ABSTRACT
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognized for its association with dementia. AIMS: This study investigated clinical and neuropathological differences between DLB and PDD. METHODS: 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. RESULTS: CAA was more common in DLB than in PDD (P = 0.003). The severity of CAA was greater in DLB than in PDD (P = 0.009), with significantly higher CAA scores in the parietal lobe (P = 0.043), and the occipital lobe (P = 0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. CONCLUSIONS: This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.
Subject(s)
Alzheimer Disease/pathology , Dementia/pathology , Lewy Bodies/pathology , Lewy Body Disease/pathology , Aged , Brain/pathology , Cerebral Amyloid Angiopathy/pathology , Female , Humans , Male , Middle Aged , Parkinson Disease/pathologyABSTRACT
AIMS: There is evidence that accumulation of α-synuclein (α-syn) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) results from impaired removal of α-syn rather than its overproduction. Kallikrein-6 (KLK6), calpain-1 (CAPN1) and cathepsin-D (CTSD) are among a small number of proteases that cleave α-syn and are dysregulated in PD and DLB. Our aim in this study was to determine whether protease activity is altered in another α-synucleinopathy, multiple system atrophy (MSA), and might thereby modulate the regional distribution of α-syn accumulation. METHODS: mRNA and protein level and/or activity of KLK6, CAPN1 and CTSD were measured and assessed in relation to α-syn load in multiple brain regions (posterior frontal cortex, caudate nucleus, putamen, occipital cortex, pontine base and cerebellar white matter), in MSA (n = 20) and age-matched postmortem control tissue (n = 20). RESULTS: CTSD activity was elevated in MSA in the pontine base and cerebellar white matter. KLK6 and CAPN1 levels were elevated in MSA in the putamen and cerebellar white matter. However, the activity or level of these proteolytic enzymes did not correlate with the regional distribution of α-syn. CONCLUSIONS: Accumulation of α-syn in MSA is not due to reduced activity of the proteases we have studied. We suggest that their upregulation is likely to be a compensatory response to increased α-syn in MSA.
Subject(s)
Calpain/metabolism , Cathepsin D/metabolism , Kallikreins/metabolism , Lewy Body Disease/metabolism , Multiple System Atrophy/metabolism , Aged , Aged, 80 and over , Brain/metabolism , Female , Humans , Male , Middle Aged , Parkinson Disease/metabolism , Synucleinopathies/metabolismABSTRACT
BACKGROUND: The anatomy of the substantia nigra on conventional MRI is controversial. Even using histological techniques it is difficult to delineate with certainty from surrounding structures. We sought to define the anatomy of the SN using high field spin-echo MRI of pathological material in which we could study the anatomy in detail to corroborate our MRI findings in controls and Parkinson's disease and progressive supranuclear palsy. METHODS: 23 brains were selected from the Queen Square Brain Bank (10 controls, 8 progressive supranuclear palsy, 5 Parkinson's disease) and imaged using high field 9.4 Tesla spin-echo MRI. Subsequently brains were cut and stained with Luxol fast blue, Perls stain, and immunohistochemistry for substance P and calbindin. Once the anatomy was defined on histology the dimensions and volume of the substantia nigra were determined on high field magnetic resonance images. RESULTS: The anterior border of the substantia nigra was defined by the crus cerebri. In the medial half it was less distinct due to the deposition of iron and the interdigitation of white matter and the substantia nigra. The posterior border was flanked by white matter bridging the red nucleus and substantia nigra and seen as hypointense on spin-echo magnetic resonance images. Within the substantia nigra high signal structures corresponded to confirmed nigrosomes. These were still evident in Parkinson's disease but not in progressive supranuclear palsy. The volume and dimensions of the substantia nigra were similar in Parkinson's disease and controls, but reduced in progressive supranuclear palsy. CONCLUSIONS: We present a histologically validated anatomical description of the substantia nigra on high field spin-echo high resolution magnetic resonance images and were able to delineate all five nigrosomes. In accordance with the pathological literature we did not observe changes in the nigrosome structure as manifest by volume or signal characteristics within the substantia nigra in Parkinson's disease whereas in progressive supranuclear palsy there was microarchitectural destruction.
Subject(s)
Aging/pathology , Brain Diseases/diagnostic imaging , Brain Diseases/pathology , Magnetic Resonance Imaging/methods , Substantia Nigra/diagnostic imaging , Substantia Nigra/pathology , Tissue Banks , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle AgedABSTRACT
Using conventional MRI the subthalamic nucleus (STN) is not clearly defined. Our objective was to define the anatomy of the STN using 9.4 T MRI of post mortem tissue with histological validation. Spin-echo (SE) and 3D gradient-echo (GE) images were obtained at 9.4 T in 8 post mortem tissue blocks and compared directly with corresponding histological slides prepared with Luxol Fast Blue/Cresyl Violet (LFB/CV) in 4 cases and Perl stain in 3. The variability of the STN anatomy was studied using internal reference points. The anatomy of the STN and surrounding structures was demonstrated in all three anatomical planes using 9.4 T MR images in concordance with LFB/CV stained histological sections. Signal hypointensity was seen in 6/8 cases in the anterior and medial STN that corresponded with regions of more intense Perl staining. There was significant variability in the volume, shape and location of the borders of the STN. Using 9.4 T MRI, the internal signal characteristics and borders of the STN are clearly defined and significant anatomical variability is apparent. Direct visualisation of the STN is possible using high field MRI and this is particularly relevant, given its anatomical variability, for planning deep brain stimulation.
Subject(s)
Magnetic Resonance Imaging/methods , Subthalamic Nucleus/anatomy & histology , Aged , Aged, 80 and over , Cadaver , Coloring Agents , Echo-Planar Imaging , Female , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , Paraffin Embedding , Reproducibility of Results , Stereotaxic Techniques , Subthalamic Nucleus/pathology , Tissue FixationABSTRACT
The use of dried blood spots (DBS) in preclinical studies has seen an enormous increase over the past two years. Despite its positive impact on the 3Rs (reduce, replace and refine), its uptake in exploratory drug discovery has been limited due mainly to protracted method development time in bioanalysis but also the need for small volumes (<20 µL) to be sampled manually. Automatic blood sampling technology such as the DiLab(®) AccuSampler(®) is widely used in drug discovery to facilitate exploratory rodent-based pharmacokinetic and pharmacokinetic/pharmacodynamic studies with minimal animal handling. Propranolol was orally administered to a Han-Wistar rat attached to either a standard DiLab(®) AccuSampler(®) or a retrofitted unit designed to directly collect the DBS samples. In all, 50 or 20 µL blood samples were then collected via the standard or retrofitted unit, respectively, at six timepoints over a 7 h period. After drying and storage the DBS samples were analysed for propranolol via liquid chromatography-mass spectrometry. In this report we demonstrate that a standard DiLab(®) AccuSampler(®) can be easily retrofitted to facilitate automatic dried blood spot sampling and that time-concentration data generated from these samples are equivalent to that from manually spotted samples.
Subject(s)
Blood Chemical Analysis/methods , Blood Specimen Collection , Drug Discovery/methods , Propranolol/blood , Animals , Blood Specimen Collection/instrumentation , Blood Specimen Collection/methods , Chromatography, Liquid/methods , Desiccation , Male , Mass Spectrometry/methods , Propranolol/pharmacokinetics , Rats , Rats, Wistar , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
A composite measure is one way of incorporating an assessment of all relevant clinical outcomes into one single measure. By definition it incorporates several dimensions of disease status often by combining these different domains into a single score. Such instruments are well established in rheumatoid arthritis (RA), and these RA-specific measures have successfully been adopted for use in clinical trials involving patients with psoriatic arthritis (PsA). However, the need for a more PsA-specific composite measure has led to a number of proposals, which, for the large part, incorporate only peripheral articular disease activity. New indices that combine the diverse clinical manifestations of PsA are now under development. These issues were discussed at the 2009 annual meeting of GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) in Stockholm, Sweden, and are summarized here.
Subject(s)
Arthritis, Psoriatic/drug therapy , Arthritis, Psoriatic/pathology , Arthritis, Psoriatic/physiopathology , Congresses as Topic , Severity of Illness Index , Humans , Treatment OutcomeABSTRACT
OBJECTIVE: Increasing research interest and emerging new therapies for treatment of fibromyalgia (FM) have led to a need to develop a consensus on a core set of outcome measures that should be assessed and reported in all clinical trials, to facilitate interpretation of the data and understanding of the disease. This aligns with the key objective of the Outcome Measures in Rheumatology (OMERACT) initiative to improve outcome measurement through a data driven, interactive consensus process. METHODS: Through patient focus groups and Delphi processes, working groups at previous OMERACT meetings identified potential domains to be included in the core data set. A systematic review has shown that instruments measuring these domains are available and are at least moderately sensitive to change. Most instruments have been validated in multiple languages. This pooled analysis study aims to develop the core data set by analyzing data from 10 randomized controlled trials (RCT) in FM. RESULTS: Results from this study provide support for the inclusion of the following in the core data set: pain, tenderness, fatigue, sleep, patient global assessment, and multidimensional function/health related quality of life. Construct validity was demonstrated with outcome instruments showing convergent and divergent validity. Content and criterion validity were confirmed by multivariate analysis showing R square values between 0.4 and 0.6. Low R square value is associated with studies in which one or more domains were not assessed. CONCLUSION: The core data set was supported by high consensus among attendees at OMERACT 9. Establishing an international standard for RCT in FM should facilitate future metaanalyses and indirect comparisons.
Subject(s)
Consensus , Fibromyalgia/therapy , Outcome Assessment, Health Care/standards , Randomized Controlled Trials as Topic/standards , Cognition Disorders/physiopathology , Delphi Technique , Fatigue/physiopathology , Fibromyalgia/physiopathology , Fibromyalgia/psychology , Humans , International Cooperation , Outcome Assessment, Health Care/methods , Pain/physiopathology , Reproducibility of Results , SyndromeABSTRACT
There have been steady efforts to develop a combined response index for systemic sclerosis (CRISS). A parallel and equally successful effort has been made by an Expert Panel on Outcome Measures in PAH related to Systemic Sclerosis (EPOSS) to measure effect in treatment of pulmonary arterial hypertension of systemic sclerosis (PAH-SSc). CRISS conducted a Delphi process combined with expert review to identify 11 candidate domains for inclusion in a core set of outcomes for SSc clinical trials: soluble biomarkers, cardiac, digital ulcers, gastrointestinal, global health, health related quality of life (HRQOL) and function, musculoskeletal, pulmonary, Raynaud's, renal, and skin. Tools within domains were also agreed upon. Concentrating on one aspect of disease, PAH, EPOSS also conducted a Delphi process and judged the following domains as the most appropriate for randomized controlled trials in PAH-SSc: lung vascular/pulmonary arterial pressure, cardiac function, exercise testing; severity of dyspnea, discontinuation of treatment; quality of life/activities of daily living; global state; and survival. Possible useful tools within each domain were also agreed on. Patient derived, physician derived, and objective measures of response will be included and combined with the idea that each reflects different aspects of PAH (EPOSS) and overall disease (CRISS) although this assumption may not prove true and can be separated if statistically and clinically valid to do so. In either case, prospective studies will require measurement of all domains, and tools are required and will be developed to define appropriate combined measures of response. CRISS and EPOSS are being developed through the OMERACT process. Through Delphi process and literature review significant progress has been made for both indices, and prospective data are being collected.
Subject(s)
Clinical Trials as Topic/standards , Hypertension, Pulmonary/therapy , Outcome Assessment, Health Care/standards , Scleroderma, Systemic/therapy , Severity of Illness Index , Consensus , Delphi Technique , Disability Evaluation , Humans , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/psychology , Quality of Life , Scleroderma, Systemic/physiopathology , Scleroderma, Systemic/psychology , Treatment OutcomeABSTRACT
The objective of the module was to (1) establish a core domain set for fibromyalgia (FM) assessment in clinical trials and practice, (2) review outcome measure performance characteristics, (3) discuss development of a responder index for assessment of FM in clinical trials, (4) review objective markers, (5) review the domain of cognitive dysfunction, and (6) establish a research agenda for outcomes research. Presentations at the module included: (1) Results of univariate and multivariate analysis of 10 FM clinical trials of 4 drugs, mapping key domains identified in previous patient focus group: Delphi exercises and a clinician/researcher Delphi exercise, and breakout discussions to vote on possible essential domains and reliable measures; (2) Updates regarding outcome measure status; (3) Update on objective markers to measure FM disease state; and (4) Review of the issue of cognitive dysfunction (dyscognition) in FM. Consensus was reached as follows: (1) Greater than 70% of OMERACT participants agreed that pain, tenderness, fatigue, patient global, multidimensional function and sleep disturbance domains should be measured in all FM clinical trials; dyscognition and depression should be measured in some trials; and stiffness, anxiety, functional imaging, and cerebrospinal fluid biomarkers were identified as domains of research interest. (2) FM domain outcome measures have generally proven to be reliable, discriminative, and feasible. More sophisticated and comprehensive measures are in development, as is a responder index for FM. (3) Increasing numbers of objective markers are being developed for FM assessment. (4) Cognitive dysfunction assessment by self-assessed and applied outcome measures is being developed. In conclusion, a multidimensional symptom core set is proposed for evaluation of FM in clinical trials. Research on improved measures of single domains and composite measures is ongoing.
Subject(s)
Clinical Trials as Topic/standards , Fibromyalgia/therapy , International Cooperation , Delphi Technique , Fibromyalgia/physiopathology , Fibromyalgia/psychology , Humans , Outcome Assessment, Health Care , SyndromeABSTRACT
OMERACT began work over a decade ago on a consensus effort to identify optimal outcome measures for knee and hip osteoarthritis clinical trials. Recent evidence indicates extensive variation in outcome measures used in clinical trials of knee and hip arthroplasty published since 2000. This heterogeneity leads to confusion, not only for conducting systematic reviews but also for applying evidence to clinical practice. Given the extensive psychometric research conducted in the past 2 decades, the timing seems ideal to design and implement a study to develop consensus on optimal outcome measures for hip and knee arthroplasty trials. We describe a Delphi survey design and an approach for synthesizing the extensive psychometric literature on the outcome measures used in hip and knee arthroplasty trials. Plans for dissemination of the findings are also discussed. This proposed study could have an important influence on the design and reporting of future randomized trials of knee arthroplasty.
Subject(s)
Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Outcome Assessment, Health Care , Humans , Osteoarthritis, Hip/psychology , Osteoarthritis, Hip/surgery , Osteoarthritis, Knee/psychology , Osteoarthritis, Knee/surgery , Psychometrics , Treatment OutcomeABSTRACT
Worker productivity is a combination of time off work (absenteeism) due to an illness and time at work but with reduced levels of productivity while at work (also known as presenteeism). Both can be gathered with a focus on application as a cost indicator and/or as an outcome state for intervention studies. We review the OMERACT worker productivity groups' progress in evaluating measures of worker productivity for use in arthritis using the OMERACT filter. Attendees at OMERACT 9 strongly endorsed the importance of work as an outcome in arthritis. Consensus was reached (94% endorsement) for fielding a broader array of indicators of absenteeism. Twenty-one measures of at-work productivity loss, ranging from single item indicators to multidimensional scales, were reviewed for measurement properties. No set of at-work productivity measures was endorsed because of variability in the concepts captured, and the need for a better framework for the measurement of worker productivity that also incorporates contextual issues such as job demands and other paid and unpaid life responsibilities. Progress has been made in this area, revealing an ambivalent set of results that directed us back to the need to further define and then contextualize the measurement of worker productivity.
Subject(s)
Arthritis , Efficiency , Outcome Assessment, Health Care/standards , Workload/standards , Arthritis/physiopathology , Arthritis/psychology , Health Status Indicators , Humans , Models, Theoretical , PsychometricsABSTRACT
Due to mounting concern about determination of benefit and risk in the context of product development and clinical practice the OMERACT Executive identified the need to bring together a variety of specialists to define risk. At the Drug Safety Summit held at OMERACT 9, specialists spoke on their given topics and the group considered risk in the context of formally posed questions.
Subject(s)
Antirheumatic Agents/therapeutic use , Drug-Related Side Effects and Adverse Reactions , Rheumatic Diseases/drug therapy , Antirheumatic Agents/adverse effects , Drug Discovery , Humans , Risk AssessmentABSTRACT
There is great concern about clearly defining benefit and risk in the context of both drug development and clinical practice. In view of this pressure, the OMERACT Executive identified the need to bring together clinical trialists, pharmacoepidemiologists, clinicians, clinical epidemiologists, statistical experts, and regulatory representatives to discuss different approaches to define risk and perhaps improved ways to express it. Each attendee spoke on a given topic and the group was charged to consider the issue of risk in the context of formally posed questions. This article provides a summary of the presentations and outlines the discussions that followed.
Subject(s)
Antirheumatic Agents/therapeutic use , Drug-Related Side Effects and Adverse Reactions , Rheumatic Diseases/drug therapy , Antirheumatic Agents/adverse effects , Biomedical Research , Humans , Pharmacoepidemiology , Product Surveillance, Postmarketing , Randomized Controlled Trials as Topic , Registries , Risk AssessmentABSTRACT
Previously reported data on 5 computer-based programs for measurement of joint space width focusing on discriminating ability and reproducibility are updated, showing new data. Four of 5 different programs for measuring joint space width were more discriminating than observer scoring for change in narrowing in the 12 months interval. Three of 4 programs were more discriminating than observer scoring for the 0-18 month interval. The program that failed to discriminate in the 0-12 month interval was not the same program that failed in the 0-18 month interval. The committee agreed at an interim meeting in November 2007 that an important goal for computer-based measurement programs is a 90% success rate in making measurements of joint pairs in followup studies. This means that the same joint must be measured in images of both timepoints in order to assess change over time in serial radiographs. None of the programs met this 90% threshold, but 3 programs achieved 85%-90% success rate. Intraclass correlation coefficients for assessing change in joint space width in individual joints were 0.98 or 0.99 for 4 programs. The smallest detectable change was < 0.2 mm for 4 of the 5 programs, representing 29%-36% of the change within the 99th percentile of measurements.
Subject(s)
Arthritis/diagnostic imaging , Arthrography/methods , Arthrography/standards , Image Processing, Computer-Assisted/methods , Image Processing, Computer-Assisted/standards , Humans , Reproducibility of Results , Software/standardsABSTRACT
OBJECTIVE: Traditional outcome measures in randomized controlled trials (RCT) include well-established response criteria as well as ACR EULAR responses using Disease Activity Score 44 (DAS44)/DAS28 to assess improvement; however, a measure to assess worsening of disease has yet to be developed. This special interest group (SIG) was established to develop an evidence-based, consensus-driven standard definition of "flare" in rheumatoid arthritis (RA). METHODS: At OMERACT 8, the need for a standardized definition of RA flare was recognized; interested individuals developed a proposal to form a SIG. A literature review was performed to identify publications and abstracts with flare definitions applied in RA, JIA, and lupus RCT as well as concerning patient perspectives on disease worsening. A SIG was held at OMERACT 9 with breakout sessions for patients and investigators. RESULTS: The RA flare SIG was attended by about 120 participants, including 11 patients. Patients and investigators held separate breakout sessions to discuss various aspects of disease worsening. The following consensus was obtained at OMERACT 9: a working definition of flare should indicate worsening of disease activity (88%), persistence, and duration as critical elements (77%), and consideration of change or increase in therapy (74%). CONCLUSION: A working definition of RA flare was developed based on these votes: flare is any worsening of disease activity that would, if persistent, in most cases lead to initiation or change of therapy; and a flare represents a cluster of symptoms of sufficient duration and intensity to require initiation, change, or increase in therapy. Using this working definition, evaluation of candidate domains will be conducted via Delphi exercise and further informed by patient focus groups. Validation of candidate definitions in appropriate RCT will be required.
Subject(s)
Arthritis, Rheumatoid/diagnosis , Consensus , Outcome Assessment, Health Care/standards , Severity of Illness Index , Arthritis, Rheumatoid/physiopathology , Consensus Development Conferences as Topic , Evidence-Based Medicine , Humans , Randomized Controlled Trials as Topic/standardsABSTRACT
OBJECTIVE: To assess prevention of bone mineral density (BMD) loss and durability of the response during treatment with prasterone in women with systemic lupus erythematosus (SLE) receiving chronic glucocorticoids. METHODS: 155 patients with SLE received 200 mg/day prasterone or placebo for 6 months in a double-blind phase. Subsequently, 114 patients were re-randomized to receive 200 or 100 mg/day prasterone for 12 months in an open-label phase. Primary efficacy endpoints were changes in BMD at the lumbar spine (L-spine) from baseline to Month 6 and maintenance of BMD from Month 6 to 18 for patients who received prasterone during the double-blind phase. RESULTS: In the double-blind phase, there was a trend for a small gain in BMD at the L-spine for patients who received 200 mg/day prasterone for 6 months versus a loss in the placebo group (mean +/- SD, 0.003 +/- 0.035 vs -0.005 +/- 0.053 g/cm(2), respectively; p = 0.293 between groups). In the open-label phase, there was dose-dependent increase in BMD at the L-spine at Month 18 between patients who received 200 versus 100 mg/day prasterone (p = 0.021). For patients who received 200 mg/day prasterone for 18 months, the L-spine BMD gain was 1.083 +/- 0.512% (p = 0.042). There was no overall change in BMD at the total hip over 18 months with 200 mg/day prasterone treatment. The safety profile reflected the weak androgenic properties of prasterone. CONCLUSION: This study suggests prasterone 200 mg/day may offer mild protection against bone loss in women with SLE receiving glucocorticoids. (ClinicalTrials.gov Identifiers NCT00053560 and NCT00082511).
Subject(s)
Bone Density Conservation Agents/administration & dosage , Dehydroepiandrosterone/administration & dosage , Glucocorticoids/adverse effects , Lupus Erythematosus, Systemic/drug therapy , Osteoporosis/prevention & control , Adult , Bone Density/drug effects , Bone Density Conservation Agents/adverse effects , Dehydroepiandrosterone/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Middle Aged , Osteoporosis/chemically induced , PostmenopauseABSTRACT
BACKGROUND: Idiopathic adult-onset primary dystonia usually affects the upper body and remains focal. Underlying mechanisms are unknown, and there are only limited neuropathologic studies in the literature. Recently, ubiquitinated perinuclear inclusion bodies were found in the brainstem of patients with DYT1-related dystonia. In X-linked recessive dystonia-parkinsonism, neuronal loss in the striosome compartment of the striatum has been described. However, it was unclear whether these changes are characteristic of these particular disorders or an epiphenomenon of dystonic conditions in general. METHODS: Six cases of adult-onset dystonia and four controls were studied using immunohistochemistry to determine the presence of inclusion bodies immunoreactive for torsinA, ubiquitin, and laminA/C in the brainstem. The distribution of calcineurin expressing neurons in the striatum was also determined to ascertain whether there is loss of neurons in the striosome compartment. RESULTS: In contrast to early-onset dystonia, neuronal inclusions immunoreactive for torsinA, ubiquitin, and laminA/C were not present in the brainstem nuclei. There was no apparent loss of the striatal striosome compartment. CONCLUSION: Our findings suggest that the underlying mechanism in the adult-onset primary torsion dystonia is different from that of early-onset DYT1-related dystonia and also DYT3 X-linked recessive dystonia-parkinsonism. Alternative mechanisms may underpin the pathophysiology of adult-onset primary dystonia.
Subject(s)
Brain Stem/pathology , Dystonic Disorders/pathology , Adult , Aged , Aged, 80 and over , Corpus Striatum/pathology , Dystonic Disorders/diagnosis , Female , Humans , Immunoenzyme Techniques , Inclusion Bodies/pathology , Laminin/analysis , Male , Molecular Chaperones/analysis , Ubiquitin/analysisABSTRACT
Testosterone (T) induces singing behavior and mediates changes in the sizes and neuroanatomical characteristics of brain regions controlling singing behavior (song control regions, SCRs) in songbirds. These effects may require the enzymatic conversion of T into androgenic and estrogenic metabolites by brain tissues and can be modulated by factors such as season and social context. Testosterone administration to adult male House Finches, Carpodacus mexicanus, in the spring increases the size of their SCRs. Here, we used males of this species to investigate effects of T and T metabolism on brain morphology and singing behavior in the fall. Birds received Silastic capsules containing androgens, estrogens, and/or inhibitors of androgenic action or estrogen synthesis to determine effects of these hormones on song rates and SCR volumes. We also manipulated the social environment by changing the number of birds in visual contact with each other. Testosterone treatment stimulated singing behavior in finches held in small, visually isolated groups and exposed to song playbacks. However, administration of T or T metabolites did not increase SCR sizes. The data suggest that photoperiodic condition and social context may modulate the effects of steroids on SCRs and singing behavior.