The role of phosphodiesterase 4 in excessive daytime sleepiness in Parkinson's disease.

INTRODUCTION: Preclinical studies suggest a link between cAMP/PKA signalling, phosphodiesterase 4 (PDE4) expression and excessive daytime sleepiness (EDS). Here, we investigated in vivo the association between PDE4 expression and EDS in Parkinson's disease (PD) patients using [11C]rolipram PET and MR imaging. METHODS: Eighteen participants, 12 PD and 6 healthy controls, underwent one [11C]rolipram PET and a multi-modal MRI scan. Probabilistic tractography was performed on subjects' diffusion data to functionally parcellate the striatum according with projections to limbic cortical areas. The severity of EDS was assessed using the Epworth Sleepiness Scale (ESS). To assess PDE4 expression in PD patients with EDS, the PD cohort was divided according to the presence (n = 5) or absence (n = 7) of EDS, defined using validated cut-off of score ≥10 on the ESS as score ≥10 on the ESS. RESULTS: PD patients with EDS showed significantly increased [11C]rolipram volume of distribution (VT) in the caudate (P = 0.029), hypothalamus (P = 0.013), hippocampus (P = 0.036) and limbic striatum (P = 0.030) compared to patients without EDS. Furthermore, higher ESS scores correlated with increased [11C]rolipram VT in the caudate (r = 0.77; P = 0.003), hypothalamus (r = 0.84; P = 0.001), hippocampus (r = 0.81; P = 0.001) and limbic subdivisions of the striatum (r = 0.80; P = 0.003). CONCLUSION: Our findings translate into humans preclinical data indicating that EDS is associated with elevated PDE4 in regions regulating sleep. The severity of EDS in PD was associated with elevated PDE4 expression; thus, suggesting a role of PDE4 in the pathophysiology of EDS in PD.

Predict cognitive decline with clinical markers in Parkinson's disease (PRECODE-1).

Over the course of the disease, about 80% of Parkinson's disease patients will develop cognitive impairment. However, predictive factors associated with cognitive decline are still under investigation. Here, we investigated which clinically available markers are predictive of cognitive impairment in a cohort of early drug-naïve Parkinson's disease patients. 294 drug-naïve Parkinson's disease patients, who were cognitively normal at baseline, were recruited from the Parkinson's Progression Markers Initiative. At 36-month follow-up, patients were diagnosed with cognitive impairment according to two levels: Level 1 diagnosis was defined as MoCA < 26 and Level 2 diagnosis was defined as MoCA < 26, alongside an impaired score on at least two neuropsychological tests. Predictive variables with a validated cut-off were divided into normal or abnormal measures, whilst others were divided into normal or abnormal measures based on the decile with the highest power of prediction. At 3 years' follow-up, 122/294 Parkinson's disease (41.5%) patients had cognitive decline. We found that age at Parkinson's disease onset, MDS-UPDRS Part-III, Hopkin's Learning Verbal Test-Revised Recall, Semantic Fluency Test and Symbol Digit Modalities Test were all predictors of cognitive decline. Specifically, age at Parkinson's disease onset, Semantic Fluency Test and symbol Digit Modalities Test were predictors of cognitive decline defined by Level 2. The combination of three abnormal tests, identified as the most significant predictors of cognitive decline, gave a 63.6-86.7% risk of developing cognitive impairment defined by Level 2 and Level 1 criteria, respectively, at 36-month follow-up. Our findings show that these clinically available measures encompass the ability to identify drug-naïve Parkinson's disease patients with the highest risk of developing cognitive impairment at the earliest stages. Therefore, by implementing this in a clinical setting, we can better monitor and manage patients who are at risk of cognitive decline.

Sleep disturbances and gastrointestinal dysfunction are associated with thalamic atrophy in Parkinson's disease.

BACKGROUND: Non-motor symptoms are common aspects of Parkinson's disease (PD) occurring even at the prodromal stage of the disease and greatly affecting the quality of life. Here, we investigated whether non-motor symptoms burden was associated with cortical thickness and subcortical nuclei volume in PD patients. METHODS: We studied 41 non-demented PD patients. Non-motor symptoms burden was assessed using the Non-Motor Symptoms Scale grading (NMSS). Cortical thickness and subcortical nuclei volume analyses were carried out using Free-Surfer. PD patients were divided into two groups according to the NMSS grading: mild to moderate (NMSS: 0-40) and severe (NMSS: ≥ 41) non-motor symptoms. RESULTS: Thalamic atrophy was associated with higher NMSQ and NMSS total scores. The non-motor symptoms that drove this correlation were sleep/fatigue and gastrointestinal tract dysfunction. We also found that PD patients with severe non-motor symptoms had significant thalamic atrophy compared to the group with mild to moderate non-motor symptoms. CONCLUSIONS: Our findings show that greater non-motor symptom burden is associated with thalamic atrophy in PD. Thalamus plays an important role in processing sensory information including visceral afferent from the gastrointestinal tract and in regulating states of sleep and wakefulness.

Dysphagia is associated with presynaptic dopaminergic dysfunction and greater non-motor symptom burden in early drug-naïve Parkinson's patients.

BACKGROUND: The underlying pathophysiology of dysphagia is multifactorial and evidence clarifying the precise mechanisms are scarce. Dysfunction in dopamine-related and non-dopamine-related pathways, changes in cortical networks related with swallowing and peripheral mechanisms have been implicated in the pathogenesis of dysphagia. We aimed at investigating whether dysphagia is associated with presynaptic dopaminergic deficits, faster motor symptom progression and cognitive decline in a population of early drug-naïve patients with Parkinson's disease. METHODS: By exploring the database of Parkinson's Progression Markers Initiative we identified forty-nine early drug-naïve Parkinson's disease patients with dysphagia. Dysphagia was identified with SCOPA-AUT question 1 (answer regularly) and was assessed with MDS-UPDRS Part-II, Item 2.3 (Chewing and Swallowing). We compared Parkinson's disease patients with dysphagia to Parkinson's disease patients without dysphagia, and investigated differences in striatal [123I]FP-CIT single photon emission computed tomography levels. Using Cox proportional hazards analyses, we also evaluated whether dysphagia can predict motor deterioration and cognitive dysfunction. RESULTS: Parkinson's disease patients with dysphagia, harbored a greater deterioration regarding motor and non-motor symptoms and decreased [123I]FP-CIT binding when compared with patients without dysphagia. Higher burden of dysphagia (MDS-UPDRS-II, item 2.3) was correlated with lower [123I]FP-CIT uptakes within the striatum (rs = -0.157; P = 0.002) and the caudate (rs = -0.156; P = 0.002). The presence of dysphagia was not a predictor of motor progression (Hazard ratio [HR]: 1.143, 95% confidence interval [CI]: 0.848-1.541; P = 0.379) or cognitive decline (HR: 1.294, 95% CI: 0.616-2.719; P = 0.496). CONCLUSIONS: Dysphagia is associated with decreased presynaptic dopaminergic integrity within caudate and greater motor and non-motor symptoms burden in early drug-naïve PD.

Comparison of phosphodiesterase 10A and dopamine transporter levels as markers of disease burden in early Parkinson's disease.

BACKGROUND: Recent work has shown loss of phosphodiesterase 10A levels in middle-stage and advanced treated patients with PD, which was associated with motor symptom severity. OBJECTIVES: To assess phosphodiesterase 10A levels in early PD and compare with loss of dopamine transporter as markers of disease burden. METHODS: Seventy-eight subjects were included in this study (17 early de novo, 15 early l-dopa-treated, 24 moderate-advanced l-dopa-treated patients with PD, and 22 healthy controls). All participants underwent [11 C]IMA107 PET, [11 C]PE2I PET, and 3-Tesla MRI scan. RESULTS: Early de novo PD patients showed loss of [11 C]IMA107 and of [11 C]PE2I binding in caudate and putamen (P < 0.001); early l-dopa-treated PD patients showed additional loss of [11 C]IMA107 in the caudate (P < 0.001; annual decline 3.6%) and putamen (P < 0.001; annual decline 2.8%), but loss of [11 C]PE2I only in the putamen (P < 0.001; annual decline 6.8%). Lower [11 C]IMA107 correlated with lower [11 C]PE2I in the caudate (rho = 0.51; P < 0.01) and putamen (rho = 0.53; P < 0.01). Longer disease duration correlated with lower [11 C]IMA107 in the caudate (rho = -0.72; P < 0.001) and putamen (rho = -0.48; P < 0.01), and with lower [11 C]PE2I only in the putamen (rho = -0.65; P < 0.001). Higher burden of motor symptoms correlated with lower [11 C]IMA107 in the caudate (rho = -0.42; P < 0.05) and putamen (rho = -0.41; P < 0.05), and with lower [11 C]PE2I only in the putamen (rho = -0.69; P < 0.001). CONCLUSION: Our findings demonstrate loss of phosphodiesterase 10A levels very early in the course of PD and is associated with the gradual and progressive increase of motor symptoms. Phosphodiesterase 10A imaging shows similar potential with dopamine transporter imaging to follow disease progression. © 2019 International Parkinson and Movement Disorder Society.

Speech difficulties in early de novo patients with Parkinson's disease.

INTRODUCTION: Speech difficulties are a common debilitating feature of Parkinson's disease and we aimed to investigate whether speech difficulties are associated with striatal dopaminergic deficits and faster disease progression. METHODS: Using the Parkinson's Progression Markers Initiative database, 143 early de novo Parkinson's disease patients with speech difficulties were identified and matched 1:1 with 143 Parkinson's disease patients without speech difficulties for age, disease duration and motor symptom severity. We investigated differences in clinical features and striatal [123I]FP-CIT single photon emission computed tomography (SPECT) uptake in Parkinson's disease patients with and without speech difficulties. Cox proportional hazards analysis was carried out to investigate whether speech difficulties were predictive of a faster motor progression and cognitive decline. RESULTS: Speech difficulties were more common in patients with an akinetic-rigid motor phenotype compared to those with a tremor-dominant phenotype. Parkinson's disease patients with speech difficulties had lower resting tremor (P = 0.027), higher autonomic dysfunction (P = 0.034), increased daytime sleepiness (ESS; P = 0.048), and a higher prevalence of REM sleep behaviour disorder (RBD) symptoms (P = 0.007) compared to those without speech difficulties. Parkinson's disease patients with speech difficulties had significantly lower [123I]FP-CIT uptake in the striatum (P < 0.001), caudate (P = 0.003) and putamen (P = 0.003) compared to those without speech difficulties. The presence of speech difficulties was a predictor of cognitive decline [Hazard Ratio (HR): 0.341, 95% Confidence Interval (CI): 0.153-0.759; Wald: 6.945; P = 0.008), whereas it had no influence on motor progression (HR: 0.885, 95% CI: 0.662-1.183; Wald: 0.680; P > 0.10). CONCLUSION: Speech difficulties are associated with greater autonomic dysfunction, sleep disturbances and striatal dopaminergic deficit, and can serve as a predictor of faster cognitive decline in early Parkinson's disease.

Predicting cognitive decline with non-clinical markers in Parkinson's disease (PRECODE-2).

OBJECTIVES: To investigate whether baseline [123I]FP-CIT SPECT and CSF markers can predict cognitive impairment (CI) in PD patients, and provide a profile of those most at risk. METHODS: 262 de novo PD patients from the Parkinson's Progression Markers Initiative database were stratified into two CI groups at the 36-month follow-up: MoCA-defined diagnosis: PD patients who had a MoCA score < 26; neuropsychological test-defined diagnosis: PD patients with MoCA-defined diagnosis and at least two test scores (of six; irrespective of test domain) greater than 1.5 standard deviation below the mean score in healthy controls. Predictive variables of CI were divided into deciles, providing us with ideal cutoff values for each variable. RESULTS: At the 36-month follow-up, 108/262 (41.2%) PD patients had CI as defined by the MoCA, of which 40/108 (37.0%) had neuropsychological test-defined CI. Baseline CSF Aß42 (hazard ratio [HR]: 0.996, confidence interval [CI]: 0.992-0.999, p = 0.025), CSF total tau ([HR]: 1.023, [CI]: 1.002-1.044, p = 0.031) and caudate [123I]FP-CIT SPECT uptake ([HR]: 0.332, [CI]: 0.115-0.960, p = 0.042) were predictors of CI. Patients with reduced CSF Aß42 (< 384.6 pg/mL), increased CSF total tau (> 45.0 pg/mL) and reduced caudate [123I]FP-CIT SPECT uptake (< 1.82) had a 65% risk of developing CI at 36-month follow-up. CONCLUSION: We report a characteristic profile (reduced CSF Aß42, increased CSF total tau and reduced caudate [123I]FP-CIT SPECT uptake) that enables identification of early PD patients at risk of developing CI. These findings confirm previous reports of low CSF Aß42, elevated CSF total tau and reduced dopaminergic integrity being associated with cognitive decline in PD.

Cortical thinning across Parkinson's disease stages and clinical correlates.

BACKGROUND: Imaging studies have revealed cortical thinning and subcortical atrophy occurring in Parkinson's disease (PD); however, the topographical distribution and clinical associations related to advancing stages of PD remains unclear. OBJECTIVE: We aimed to investigate the topographical distribution of cortical and subcortical morphometric changes, and their clinical associations, related to increasing disease severity. METHODS: In this cross-sectional imaging study, T1-weighted structural magnetic resonance imaging data for 80 non-demented PD patients and 30 age-matched healthy controls were analysed using FreeSurfer software suite to derive morphometric changes using whole-brain vertex-wise analysis, and surface-based (cortical) and volume-based (subcortical) parcellation maps. PD patients were divided into three groups of mild (n = 27), moderate (n = 27), and severe (n = 26) PD based disease duration and Hoehn and Yahr and Unified Parkinson's Disease Rating Scale Part-III motor severity scores. RESULTS: Whole-brain vertex-wise analysis revealed cortical thinning in the orbitofrontal cortex in early PD (P = .011), and in the superior frontal (P = .002), caudal middle frontal gyrus (P = .001) and inferior parietal cortex (P = .006) in moderate PD. Severe PD patients showed additional cortical thinning in temporal and occipital cortices (P < .005). Subcortical volume loss was detected in the thalamus (P = .012) and hippocampus (P = .032) in moderate PD, which extended to the caudate (P = .012), putamen (P = .042) and amygdala (P = .008) in severe PD. Increasing disease duration and motor severity scores, correlated with cortical thinning in frontal, temporal, parietal and occipital cortices, and subcortical volumetric loss in the thalamus, caudate, putamen, amygdala and hippocampus. Lower global cognitive status, measured with MMSE, correlated with cortical thinning in temporal, parietal, frontal and cingulate cortices, and with volumetric loss in the hippocampus (r = 0.31; P = .009); suggesting subclinical pathogenic changes occur prior to the onset of cognitive impairment. CONCLUSION: In conclusion, in more severe disease stages PD patients exhibit progressive cortical thinning and subcortical volume loss which could have relevance to the development of cognitive impairment.

Molecular Imaging of the Dopaminergic System in Idiopathic Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic nigrostriatal connections which is recognized as the major pathophysiological event underlying the onset of motor symptoms. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging allow the study of these connections in vivo at a molecular level. Several radiotracers have been developed targeting the synthesis and metabolism of dopamine and dopaminergic receptors to investigate the nigrostriatal pathway in vivo. Molecular imaging has greatly increased our knowledge on the progression and natural history of PD, as well as the development of motor and non-motor symptoms. PET molecular imaging could be a reliable biomarker to aid earlier diagnosis and for monitoring disease progression. Furthermore, PET imaging could be used as outcome measure in the design of clinical trials testing novel pharmacological compounds aiming to slow, and ultimately halt, disease progression.

PDE10A and ADCY5 mutations linked to molecular and microstructural basal ganglia pathology.

BACKGROUND: Striatal cyclic adenosine monophosphate activity modulates movement and is determined from the balance between its synthesis by adenylate cyclase 5 (ADCY5) and its degradation by phosphodiesterase 10A (PDE10A). OBJECTIVE: We assessed the integrity of striatocortical pathways, in vivo, in 2 genetic hyperkinetic disorders caused by ADCY5 and PDE10A mutations. METHODS: We studied 6 subjects with PDE10A and ADCY5 mutations using [11 C]IMA107 PET, [123 I]FP-CIT Single-photon emission computed tomography (SPECT) and multimodal MRI to investigate PDE10A and dopamine transporter availability, neuromelanin-containing neurons, and microstructural white and gray matter changes, respectively. RESULTS: We found that PDE10A and ADCY5 mutations were associated with decreased PDE10A expression in the striatum and globus pallidus, decreased dopamine transporter expression in the striatum, loss of substantia nigra neuromelanin-containing neurons, and microstructural white and gray matter changes within the substantia nigra, striatum, thalamus, and frontoparietal cortices. CONCLUSIONS: Our findings indicate an association between PDE10A and ADCY5 mutations and pre/postsynaptic molecular changes, substantia nigra damage, and white and gray matter changes within the striatocortical pathways. © 2018 International Parkinson and Movement Disorder Society.

Disease-related patterns of in vivo pathology in Corticobasal syndrome.

PURPOSE: To assess disease-related patterns of in vivo pathology in 11 patients with Corticobasal Syndrome (CBS) compared to 20 healthy controls and 33 mild cognitive impairment (MCI) patients due to Alzheimer's disease. METHODS: We assessed tau aggregates with [18F]AV1451 PET, amyloid-ß depositions with [18F]AV45 PET, and volumetric microstructural changes with MRI. We validated for [18F]AV1451 standardised uptake value ratio (SUVRs) against input functions from arterial metabolites and found that SUVRs and arterial-derived distribution volume ratio (DVRs) provide equally robust measures of [18F]AV1451 binding. RESULTS: CBS patients showed increases in [18F]AV1451 SUVRs in parietal (P < 0.05) and frontal (P < 0.05) cortices in the affected hemisphere compared to healthy controls and in precentral (P = 0.008) and postcentral (P = 0.034) gyrus in the affected hemisphere compared to MCI patients. Our data were confirmed at the histopathological level in one CBS patient who underwent brain biopsy and showed sparse tau pathology in the parietal cortex co-localizing with increased [18F]AV1451 signal. Cortical and subcortical [18F]AV45 uptake was within normal levels in CBS patients. In parietal and frontal cortices of the most affected hemisphere we found also grey matter loss (P < 0.05), increased mean diffusivity (P < 0.05) and decreased fractional anisotropy (P < 0.05) in CBS patients compared to healthy controls and MCI patients. Grey matter loss and white matter changes in the precentral gyrus of CBS patients were associated with worse motor symptoms. CONCLUSIONS: Our findings demonstrate disease-related patterns of in vivo tau and microstructural pathology in the absence of amyloid-ß, which distinguish CBS from non-affected individuals and MCI patients.

Diabetes mellitus and Parkinson disease.

OBJECTIVE: To investigate whether diabetes mellitus is associated with Parkinson-like pathology in people without Parkinson disease and to evaluate the effect of diabetes mellitus on markers of Parkinson pathology and clinical progression in drug-naive patients with early-stage Parkinson disease. METHODS: We compared 25 patients with Parkinson disease and diabetes mellitus to 25 without diabetes mellitus, and 14 patients with diabetes mellitus and no Parkinson disease to 14 healthy controls (people with no diabetes mellitus or Parkinson disease). The clinical diagnosis of diabetes mellitus was confirmed by 2 consecutive fasting measurements of serum glucose levels >126 mL/dL. Over a 36-month follow-up period, we then investigated in the population with Parkinson disease whether the presence of diabetes mellitus was associated with faster motor progression or cognitive decline. RESULTS: The presence of diabetes mellitus was associated with higher motor scores (p < 0.01), lower striatal dopamine transporter binding (p < 0.05), and higher tau CSF levels (p < 0.05) in patients with Parkinson disease. In patients with diabetes but without Parkinson disease, the presence of diabetes mellitus was associated with lower striatal dopamine transporter binding (p < 0.05) and higher tau (p < 0.05) and α-synuclein (p < 0.05) CSF levels compared to healthy controls. At the Cox survival analysis in the population of patients with Parkinson disease, the presence of diabetes mellitus was associated with faster motor progression (hazard ratio = 4.521, 95% confidence interval = 1.468-13.926; p < 0.01) and cognitive decline (hazard ratio = 9.314, 95% confidence interval = 1.164-74.519; p < 0.05). CONCLUSIONS: Diabetes mellitus may predispose toward a Parkinson-like pathology, and when present in patients with Parkinson disease, can induce a more aggressive phenotype.

Excessive daytime sleepiness may be associated with caudate denervation in Parkinson disease.

Excessive daytime sleepiness (EDS) is one of the earliest and most common non-motor symptoms of PD, substantially impacting on patient's quality of life. Using the Parkinson's Progression Markers Initiative database, we performed a case-control study to investigate whether dopaminergic deficit is associated with the development of EDS using dopaminergic specific single photon emission computed tomography (SPECT) molecular imaging of dopamine transporters (DAT). We enrolled 84 early de novo PD patients with EDS and 84 without EDS, who were matched for age, gender, age of diagnosis, years of education and disease duration. We assessed and compared semi-quantified [123I]FP-CIT SPECT, and motor and non-motor features among these two groups, alongside exploring the clinical and imaging correlates of EDS and the predictive significance of these markers in the development of EDS. PD patients with EDS had worse non-motor (MDS-UPDRS Part-I, P < 0.001) and motor (MDS-UPRDS Part-II, P = 0.005) experiences of daily living, as well as worse autonomic (SCOPA-AUT, P < 0.0001) and cognitive (MoCA P = 0.05) function, depression (GDS, P = 0.002), and reduced caudate DAT ([123I]FP-CIT, P = 0.024) compared to PD patients without EDS. Lower caudate [123I]FP-CIT values correlated with higher EDS scores (r = -0.192, P = 0.013). Among patients without EDS, 47 PD patients (56%) developed EDS over a median follow-up of 36 months. Cox multivariate analysis, including all clinical and imaging data available, revealed that abnormal caudate [123I]FP-CIT uptake (P = 0.030) and disease duration (P = 0.018) were predictors for the development of EDS. Although our findings indicate that dopaminergic deficits in the caudate may be associated to EDS in patients with PD, the pathophysiological causality is debateable, given that dopamine caudate denervation may covary with dopaminergic involvement at other targets and with non-dopaminergic involvement.

Increased dopaminergic function in the thalamus is associated with excessive daytime sleepiness.

OBJECTIVES/BACKGROUND: Excessive daytime sleepiness (EDS) is a common disorder, which can manifest in isolation or in combination with other neurological or psychiatric disorders. We know relatively little about the mechanisms underlying the development of EDS and the clinical management of patients with EDS remains an unmet need. In this study, we hypothesised that thalamic dopaminergic function would be altered in subjects with EDS and we sought to investigate this by assessing [123I]FP-CIT Single Photon Emission Computed Tomography (SPECT) data, which is a molecular imaging marker of dopamine transporter (DAT). PATIENTS/METHODS: We performed a case-control study using people registered as healthy subjects in the Parkinson's Progression Markers Initiative database. We assessed and compared semi-quantified [123I]FP-CIT-SPECT in two groups of 21 healthy subjects with and without EDS, who were matched for age, gender, years of education and Rapid eyemovement (REM) sleep behaviour disorder (RBD) Questionnaire scores. RESULTS: Our findings show increased thalamic DAT binding in people with EDS compared to matched healthy subjects without EDS. Higher thalamic DAT binding also correlated with worse EDS scores. CONCLUSION: Our findings provide evidence that increased dopaminergic function in the thalamus may mediate excessive daytime sleepiness in humans.

Striatal molecular alterations in HD gene carriers: a systematic review and meta-analysis of PET studies.

BACKGROUND: Over the past years, positron emission tomography (PET) imaging studies have investigated striatal molecular changes in premanifest and manifest Huntington's disease (HD) gene expansion carriers (HDGECs), but they have yielded inconsistent results. OBJECTIVE: To systematically examine the evidence of striatal molecular alterations in manifest and premanifest HDGECs as measured by PET imaging studies. METHODS: MEDLINE, ISI Web of Science, Cochrane Library and Scopus databases were searched for articles published until 7 June 2017 that included PET studies in manifest and premanifest HDGECs. Meta-analyses were conducted with random effect models, and heterogeneity was addressed with I2 index, controlling for publication bias and quality of study. The primary outcome was the standardised mean difference (SMD) of PET uptakes in the whole striatum, caudate and putamen in manifest and premanifest HDGECs compared with healthy controls (HCs). RESULTS: Twenty-four out of 63 PET studies in premanifest (n=158) and manifest (n=191) HDGECs and HCs (n=333) were included in the meta-analysis. Premanifest and manifest HDGECs showed significant decreases in dopamine D2 receptors in caudate (SMD=-1.233, 95% CI -1.753 to -0.713, p<0.0001; SMD=-5.792, 95% CI -7.695 to -3.890, p<0.0001) and putamen (SMD=-1.479, 95% CI -1.965 to -0.992, p<0.0001; SMD=-5.053, 95% CI -6.558 to -3.549, p<0.0001), in glucose metabolism in caudate (SMD=-0.758, 95% CI -1.139 to -0.376, p<0.0001; SMD=-3.738, 95% CI -4.880 to -2.597, p<0.0001) and putamen (SMD=-2.462, 95% CI -4.208 to -0.717, p=0.006; SMD=-1.650, 95% CI -2.842 to -0.458, p<0.001) and in striatal PDE10A binding (SMD=-1.663, 95% CI -2.603 to -0.723, p=0.001; SMD=-2.445, 95% CI -3.371 to -1.519, p<0.001). CONCLUSIONS: PET imaging has the potential to detect striatal molecular changes even at the early premanifest stage of HD, which are relevant to the neuropathological mechanisms underlying the development of the disease.

The serotonergic system in Parkinson's patients with dyskinesia: evidence from imaging studies.

The purpose of review is to review the current status of positron emission tomography (PET) molecular imaging of serotonergic system in Parkinson's patients who experience levodopa-induced (LIDs) and graft-induced dyskinesias (GIDs). PET imaging studies have shown that Parkinson's disease is characterized by progressive loss of dopaminergic and serotonergic neurons. Parkinson's patients who experienced LIDs and GIDs have an aberrant spreading of serotonergic terminals, which lead to an increased serotonergic/dopaminergic terminals ratio within the putamen. Serotonergic terminals convert exogenous levodopa into dopamine in a non-physiological manner and release an abnormal amount of dopamine without an auto-regulatory feedback. This results in higher swings in synaptic levels of dopamine, which leads to the development of LIDs and GIDs. The modulation of serotonergic terminals with 5-HT1A and 5-HT1B receptors agonists partially reduced these motor complications. In vivo PET studies confirmed that abnormal spreading of serotonergic terminals within the putamen has a pivotal role in the development of LIDs and GIDs. However, glutamatergic, adenosinergic, opioid systems, and phosphodiesterases 10A may also play a role in the development of these motor complications. An integrative multimodal imaging approach combining PET and MRI imaging techniques is needed to fully understand the mechanisms underlying the development of LIDs and GIDs.

Be vigilant for dementia in Parkinson's disease.

It is estimated that up to 80% of patients with Parkinson's disease will eventually develop cognitive impairment over the course of their illness. Even at the time of diagnosis, cognitive impairment has been reported in 20-25% of patients. Commonly affected cognitive domains are executive function, visuospatial ability and attention control. In addition, patients with Parkinson's disease dementia may present with deficits in language function and verbal memory. Psychosis may occur in approximately 40% of patients with Parkinson's disease, and is associated with an increased risk of developing cognitive impairment. Studies have shown that patients with Parkinson's disease with a history of visual hallucinations had an increased risk of developing dementia, four to eight years following diagnosis of the disease. Other clinical risk factors associated with cognitive decline in patients with Parkinson's disease include older age of onset, severe motor symptom burden and in particular akinetic-rigid subtype and olfactory dysfunction. Patients with Parkinson's disease who present with symptoms of cognitive decline, behavioural changes or psychotic symptoms should be referred for further investigation.

Loss of phosphodiesterase 4 in Parkinson disease: Relevance to cognitive deficits.

OBJECTIVE: To assess in vivo the expression of phosphodiesterase 4 (PDE4) and its relevance to cognitive symptoms in patients with Parkinson disease (PD) using [11C]rolipram PET. METHODS: We studied 12 levodopa-treated patients with PD with no concurrent diagnosis of mild cognitive impairment or dementia. Their data were compared with those from 12 healthy controls. All participants underwent neuropsychiatric and cognitive assessment using the Cambridge Neuropsychological Test Automated Battery. Parametric images of [11C]rolipram volume of distribution (VT) values were determined with the Logan plot. RESULTS: Patients with PD performed worse than healthy controls in cognitive examinations assessing psychomotor speed, episodic memory, and spatial working memory and executive function. Patients with PD showed reductions in [11C]rolipram VT compared to healthy controls, in the caudate (28%), thalamus (23%), hypothalamus (32%), and cortex (16%). Within thalamic subregions, [11C]rolipram VT values in patients with PD were decreased by 12%-32%, with most marked decreases observed in prefrontal and temporal thalamic nuclei, whereas motor nuclei were less affected. Within the cortex, [11C]rolipram VT values in patients with PD were decreased by 11%-20%, with most marked decreases observed in posterior dorsolateral frontal cortex, medial frontal cortex, and supplementary motor area, whereas orbitofrontal cortex was less affected. Worse performance in spatial working memory correlated with lower [11C]rolipram VT values in posterior dorsolateral frontal cortex, medial frontal cortex, supplementary motor area, precentral gyrus, caudate, and prefrontal thalamic nuclei. CONCLUSIONS: Our findings demonstrate loss of PDE4 expression in the striato-thalamo-cortical circuit, which is associated with deficits of spatial working memory in patients with PD.

PET image reconstruction using multi-parametric anato-functional priors.

In this study, we investigate the application of multi-parametric anato-functional (MR-PET) priors for the maximum a posteriori (MAP) reconstruction of brain PET data in order to address the limitations of the conventional anatomical priors in the presence of PET-MR mismatches. In addition to partial volume correction benefits, the suitability of these priors for reconstruction of low-count PET data is also introduced and demonstrated, comparing to standard maximum-likelihood (ML) reconstruction of high-count data. The conventional local Tikhonov and total variation (TV) priors and current state-of-the-art anatomical priors including the Kaipio, non-local Tikhonov prior with Bowsher and Gaussian similarity kernels are investigated and presented in a unified framework. The Gaussian kernels are calculated using both voxel- and patch-based feature vectors. To cope with PET and MR mismatches, the Bowsher and Gaussian priors are extended to multi-parametric priors. In addition, we propose a modified joint Burg entropy prior that by definition exploits all parametric information in the MAP reconstruction of PET data. The performance of the priors was extensively evaluated using 3D simulations and two clinical brain datasets of [18F]florbetaben and [18F]FDG radiotracers. For simulations, several anato-functional mismatches were intentionally introduced between the PET and MR images, and furthermore, for the FDG clinical dataset, two PET-unique active tumours were embedded in the PET data. Our simulation results showed that the joint Burg entropy prior far outperformed the conventional anatomical priors in terms of preserving PET unique lesions, while still reconstructing functional boundaries with corresponding MR boundaries. In addition, the multi-parametric extension of the Gaussian and Bowsher priors led to enhanced preservation of edge and PET unique features and also an improved bias-variance performance. In agreement with the simulation results, the clinical results also showed that the Gaussian prior with voxel-based feature vectors, the Bowsher and the joint Burg entropy priors were the best performing priors. However, for the FDG dataset with simulated tumours, the TV and proposed priors were capable of preserving the PET-unique tumours. Finally, an important outcome was the demonstration that the MAP reconstruction of a low-count FDG PET dataset using the proposed joint entropy prior can lead to comparable image quality to a conventional ML reconstruction with up to 5 times more counts. In conclusion, multi-parametric anato-functional priors provide a solution to address the pitfalls of the conventional priors and are therefore likely to increase the diagnostic confidence in MR-guided PET image reconstructions.