Clinical Diagnosis Of Parkinson's Disease Research Articles

Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease.

Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor. [(123)I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates. Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen. The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor.

Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome

Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 deletions may lead to increased risk of early-onset Parkinson disease (PD). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition. To evaluate a possible association between 22q11.2 deletions and PD. An observational study of the occurrence of PD in the world's largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (n = 159 [6 with postmortem tissue]; age range, 18.1-68.6 years) was conducted in Toronto, Ontario, Canada. Rare postmortem brain tissue from individuals with 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder. A clinical diagnosis of PD made by a neurologist and neuropathological features of PD. RESULTS Adults with 22q11.2DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69.7; 95% CI, 19.0-178.5). All cases showed early onset and typical PD symptom pattern, treatment response, and course. All were negative for family history of PD and known pathogenic PD-related mutations. The common use of antipsychotics in patients with 22q11.2DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years. Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22q11.2DS-PD cases. Typical α-synuclein-positive Lewy bodies were present in the expected distribution in 2 cases but absent in another. These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological presentation reminiscent of LRRK2-associated PD neuropathology. Individuals with early-onset PD and classic features of 22q11.2DS should be considered for genetic testing, and those with a known 22q11.2 deletion should be monitored for the development of parkinsonian symptoms. Molecular studies of the implicated genes, including DGCR8, may help shed light on the underlying pathophysiology of PD in 22q11.2DS and idiopathic PD.

MOLECULAR GENETIC STUDIES OF NEURODEGENERATIVE DISEASE

IntroductionLarge scale genetic studies such as genome–wide association studies (GWAS) in Parkinson's disease (PD) have revealed genetic susceptibility factors and continue to offer new insights both into the genetics of...

New guidelines for diagnosis of Parkinson disease

At least 10% of diagnoses of Parkinson disease that are made while the patient is alive are not confirmed at autopsy. To help address this issue, the European Federation of Neurology and the Movement Disorder Society European Section have provided evidence-based guidelines and recommendations for clinical diagnosis of Parkinson disease.

Cardiac sympathetic denervation is not related to nigrostriatal degeneration in Parkinson’s disease

The aim of our study was to investigate the relationship between myocardial sympathetic degeneration and nigrostriatal impairment in patients affected by Parkinson's disease (PD) by means of (123)I-metaiodobenzylguanidine ((123)I MIBG) scintigraphy and N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-[(123)I]iodophenyl)nortropane ((123)I FP-CIT) scintigraphy. The study involved 37 patients with clinical diagnosis of PD (22 males and 15 females, mean age 62 years (±10), evaluated with (123)I FP-CIT single photon emission computed tomography (SPECT) followed by (123)I MIBG scintigraphy within 20 (±3) days. Early and delayed anterior chest images were acquired and the heart/mediastinum ratio (H/M ratio) was calculated. Furthermore, the population has been divided on the basis of the main clinical pattern to investigate the possible role of a tremor-dominant or an akinetic-dominant phenotype in this comparison. In PD population, there were no statistical relationships between early and delayed (123)I MIBG cardiac and (123)I FP-CIT striatal uptake in contralateral caudate (P > 0.05) and in contralateral putamen (P > 0.05) to the side mainly affected; no statistically significant relationships have been found at any level when considering ipsilateral striatum. We did not find statistically significant relationships when considering the single PD phenotypes. The results of our study suggest that cardiac sympathetic system and nigrostriatal system are differently affected in PD. In particular, the sympathetic neurodegeneration rate is not related to nigrostriatal degeneration rate and vice versa in our series as detectable scintigraphically.

Cerebrospinal fluid biomarkers in Parkinson disease

Clinical diagnosis of Parkinson disease (PD) is difficult in early stages of disease, with high risk of misdiagnosis. The long preclinical phase of PD provides the possibility for early therapeutic intervention once disease-modifying therapies have been developed, but lack of biomarkers for early diagnosis and monitoring of disease progression represents a major obstacle to achievement of this goal. Accordingly, research efforts aimed at identification of novel biomarkers have been increasing in the past 5 years. Cerebrospinal fluid (CSF) is an accessible source of brain-derived proteins, which mirror molecular changes that take place in the CNS. In this Review, we discuss evidence from numerous studies that have focused on identification of candidate CSF biomarkers for PD. Notably, molecular pathways related to α-synuclein, tau and β-amyloid peptides have received considerable attention. CSF levels of the protein DJ-1 are also of interest, although further investigation of this candidate marker is required. These studies support the usefulness of a combination of various CSF biomarkers of PD to increase diagnostic accuracy during early phases of the disease, and to differentiate PD from other neurodegenerative disorders.

Levodopa challenge test and123I-metaiodobenzylguanidine scintigraphy for diagnosing Parkinson's disease

To explore the possibility of a generally applicable tool for the immediate diagnosis of Parkinson's disease (PD) in its early stage, we compared the sensitivity and specificity of an acute levodopa challenge test with that of (123) I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. A consecutive series of 45 patients with extrapyramidal symptoms were recruited to the acute levodopa challenge and evaluated for improvement by use of the Unified Parkinson's Disease Rating Scale motor scores. Of these patients, 32 of them were also examined by MIBG scintigraphy. The patients were followed up for at least 24 months, and 22 patients were diagnosed as having clinically definite PD. The sensitivity and specificity of the acute levodopa challenge test to predict clinical diagnosis of PD were 81.8% and 81.8%, respectively, which were better than those obtained by MIBG scintigraphy (62.5% and 62.5%). In both early- and middle-stages of PD, the test gave better sensitivity than MIBG scintigraphy. Considering that the well-established and frequently referred clinical diagnostic criteria require longitudinal observation for at least 24 months, the acute levodopa challenge test can be used as an immediate diagnostic tool for PD with sensitivity and specificity comparable to those of MIBG.

Submandibular Gland Biopsy for the Diagnosis of Parkinson Disease

The clinical diagnosis of Parkinson disease (PD) is incorrect in 30% or more of subjects particularly at the time of symptom onset. Because Lewy-type α-synucleinopathy is present in the submandibular glands of PD patients, we assessed the feasibility of submandibular gland biopsy for diagnosing PD. We performed immunohistochemical staining for Lewy-type α-synucleinopathy in sections of large segments (simulating open biopsy) and needle cores of submandibular glands from 128 autopsied and neuropathologically classified subjects, including 28 PD, 5 incidental Lewy body disease, 5 progressive supranuclear palsy (3 with concurrent PD), 3 corticobasal degeneration, 2 multiple system atrophy, 22 Alzheimer disease with Lewy bodies, 16 Alzheimer disease without Lewy bodies, and 50 normal elderly. Immunoreactive nerve fibers were present in large submandibular gland sections of all 28 PD subjects (including 3 that also had progressive supranuclear palsy); 3 Alzheimer disease with Lewy bodies subjects were also positive, but none of the other subjects were positive. Cores from frozen submandibular glands taken with 18-gauge needles (total length, 15-38 mm; between 10 and 118 sections per subject examined) were positive for Lewy-type α-synucleinopathy in 17 of 19 PD patients. These results suggest that biopsy of the submandibular gland may be a feasible means of improving PD clinical diagnostic accuracy. This would be particularly advantageous for subject selection in early-stage clinical trials for invasive therapies or for verifying other biomarker studies.

Evaluación de la sustancia negra mediante ultrasonografía transcraneal

AIM. To describe the prevalence of hyperechogenicity of the substantia nigra in two samples of patients: one group who had been diagnosed with Parkinson's disease (PD) in accordance with United Kingdom Parkinson's Disease Society criteria and a control population, so as to be able to establish the reference values for our neurosonology laboratory. SUBJECTS AND METHODS. Two samples of patients consisting of healthy controls with no neurodegenerative disease and patients with PD were selected. Planimetric measurements of the area of echogenicity in the substantia nigra were performed in both groups. The greatest area of echogenicity measured on each side of each patient was considered. Descriptive statistics of the sample were carried out. The ROC curve was constructed in order to show the overall precision, sensitivity and specificity of transcranial Doppler ultrasonography in comparison to the clinical diagnosis of PD. RESULTS. Altogether 45 patients with PD and 91 controls were analysed. Using our own cut-off point (percentile 90 of the controls = 0.22 cm2), hyperechogenicity of the substantia nigra was observed in 73.33% of patients with PD and 8.79% of the controls (p = 0). An area below the curve of 93% was seen, which represents good overall precision for transcranial Doppler ultrasonography in the diagnosis of PD. CONCLUSIONS. The evaluation of the substantia nigra conducted in our laboratory using ultrasound imaging reveals significant differences between subjects with PD and normal subjects. The values obtained in our laboratory are slightly below those established as an international reference and offer excellent values for specificity and an acceptable level of sensitivity in our locale.

Multiclass classification of FDG PET scans for the distinction between Parkinson's disease and atypical parkinsonian syndromes

Most available pattern recognition methods in neuroimaging address binary classification problems. Here, we used relevance vector machine (RVM) in combination with booststrap resampling (‘bagging’) for non-hierarchical multiclass classification. The method was tested on 120 cerebral 18fluorodeoxyglucose (FDG) positron emission tomography (PET) scans performed in patients who exhibited parkinsonian clinical features for 3.5 years on average but that were outside the prevailing perception for Parkinson's disease (PD). A radiological diagnosis of PD was suggested for 30 patients at the time of PET imaging. However, at follow-up several years after PET imaging, 42 of them finally received a clinical diagnosis of PD. The remaining 78 APS patients were diagnosed with multiple system atrophy (MSA, N = 31), progressive supranuclear palsy (PSP, N = 26) and corticobasal syndrome (CBS, N = 21), respectively. With respect to this standard of truth, classification sensitivity, specificity, positive and negative predictive values for PD were 93% 83% 75% and 96%, respectively using binary RVM (PD vs. APS) and 90%, 87%, 79% and 94%, respectively, using multiclass RVM (PD vs. MSA vs. PSP vs. CBS). Multiclass RVM achieved 45%, 55% and 62% classification accuracy for, MSA, PSP and CBS, respectively. Finally, a majority confidence ratio was computed for each scan on the basis of class pairs that were the most frequently assigned by RVM. Altogether, the results suggest that automatic multiclass RVM classification of FDG PET scans achieves adequate performance for the early differentiation between PD and APS on the basis of cerebral FDG uptake patterns when the clinical diagnosis is felt uncertain. This approach cannot be recommended yet as an aid for distinction between the three APS classes under consideration.

Effect of Global Postural Rehabilitation program on spatiotemporal gait parameters of parkinsonian patients: a three-dimensional motion analysis study

The aim of the present study was to evaluate the effects of a Global Postural Rehabilitation (GPR) program on motor symptoms and gait parameters of patients with Parkinson's disease (PD) by means of three-dimensional motion analysis study. Ten subjects with clinical diagnosis of PD were enrolled (study group). Age-, sex- and disease duration-matched PD patients were recruited as a control group (no treatment). Three-dimensional motion analysis was conducted by means of a stereophotogrammetric system. After basal evaluation, the study group underwent a specific rehabilitation program consisting of individual 40 min GPR daily sessions, 3 days a week for 4 consecutive weeks. Neurological status and spatiotemporal gait parameters of the two groups were evaluated at study entry (t (0)), at 4 weeks (t (1), end of rehabilitation protocol) and at 8 and 12 weeks (t (2) and t (3), follow-up evaluation). At baseline evaluation, the two groups did not differ in clinical features and gait parameters. At the end of rehabilitation protocol (t (1)) and at follow-up evaluation (t (2) and t (3)), a significant improvement in temporal gait parameters and UPDRS scores was observed in all treated patients as compared to baseline and controls. Our preliminary findings showed that significant improvements in mobility and gait parameters of PD patients can be obtained through GPR treatment, with a parallel improvement in clinical status. Quantitative analysis of gait pattern can be considered a useful tool to assess the efficacy of rehabilitation interventions in patients affected by PD.

Locus coeruleus neuron density and parkinsonism in older adults without Parkinson's disease

Previous work has showed that nigral neuron density is related to the severity of parkinsonism proximate to death in older persons without a clinical diagnosis of Parkinson's disease (PD). We tested the hypothesis that neuron density in other brain stem aminergic nuclei is also related to the severity of parkinsonism. We studied brain autopsies from 125 deceased older adults without PD enrolled in the Memory and Aging Project, a clinicopathologic investigation. Parkinsonism was assessed with a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). We measured neuron density in the substantia nigra, ventral tegmental area, locus coeruleus, and dorsal raphe, along with postmortem indices of Lewy body disease, Alzheimer's disease and cerebrovascular pathologies. Mean age at death was 88.0 years, and global parkinsonism was 14.8 (SD, 9.50). In a series of regression models that controlled for demographics and neuron density in the substantia nigra, neuron density in the locus coeruleus (estimate, -0.261; SE, 0.117; P = .028) but not in the ventral tegmental area or dorsal raphe was associated with severity of global parkinsonism proximate to death. These findings were unchanged in models that controlled for postmortem interval, whole-brain weight, and other common neuropathologies including Alzheimer's disease and Lewy body pathology and cerebrovascular vascular pathologies. In older adults without a clinical diagnosis of PD, neuron density in locus coeruleus nuclei is associated with the severity of parkinsonism and may contribute to late-life motor impairments.

Neuropathologic substrates of Parkinson disease dementia

A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD). One hundred forty patients with a clinical diagnosis of PD and either normal cognition or onset of dementia 2 or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded. Autopsy records of genetic data and semiquantitative scores for the burden of neurofibrillary tangles, senile plaques, Lewy bodies (LBs), and Lewy neurites (LNs) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of comorbid Alzheimer disease (AD) were also examined. Niney-two PD patients developed dementia, and 48 remained cognitively normal. Severity of cortical LB (CLB)/LN pathology was positively associated with dementia (p < 0.001), with an odds ratio (OR) of 4.06 (95% confidence interval [CI], 1.87-8.81), as was apolipoprotein E4 (APOE4) genotype (p = 0.018; OR, 4.19; 95% CI, 1.28-13.75). A total of 28.6% of all PD cases had sufficient pathology for comorbid AD, of whom 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p = 0.001; OR, 1.12; 95% CI, 1.04-1.21), higher CLB/LN burden (p = 0.037; OR, 2.48; 95% CI, 1.06-5.82), and cerebral amyloid angiopathy severity (p = 0.032; OR, 4.16; 95% CI, 1.13-15.30). CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or amyloid β could potentially improve cognitive performance in PD.

Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic

BackgroundRecently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson's Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist...

Effects of Manganese From a Commercial Multi–Trace Element Supplement in a Population Sample of Canadian Patients on Long‐Term Parenteral Nutrition

Long-term parenteral nutrition (PN) can be associated with micronutrient deficiency or toxicity depending on supplementation. Recently, hypermanganesemia and potential neurological toxicity were reported. The aim of this study was to assess the effect of manganese supplementation in a sample of patients on long-term PN receiving manganese (Mn) as part of a multi-trace element (TE) supplement. A convenience sample of 16 patients underwent clinical and blood biochemical measurements as well as magnetic resonance imaging (MRI) of the brain. Descriptive statistics were performed. The mean daily Mn supplementation was 7.28 ± 0.97 µmol/d (400 ± 53 µg/d), which was within the American Medical Association Nutrition Advisory Group guidelines of 2.73-14.56 μmol/d (150-800 µg/d) but exceeded the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) 2002 recommendations of 1.09-1.82 µmol/d (60-100 µg/d). The mean whole blood Mn level was 1.38 ± 0.29 times the upper limit of normal (ULN), and 8 of 14 patients with blood measurements had Mn levels above ULN. On MRI, 81% of patients had high signals on T1-weighted images assumed to be Mn deposits in their basal ganglia. Two patients with positive MRI (15%) had a clinical diagnosis of Parkinson disease. Multiple neuropsychiatric complaints were reported, including depression (66%), lack of concentration (42%), memory disturbances (17%), and gait instability (8%). These results suggest that Mn status is elevated in these patients. Manganese supplementation should be used with caution in patients receiving long-term PN, and attention should be paid to the Mn content of multi-TE supplements.

Parkinson disease, cancer, and LRRK2

At a superficial level, Parkinson disease (PD) and cancer seem to be like the 2 sides of a coin: uncontrolled cell growth in cancer contrasting with untimely cell death in PD. The underlying mechanisms could therefore be 2 opposite endpoints of those intracellular pathways that regulate the cell cycle, cell death, and cell survival.1 Extrapolating this point, if there is a systemic difference in a person's tendency of cells to undergo programmed cell death, then an individual who has increased risk of PD would have a lower risk for cancer and vice versa. This hypothesis is supported by the results of a systematic review and meta-analysis of clinical and epidemiologic studies in which the risk of PD and cancer showed an inverse relationship.2 However, at least some of these studies have methodologic shortcomings, and a recent study that controlled for known confounding factors did not reveal a significantly lower prevalence of cancer in patients with PD, either prior to the clinical diagnosis of PD or after they had developed clinically manifest PD.3 The one exception is melanoma, which is more common in PD both before and after the diagnosis of PD is made. This led to the hypothesis that there are common pathogenic pathways …

Genetic influences on cognitive decline in Parkinson's disease

The role of genetic factors in cognitive decline associated with Parkinson's disease (PD) is unclear. We examined whether variations in apolipoprotein E (APOE), microtubule-associated protein tau (MAPT), or catechol-O-methytransferase (COMT) genotypes are associated with cognitive decline in PD. We performed a prospective cohort study of 212 patients with a clinical diagnosis of PD. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed-effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. The ε4 allele of APOE was associated with more rapid decline (loss of 2.9; 95% confidence interval [CI]: 1.7-4.1) of more points per year; P < 0.001) in total score and an increased risk of a ≥ 10 point drop during the follow-up period (hazard ratio, 2.8; 95% CI: 1.4-5.4; P = 0.003). MAPT haplotype and COMT genotype were associated with measures of memory and attention, respectively, over the entire follow-up period, but not with the overall rate of cognitive decline. These results confirm and extend previously described genetic associations with cognitive decline in PD and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one APOE ε4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimer's disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.

116 Serotonergic function in early Parkinson's disease with and without depression: a pilot study

IntroductionThe role of the serotonergic system in Parkinson's disease (PD) depression is unclear. [123I] β-CIT, a single photon emission computed tomography (SPECT) radioligand, binds differentially to both dopamine and serotonin...

Role of DaTSCAN and clinical diagnosis in Parkinson disease

To assess the role of DaTSCAN in the diagnosis of Parkinson disease (PD). Using the sensitivity and specificity values obtained in the 2 studies that recently led the US Food and Drug Administration to approve the use of DaTSCAN for the diagnosis of PD, calculations were carried out to estimate the accuracy of the clinical diagnosis taking DaTSCAN findings as the standard of truth. In early PD, a clinical diagnosis of "possible" or "probable" PD has a sensitivity of 98% and a specificity of 67%. The specificity increases to 94% once the clinical diagnosis becomes established. The overall accuracy of the clinical diagnosis is 84% in early PD and 98% at later stages. The clinical diagnostic accuracy is mathematically identical to the diagnostic accuracy of DaTSCAN imaging. In the absence of neuropathologic validation, the overall accuracy of a clinical diagnosis of PD is very high and mathematically identical to the accuracy of DaTSCAN imaging, which calls into question the use of radiotracer neuroimaging as a diagnostic tool in clinical practice.

SPECT Molecular Imaging in Parkinson's Disease

Parkinson's disease (PD) is a common disorder, and the diagnosis of Parkinson's disease is clinical and relies on the presence of characteristic motor symptoms. The accuracy of the clinical diagnosis of PD is still limited. Functional neuroimaging using SPECT technique is helpful in patients with first signs of parkinsonism. The changes detected may reflect the disease process itself and/or compensatory responses to the disease, or they may arise in association with disease- and/or treatment-related complications. This paper addresses the value of SPECT in early differential diagnosis of PD and its potential as a sensitive tool to assess the pathophysiology and progression, as well as the therapeutic efficacy of PD.