In the neocortex of an aged (26-year-old) rhesus monkey, a small percentage of abnormal neurites within some senile plaques (defined by the presence of amyloid) were immunoreactive for glutamic acid ...decarboxylase. This suggests that gamma-aminobutyric acid-synthesizing neurons may contribute to plaque formation in the aged brain.
Pharmacotherapy is the basis of treatment of Parkinson’s disease and there are effective medications, especially in the early stages. However, a number of possible side effects related to ...antiparkinsonian therapy need to be considered. This chapter describes nonmotor symptoms attributable to antiparkinsonian medication. These include rare but serious side effects such as serotonin syndrome and malignant neuroleptic syndrome. Data on chronic side effects such as ergotrelated fibrosis and cardiac valvulopathy are also reviewed in detail. Furthermore, medicationinduced fluctuation of mood, cognition and perception is exemplified. Lastly, the chapter describes how the disease process and dopamimetic medication contribute to excessive daytime sleepiness and notes advice for patients affected by this condition. A number of tables are included detailing the pharmacological properties and effects of selected dopamimetic drugs.
Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency results in Lesch-Nyhan disease (LND), where affected individuals exhibit a characteristic neurobehavioral disorder that has been ...linked with dysfunction of dopaminergic pathways of the basal ganglia. Since the functions of HPRT, a housekeeping enzyme responsible for recycling purines, have no direct relationships with the dopaminergic pathways, the mechanisms whereby HPRT deficiency affect them remain unknown. The current studies demonstrate that HPRT deficiency influences early developmental processes controlling the dopaminergic phenotype, using several different cell models for HPRT deficiency. Microarray methods and quantitative PCR were applied to 10 different HPRT-deficient (HPRT−) sublines derived from the MN9D cell line. Despite the variation inherent in such mutant sublines, several consistent abnormalities were evident. Most notable were increases in the mRNAs for engrailed 1 and 2, transcription factors known to play a key role in the specification and survival of dopamine neurons. The increases in mRNAs were accompanied by increases in engrailed proteins, and restoration of HPRT reverted engrailed expression towards normal levels, demonstrating a functional relationship between HPRT and engrailed. The functional relevance of the abnormal developmental molecular signature of the HPRT− MN9D cells was evident in impoverished neurite outgrowth when the cells were forced to differentiate chemically. To verify that these abnormalities were not idiosyncratic to the MN9D line, HPRT− sublines from the SK-N-BE(2) M17 human neuroblastoma line were evaluated and an increased expression of engrailed mRNAs was also seen. Over-expression of engrailed occurred even in primary fibroblasts from patients with LND in a manner that suggested a correlation with disease severity. These results provide novel evidence that HPRT deficiency may affect dopaminergic neurons by influencing early developmental mechanisms.
A growing body of evidence supports a prodromal neurodegenerative process preceding the clinical onset of Parkinson's disease (PD). Studies have identified several different prodromal markers that ...may have the potential to predict the conversion from healthy to clinical PD but use considerably different approaches. We systematically reviewed 35 longitudinal studies reporting prodromal PD features and evaluated the methodological quality across 10 different predefined domains. We found limitations in the following domains: PD diagnosis (57% of studies), prodromal marker assessments (51%), temporal information on prodromal markers or PD diagnosis (34%), generalizability of results (17%), statistical methods (accounting for at least age as confounder; 17%), study design (14%), and sample size (9%). However, no limitations regarding drop-out (or bias investigation), or report of inclusion/exclusion criteria or prodromal marker associations were revealed. Lessons learned from these limitations and additional aspects of current prodromal marker studies in PD are discussed to provide a basis for the evaluation of findings and the improvement of future research in prodromal PD. The observed heterogeneity of studies, limitations and analyses might be addressed in future longitudinal studies using a, yet to be established, modular minimal set of assessments improving comparability of findings and enabling data sharing and combined analyses across studies.
Enormous effort is being put into the identification and characterization of symptoms that may be used as predictive and progression markers in Parkinson's disease (PD). An impressive number of PD ...patients and individuals at risk for or in the prodromal stage of PD are currently followed in longitudinal studies; however, there does not exist an overview on the kind of markers evaluated and the assessments used.
Information on the design, sample size, evaluated markers and assessments of 21 studies of the Joint Programme - Neurodegenerative Disease Research BioLoC-PD working group were collected by questionnaire. The studies were classified into at risk/prodromal or clinical PD cohorts. The assessments were grouped into quantitative assessments, investigator-rated assessments, investigator interviews, patient-rated questionnaires and caregiver-rated questionnaires.
Compilation of these data revealed an interesting consensus on evaluated markers, but there was an enormous variability of assessments. Furthermore, there is a remarkable similarity in the markers assessed and evaluation methods applied in the risk/prodromal and clinical PD cohorts.
The inventory of the longitudinal cohorts that are part of the BioLoC-PD consortium reveals that there is a growing consensus on the markers that should be assessed in longitudinal cohort studies in PD. However, controversy still exists on the specific type of assessment. To allow comparison of data and common analyses it will be essential to harmonize scales and assessment outcomes.
Because of the complexity, heterogeneity, and the progressive nature of PD, such predictive and progression markers can only be identified in large cohorts and in studies with a longitudinal design. ......the pivotal combination of data and findings across studies is hampered by the lack of comparability of symptoms/factors that are being assessed and the specific assessments that are being applied. ...a common approach is needed to enable harmonization and combination of data across studies to define and validate predictive and progression markers. ...according to the main research aim of the study, different extension modules can be added. The variability in the choice of the assessments may be explained by a number of different factors: (i) Not all scales/questionnaires are available and validated in all languages. (ii) Study designs vary with regard to outcome variables which influences the choice of assessments. (iii) Some assessments require more resources than others (more time-consuming, more costly or requiring trained staff members), which also influenced the selection and composition of the selected assessment battery. (iv) Advances in knowledge about assessments and biomarkers have led to revision or expansion of assessments after the respective study was initiated. (v) Preference for a specific assessment based on previous experience of the individual researchers involved.
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