Juho Joutsa

Expression profiles and clinical correlations of degradome components in the tumor microenvironment of head and neck squamous cell carcinoma.

Purpose: Head and neck squamous cell carcinomas (HNSCC) are characterized by high morbidity and mortality, largely due to the high invasive and metastatic potential of these tumors, high recurrence rates, and low treatment responses. Proteinases have been implicated in several aspects of tumor growth and metastasis in a broad range of tumors including HNSCC. Experimental Design: Comprehensive expression profiling of proteinases [matrix metalloproteinases (MMPs), A disintegrin and metalloproteinase (ADAMs), and ADAMs with thrombospondin motif (ADAMTSs)] and their inhibitors [tissue inhibitor of metalloproteinases (TIMPs)] was done using quantitative real-time reverse transcription-PCR analysis of a large cohort of tissue samples representing the tumor (n = 83), the invasive margin (n = 41), and the adjacent tissue (n = 41) from 83 HNSCC patients, along with normal tissue controls (n = 13), as well as cell lines established from tumors of 34 HNSCC patients. Results: The results show specifically elevated gene expression of several proteinases, including MMP1, MMP3, MMP10, and MMP13 within tumor tissue and peritumoral adjacent tissue. In addition, the results identify several novel HNSCC-associated proteinases, including ADAM8, ADAM9, ADAM17, ADAM28, ADAMTS1, ADAMTS8, and ADAMTS15. There were also significant differences in proteinase expression based on clinical parameters, i.e., tumor location, grade, and local invasion. MMP13 expression was significantly higher in large (>4 cm) locally invasive tumors (P < 0.05). MMP9 expression was significantly decreased in tumors with regional metastasis, whereas increased expression of ADAM8 was noted in the metastatic tumors (P < 0.001 for both). Conclusions: These findings suggest the HNSCC degradome as a valuable source of diagnostic, predictive, and prognostic molecular markers for these malignant tumors. Clin Cancer Res; 16(7); 2022–35. ©2010 AACR.

Diagnostic accuracy of parkinsonism syndromes by general neurologists

INTRODUCTION Movement disorder specialists can achieve a high level of accuracy when clinically diagnosing parkinsonism syndromes. However, data about the diagnostic accuracy among general neurologists is limited. OBJECTIVES This study investigated the recent diagnostic accuracy of parkinsonism syndromes by general neurologists. METHODS A retrospective examination of 1362 post-mortem cases diagnosed in the years 2000-2012 by neuropathologists was performed. Out of these cases, we identified 111 patients who received a clinical parkinsonism diagnosis during life and 122 patients who received a neuropathological diagnosis of a parkinsonism syndrome post-mortem including 11 incidental cases. RESULTS Fifty-eight (75.3%) of the 77 patients who had received clinical Parkinsons disease (PD) diagnoses were confirmed after the neuropathological examination. The sensitivity of the clinical diagnosis for idiopathic Parkinsons disease (PD) was 89.2% and the specificity was 57.8%. The corresponding numbers for progressive supranuclear palsy (PSP) were 52.9% and 100%, and for multiple system atrophy (MSA) were 64.3% and 99.0%, respectively. CONCLUSIONS Parkinsons disease is heavily overdiagnosed by general neurologists, whereas parkinsonism plus syndromes are underdiagnosed. Despite improvements in the diagnostic methods during recent decades and the development of diagnostic clinical criteria for parkinsonian syndromes, the diagnostic accuracy of Parkinsons disease remains relatively low, and 1/4 of diagnoses are incorrect.

Extensive abnormality of brain white matter integrity in pathological gambling.

Several magnetic resonance imaging (MRI) studies in substance use disorders have shown brain white matter integrity abnormalities, but there are no studies in pathological gambling, a form of behavioral addiction. Our objective was to investigate possible changes in regional brain gray and white matter volumes, and axonal white matter integrity in pathological gamblers compared to healthy controls. Twenty-four subjects (12 clinically diagnosed male pathological gamblers and 12 age-matched healthy male volunteers) underwent structural and diffusion weighted brain MRI scans, which were analyzed with voxel-based morphometry and tract based spatial statistics. In pathological gamblers, widespread lower white matter integrity (lower fractional anisotropy, higher mean diffusivity) was seen in multiple brain regions including the corpus callosum, the cingulum, the superior longitudinal fascicle, the inferior fronto-occipital fascicle, the anterior limb of internal capsule, the anterior thalamic radiation, the inferior longitudinal fascicle and the uncinate/inferior fronto-occipital fascicle. There were no volumetric differences in gray or white matter between pathological gamblers and controls. The results suggest that pathological gambling is associated with extensive lower integrity of several brain white matter tracts. The diffusion abnormality closely resembles previous findings in individuals with substance addictions.

Dopaminergic function and intertemporal choice.

The discounting of delayed rewards, also known as temporal or delay discounting, is intrinsic to everyday decisions and can be impaired in pathological states such as addiction disorders. Preclinical and human studies suggest a role for dopaminergic function in temporal discounting but this relationship has not yet been verified using molecular imaging of the living human brain. Here, we evaluated dopaminergic function in temporal discounting using positron emission tomography (PET) with two different dopaminergic ligands assessing three populations in whom temporal discounting has been shown to be impaired. First, we show using [11C]raclopride PET that in pathological gamblers, greater temporal discounting correlates with decreased ventral striatal binding potential, convergent with translational findings of lower nucleus accumbens D2/D3 receptor density in high-impulsive rodents. Temporal discounting also correlates with lower ventral striatal dopamine release in response to high-reward magnitude suggesting that dopamine-mediated devaluation of larger delayed rewards may drive choice preferences. Second, we show using [18F]fluorodopa PET that in Parkinson’s disease, temporal discounting correlates with greater left caudate dopaminergic terminal function. Finally, in subjects with Parkinson’s disease and dopamine medication-induced behavioral addictions, temporal discounting is further correlated with greater dopaminergic terminal function in the anterior putamen. These findings provide insights into the relationship between striatal dopamine function and temporal discounting, and its potential role in pathological disorders and mechanisms underlying treatment interventions.

Childhood-onset epilepsy five decades later. A prospective population-based cohort study

To study the impact of childhood‐onset epilepsy on a variety of outcomes across the life span.

Increased medial orbitofrontal [18F]fluorodopa uptake in Parkinsonian impulse control disorders

Impulse control disorders (ICDs) occur frequently in PD patients.

Effects of dopamine agonist dose and gender on the prognosis of impulse control disorders in Parkinson's disease

INTRODUCTION Cross-sectional studies have demonstrated that Parkinsons disease patients have an increased risk of impulse control disorders, and that the disorders frequently co-exist with depressive symptoms. There have been no previous large-scale prospective studies investigating predictive and prognostic factors of these disorders. METHODS A population of 290 Parkinsons disease patients was studied at baseline and approximately 15 months later. The same screening methodology was used at both time-points (demographic and medication data together with the Questionnaire for Impulsive-compulsive Disorders in Parkinsons disease and the Beck Depression Inventory). The data was analyzed separating patients with and without impulse control disorders at baseline to obtain clinically useful prognostic factors. RESULTS In patients who had impulse control disorders at baseline (n = 119), high dopamine agonist dose was associated with the presence of disorders at follow-up. Dopamine agonist levodopa equivalent daily dose over 160 mg was significantly associated with impulse control disorders with a positive predictive value of 92.5% (95% confidence interval 79.6%-98.4%). In addition, females had a better prognosis of impulse control disorders compared to males. The development of novel impulse control disorders (no disorder at baseline, disorder at follow-up) was associated with a concurrent increase in depression scores. CONCLUSIONS The results suggest that dopamine agonist dose and gender are associated with the prognosis of impulse control disorders. Symptoms of depression emerge together with novel impulse control disorders in Parkinsons disease.

Dopamine transporter imaging does not predict the number of nigral neurons in Parkinson disease

Objective: To examine possible associations between in vivo brain dopamine transporter SPECT imaging and substantia nigra pars compacta (SNc) neuronal survival in Parkinson disease (PD). Methods: Nigral neuron numbers were calculated for 18 patients (11 patients with neuropathologically confirmed PD) who had been examined with dopamine transporter (DAT) SPECT before death. Correlation analyses between SNc tyrosine hydroxylase (TH)–positive and neuromelanin-containing neuron counts and DAT striatal specific binding ratios (SBRs) were performed with semiquantitative region of interest–based and voxel-based analyses. Results: Mean putamen SBR did not correlate with the number of substantia nigra TH-positive (r = −0.11, p = 0.66) or neuromelanin-containing (r = −0.07, p = 0.78) neurons. Correlations remained clearly nonsignificant when the time interval between SPECT and death was used as a covariate, when the voxel-based analysis was used, and when only patients with PD were included. Conclusions: This cohort study demonstrates that postmortem SNc neuron counts are not associated with striatal DAT binding in PD. These results fit with the theory that there is no correlation between the number of substantia nigra neurons and striatal dopamine after a certain level of damage has occurred. Striatal DAT binding in PD may reflect axonal dysfunction or DAT expression rather than the number of viable neurons.

Effects of aging and gender on striatal and extrastriatal [123I]FP-CIT binding in Parkinson's disease.

To investigate the effects of aging and gender on brain dopamine and serotonin transporter bindings, we analyzed [(123)I]FP-CIT single-photon emission computed tomography scans of 231 Parkinsons disease (PD) patients and 230 controls. An automated region-of-interest-based method (BRASS automated analysis software) was used for striatal regions and a voxel-based method (Statistical Parametric Mapping software, SPM8) for the entire brain. In controls, aging was associated with a decline of 3.6%-4.6% per decade in striatal binding. Multiple extrastriatal regions also showed age-related declines. In PD patients, age-related declines were only observed in the caudate nuclei, thalamus, olfactory, and cingulate cortices with a comparable rate of decline as that in controls. Female subjects had higher caudate nucleus binding compared with males with a similar near-significant difference in the right putamen. The results demonstrate that the aging effect is limited in PD, which is possibly because of disease-related excess variation, and the results do not support the theory of accelerated aging of the dopaminergic system in PD. Women have higher caudate nucleus dopamine transporter binding compared with men in both normal and degenerated dopamine systems.

Dorsal-to-Ventral Shift in Midbrain Dopaminergic Projections and Increased Thalamic/Raphe Serotonergic Function in Early Parkinson Disease

Loss of nigrostriatal neurons leading to dopamine depletion in the dorsal striatum is the pathologic hallmark of Parkinson disease contributing to the primary motor symptoms of the disease. However, Parkinson pathology is more widespread in the brain, affecting also other dopaminergic pathways and neurotransmitter systems, but these changes are less well characterized. This study aimed to investigate the mesencephalic striatal and extrastriatal dopaminergic projections together with extrastriatal serotonin transporter binding in Parkinson disease. Methods: Two hundred sixteen patients with Parkinson disease and 204 control patients (patients without neurodegenerative parkinsonism syndromes and normal SPECT imaging) were investigated with SPECT using the dopamine/serotonin transporter ligand 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) in the clinical setting. The group differences and midbrain correlations were analyzed voxel by voxel over the entire brain. Results: We found that Parkinson patients had lower 123I-FP-CIT uptake in the striatum and ventral midbrain but higher uptake in the thalamus and raphe nuclei than control patients. In patients with Parkinson disease, the correlation of the midbrain tracer uptake was shifted from the putamen to widespread corticolimbic areas. All findings were highly significant at the voxel level familywise error–corrected P value of less than 0.05. Conclusion: Our findings show that Parkinson disease is associated not only with the degeneration of the nigrostriatal dopamine neurotransmission, but also with a parallel shift toward mesolimbic and mesocortical function. Furthermore, Parkinson disease patients seem to have upregulation of brain serotonin transporter function at the early phase of the disease.