dopaminergic denervation, clinical, and cognitive assessments. Magnetic resonance images were postprocessed to determine total and lobar cortical gray matter volumes. Cognitive testing scores were converted to z-scores for specific cognitive domains and a composite global cognitive z-score based on normative data computed. Analysis of covariance, accounting for effects of age, gender, intracranial volume, and striatal [(11)C]dihydrotetrabenazine binding, was used to test the relationship between DM and gray matter volumes. RESULTS: Impact of DM on total gray matter volume was significant (P = 0.02). Post hoc analyses of lobar cortical gray matter volumes revealed that DM was more selectively associated with lower gray matter volumes in the frontal regions (P = 0.01). Cognitive post hoc analyses showed that interaction of total gray matter volume and DM status was significantly associated with composite (P = 0.007), executive (P = 0.02), and visuospatial domain cognitive z-scores (P = 0.005). These associations were also significant for the frontal cortical gray matter. CONCLUSION: DM may exacerbate brain atrophy and cognitive functions in PD with greater vulnerability in the frontal lobes. Given the high prevalence of DM in the elderly, delineating its effects on patient outcomes in the PD population is of importance.

It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder.

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 [(11)C]carfentanil to test the hypothesis that MOR system activation (reflecting endogenous opioid release) in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n=17) compared with healthy controls (HCs, n=18). During rejection, MDD patients showed reduced endogenous opioid release in brain regions regulating stress, mood and motivation, and slower emotional recovery compared with HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with endogenous opioid release in the nucleus accumbens, a reward structure. Altered endogenous opioid activity 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.

APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study.

Deposition of amyloid-ß (Aß) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aß load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aß levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aß load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aß levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aß deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aß burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.

Response of the µ-opioid system to social rejection and acceptance.

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 an µ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography 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 have 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.

Selection of weighting factors for quantification of PET radioligand binding using simplified reference tissue models with noisy input functions.

Input function noise contributes to model-predicted values and should be accounted for during parameter estimation. This problem has been examined in the context of PET data analysis using a noisy image-derived arterial input function. Huesman and Mazoyer (1987 Phys. Med. Biol 32 1569-79) incorporated the effect of error in the measured input function into the objective function and observed a subsequent improvement in the accuracy of parameters estimated from a kinetic model of cardiac blood flow. Such a treatment has not been applied to the reference region models commonly used to analyze dynamic positron emission tomography data with receptor-ligand tracers. Here, we propose a strategy for selection of weighting factors that accounts for noise in the reference region input function and test the method on two common formulations of the simplified reference tissue model (SRTM). We present a simulation study which demonstrates that the proposed weighting approach improves the accuracy of estimated binding potential at high noise levels and when the reference tissue and target regions of interest are of comparable size. In the second simulation experiment, we show that using a small, homogeneous reference tissue with our weighting technique may have advantages over input functions derived from a larger (and thus less noisy), heterogeneous region with conventional weighting. A comparative analysis of clinical [(11)C]flumazenil data found a small but significant increase in estimated binding potential when using the proposed weighting method, consistent with the finding of reduced negative bias in our simulation study. The weighting strategy described here accounts for noise in the reference region input function and may improve the performance of the SRTM in applications where data are noisy and the reference region is relatively small. This technique may offer similar benefits to other models using reference region inputs, particularly those derived from the SRTM.

Cerebral cortical and subcortical cholinergic deficits in parkinsonian syndromes.

OBJECTIVES: Cholinergic projections to cerebral cortical and subcortical regions are decreased in Parkinson disease (PD), but not evaluated in the parkinsonian syndromes of multiple system atrophy (MSA-P) and progressive supranuclear palsy (PSP). We studied cholinergic innervation in these disorders as compared to age-appropriate normal control subjects. METHODS: We used PET with [(11)C]PMP to measure acetylcholinesterase (AChE) activity in multiple cerebral cortical and subcortical regions. We studied 22 normal controls, 12 patients with PD, 13 patients with MSA-P, and 4 patients with PSP. RESULTS: We found significantly decreased AChE activity in most cerebral cortical regions in PD and MSA-P, and a similar but nonsignificant decrease in PSP. No differences were found between PD and MSA-P. Significantly decreased AChE activity was found in PD in striatum, cerebellum, and thalamus, with a marginally significant decrease in mesencephalon and no change in pons. Significantly greater declines in AChE activity in all subcortical regions were seen in MSA-P and PSP vs in PD. Decreased AChE activity in brainstem and cerebellum of all 3 disorders correlated with disturbances of balance and gait. CONCLUSIONS: Cerebral cortical cholinergic activity is decreased to a similar level in Parkinson disease (PD), parkinsonian syndromes of multiple system atrophy (MSA-P), and progressive supranuclear palsy (PSP) as compared to normal controls. Subcortical cholinergic activity is significantly more decreased in MSA-P and PSP than in PD. The more substantial decrease reflects greater impairment in the pontine cholinergic group, which is important in motor activity, particularly gait. These differences may account for the greater gait disturbances in the early stages of MSA-P and PSP than in PD.

History of falls in Parkinson disease is associated with reduced cholinergic activity.

OBJECTIVE: To investigate the relationships between history of falls and cholinergic vs dopaminergic denervation in patients with Parkinson disease (PD). BACKGROUND: There is a need to explore nondopaminergic mechanisms of gait control as the majority of motor impairments associated with falls in PD are resistant to dopaminergic treatment. Alterations in cholinergic neurotransmission in PD may be implicated because of evidence that gait control depends on cholinergic system-mediated higher-level cortical and subcortical processing, including pedunculopontine nucleus (PPN) function. METHODS: In this cross-sectional study, 44 patients with PD (Hoehn & Yahr stages I-III) without dementia and 15 control subjects underwent a clinical assessment and [(11)C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and [(11)C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 (VMAT2) brain PET imaging. RESULTS: Seventeen patients (38.6%) reported a history of falls and 27 patients had no falls. Analysis of covariance of the cortical AChE hydrolysis rates demonstrated reduced cortical AChE in the PD fallers group (-12.3%) followed by the PD nonfallers (-6.6%) compared to control subjects (F = 7.22, p = 0.0004). Thalamic AChE activity was lower only in the PD fallers group (-11.8%; F = 4.36, p = 0.008). There was no significant difference in nigrostriatal dopaminergic activity between PD fallers and nonfallers. CONCLUSIONS: Unlike nigrostriatal dopaminergic denervation, cholinergic hypofunction is associated with fall status in Parkinson disease (PD). Thalamic AChE activity in part represents cholinergic output of the pedunculopontine nucleus (PPN), a key node for gait control. Our results are consistent with other data indicating that PPN degeneration is a major factor leading to impaired postural control and gait dysfunction in PD.

Relationships between biomarkers in aging and dementia.

BACKGROUND: PET imaging using [(18)F]fluorodeoxyglucose (FDG) and [(11)C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid beta-amyloid protein (Abeta(1-42)) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood. METHODS: Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Abeta(1-42), t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as "positive" or "negative" for AD based on cutoffs established in patients with AD and controls from other cohorts. RESULTS: Dichotomous categorization showed substantial agreement between PIB-PET and CSF Abeta(1-42) measures (91% agreement, kappa = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, kappa = 0.50), and minimal agreement for other comparisons (kappa <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Abeta(1-42). Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Abeta(1-42), t-tau, and p-tau(181p), whereas FDG-PET was correlated only with Abeta(1-42). CONCLUSIONS: PET and CSF biomarkers of Abeta agree with one another but are not related to cognitive impairment. [(18)F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.

Striatal [11C]dihydrotetrabenazine and [11C]methylphenidate binding in Tourette syndrome.

OBJECTIVE: Tourette syndrome (TS) is a common neurodevelopmental disorder marked by tics and behavioral comorbidities. Clinical pharmacology suggests that dopaminergic signaling abnormalities are part of the pathophysiology of TS. Prior molecular imaging studies of nigrostriatal dopaminergic terminal markers report conflicting results. Our goal was to characterize the distribution of nigrostriatal dopaminergic terminals in subjects with TS. METHODS: Thirty-three adult subjects with TS were studied with PET using [11C]dihydrotetrabenazine (DTBZ), a ligand for the type 2 vesicular monoamine transporter, and with [11C] methylphenidate (MP), a ligand for the plasmalemmal dopamine transporter. Subjects were characterized with standard rating instruments for tic severity, obsessive-compulsive behaviors, and attentional deficits. RESULTS: We found no differences between subjects with TS and control subjects in DTBZ and MP binding in any striatal region. There was no correlation between binding measures and clinical variables. Ventral striatal DTBZ and MP binding distributions in subjects with TS were normal. CONCLUSIONS: We found no evidence of increased striatal dopaminergic innervation in Tourette syndrome (TS). Discrepancy between our present results and those of other studies may be explained by heterogeneity of TS.

Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects.

Although beta-amyloid (Abeta) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Abeta and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Abeta deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Abeta deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Abeta-induced hippocampus atrophy.

Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease.

OBJECTIVES: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy. METHODS: Cognitive and N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy. RESULTS: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = -7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = -14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R(2) = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = -2.7; p<0.05). CONCLUSIONS: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.

Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis.

A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.

Increased ventral striatal monoaminergic innervation in Tourette syndrome.

BACKGROUND: Excessive striatal dopaminergic innervation is suggested to underlie Tourette syndrome (TS). Prior imaging and postmortem studies yield conflicting data. METHODS: The authors used PET with the type 2 vesicular monoamine transporter ligand [(11)C]dihydrotetrabenazine (DTBZ) to quantify striatal monoaminergic innervation in patients with TS (n = 19) and control subjects (n = 27). Compartmental modeling was used to determine blood to brain ligand transport (K(1)) and tissue to plasma distribution volume (a measure of ligand binding) during continuous infusion of DTBZ. TS data were compared with control data using predefined regions of interest and on a voxel by voxel basis. RESULTS: There were no significant differences in ligand binding or ligand transport between patients with TS and control subjects in the dorsal striatum. With voxel by voxel analysis, there was increased DTBZ binding in the right ventral striatum. CONCLUSIONS: Previously reported differences between patients with TS and control subjects in dorsal striatal dopamine terminal markers may reflect medication-induced regulation of terminal marker expression or be the result of intrinsic differences in striatal dopaminergic synaptic function. Increased right ventral striatal DTBZ binding suggests that abnormal ventral striatal dopaminergic innervation may underlie tics.

REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA.

OBJECTIVE: To explore the neurochemical basis of REM sleep behavior disorder (RBD) in multiple-system atrophy (MSA). METHODS: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of REM atonia loss by the percentage of REM sleep with tonically increased electromyographic (EMG) activity and the percentage of REM sleep with phasic EMG bursts. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was employed to measure the density of striatal monoaminergic terminals and SPECT with (-)-5-[123I]iodobenzovesamicol ([123I]IBVM) to measure the density of 123I]IBVM. RESULTS: Age and gender distributions were similar in patient and normal control groups. The MSA subjects showed decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) and decreased [123I]IBVM binding in the thalamus (p < 0.001). Moreover, in the MSA group, striatal [11C]DTBZ binding was inversely correlated with the severity of REM atonia loss (p = 0.003). Thalamic [123I]IBVM binding, however, was not correlated to the severity of REM atonia loss. CONCLUSION: Decreased nigrostriatal dopaminergic projections may contribute to RBD in MSA.

Obstructive sleep apnea is related to a thalamic cholinergic deficit in MSA.

OBJECTIVE: To explore the neurochemical basis of obstructive sleep apnea (OSA) in multiple-system atrophy (MSA). METHODS: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of OSA using the apnea-hypopnea index during sleep. SPECT with (-)-5-[123I]iodobenzovesamicol ([123I]IBVM) was utilized to measure the density of thalamic cholinergic terminals, which project from the brainstem pedunculopontine and laterodorsal tegmental nuclei. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was also used to measure the density of striatal monoaminergic terminals, which project from the brainstem. Findings in the patient group were compared with data from 12 normal control subjects scanned utilizing [123I]IBVM and 15 normal control subjects utilizing [11C]DTBZ. RESULTS: Age and gender distributions were similar in patient and control groups. The MSA subjects showed decreased [123I]IBVM binding in the thalamus (p < 0.001) and decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) in comparison with the control subjects. In the MSA group, thalamic [123I]IBVM binding was inversely correlated with the severity of OSA (p = 0.011). Striatal [11C]DTBZ binding was not correlated with the severity of OSA (p = 0.19). CONCLUSION: Decreased pontine cholinergic projections may contribute to OSA in MSA.

Patterns of neuropsychological performance in multiple system atrophy compared to sporadic and hereditary olivopontocerebellar atrophy.

Although neuropsychological symptoms are associated with multiple system atrophy (MSA), sporadic olivopontocerebellar atrophy (sOPCA), and dominantly inherited olivopontocerebellar atrophy (dOPCA), the differences between these groups have not been explored. We compared 28 MSA patients on psychiatric rating scales and neuropsychological measures to 67 sOPCA patients, 42 dOPCA patients, and 30 normal controls. Patients with dOPCA, sOPCA, and MSA all exhibited significant deficits on motor-related tasks, as well as relatively mild deficits in cognitive functioning. Patients with MSA had greater neuropsychological dysfunction, particularly in memory and other "higher order" cognitive processes, than patients with either sOPCA or dOPCA.

Dual-[11C]tracer single-acquisition positron emission tomography studies.

The ability to study multiple physiologic processes of the brain simultaneously within the same subject would provide a new means to explore the interactions between neurotransmitter systems in vivo. Currently, examination of two distinct neuropharmacologic measures with positron emission tomography (PET) necessitates performing two separate scans spaced in time to allow for radionuclide decay. The authors present results from a dual-tracer PET study protocol using a single dynamic-scan acquisition where the injections of two tracers are offset by several minutes. Kinetic analysis is used to estimate neuropharmacologic parameters for both tracers simultaneously using a combined compartmental model configuration. This approach results in a large reduction in total study time of nearly 2 hours for carbon-11-labeled tracers. As multiple neuropharmacologic measures are obtained at nearly the same time, interventional protocols involving a pair of dual-tracer scans become feasible in a single PET session. Both computer simulations and actual human PET studies were performed using combinations of three different tracers: [11C]flumazenil, N-[11C]methylpiperidinyl propionate, and [ 11 C]dihydrotetrabenazine. Computer simulations of tracer-injection separations of 10 to 30 minutes showed the feasibility of the approach for separations down to 15 to 20 minutes or less. Dual-tracer PET studies were performed in 32 healthy volunteers using injection separations of 10, 15, or 20 minutes. Model parameter estimates for each tracer were similar to those obtained from previously performed single-injection studies. Voxel-by-voxel parametric images were of good quality for injections spaced by 20 minutes and were nearly as good for 15-minute separations, but were degraded noticeably for some model parameters when injections were spaced by only 10 minutes. The authors conclude that dual-tracer single-scan PET is feasible, yields accurate estimates of multiple neuropharmacologic measures, and can be implemented with a number of different radiotracer pairs.

Imaging the vesicular monoamine transporter.

Quantitative measures of striatal VMAT2 binding sites appear to represent an excellent surrogate of nigrostriatal projection integrity in experimental animal models. Importantly, there does not appear to be a significant effect of dopaminergic drugs or of lesion compensatory effect on the expressed level of VMAT2 binding sites in the striatum. Highly precise and specific measures of human VMAT2 are possible with PET employing the novel tracer (+)11C-DTBZ. This methodology appears particularly suited to the objective measure of PD severity and of its progression. Such measures will be indispensable in the search for disease-modifying effects of PD therapy.