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Discovering genes following Medelian inheritance, such as autosomal dominant-synuclein and leucine-rich repeat kinase 2 gene, or autosomal recessive Parkin, P-TEN-induced putative kinase 1 gene and Daisuke-Junko 1 gene, has provided great insights into the pathogenesis of Parkinson’s disease (PD). Genes found to be associated with PD through investigating genetic polymorphisms or via the whole genome association studies suggest that such genes could also contribute to an increased risk of PD in the general population. Some environmental factors have been found to be associated with genetic factors in at-risk patients, further implicating the role of gene-environment interactions in sporadic PD. There may be confusion for clinicians facing rapid progresses of genetic understanding in PD. After a brief review of PD genetics, we will discuss the insight of new genetic discoveries to clinicians, the implications of ethnic differences in PD genetics and the role of genetic testing for general clinicians managing PD patients.
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Orthostatic hypotension (OH) is known to be present even in patients with early Parkinson’s disease (PD). To affirm the presence of OH and find correlation between OH and other dysautonomic symptoms in PD, this study has done in newly-diagnosed PD patients.
Forty-five non-demented patients with no prior history of treatment for PD were recruited (17 men, 63.8 ± 10.1 years of age). All the patients were evaluated for OH before starting medications. Autonomic symptoms were evaluated with structured questionnaires. Clinical characteristics of PD were evaluated (median Hoehn and Yahr stage 2.0 (1–3), 1.3 ± 1.1 years of disease duration), and comorbid medical conditions that could affect blood pressure were also recorded.
OH was prevalent, and eighteen patients (40%) showed orthostatic hypotension, and twenty-seven (60%) did not (normotensive group). There was no significant difference in demographic and clinical characteristics between groups. The presence or severity of symptoms of autonomic dysfunction in the OH group also not differed from those of the normotensive group.
OH was prevalent even in the early stage of PD, and was not related to presence or severity of any other symptoms of autonomic dysfunction. Our findings suggest that clinicians should pay attention to OH from the early stage of disease.
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Symptoms of autonomic dysfunctions are common in the patients with parkinsonian disorders. Because clinical features of autonomic dysfunctions are diverse, the comprehensive evaluation is essential for the appropriate management. For the appreciation of autonomic dysfunctions and the identification of differences, patients with degenerative parkinsonisms are evaluated using structured questionnaire for autonomic dysfunction (ADQ).
Total 259 patients, including 192 patients with [idiopathic Parkinson’s disease (IPD, age 64.6 ± 9.6 years)], 37 with [multiple system atrophy (MSA, 62.8 ± 9.1)], 9 with [dementia with Lewy body (DLB, 73.9 ± 4.3)], and 21 with [progressive supranuclear palsy (PSP, 69.4 ± 9.6)]. The ADQ was structured for evaluation of the presence of symptoms and its severity due to autonomic dysfunction, covering gastrointestinal, urinary, sexual, cardiovascular and thermoregulatory domains. Patients were also evaluated for the orthostatic hypotension.
Although dementia with Lewy body (DLB) patients were oldest and duration of disease was longest in IPD, total ADQ scores of MSA and PSP (23.9 ± 12.6 and 21.1 ± 7.8) were significantly increased than that of IPD (15.1 ± 10.6). Urinary and cardiovascular symptom scores of MSA and gastrointestinal symptom score of PSP were significantly worse than those of IPD. The ratio of patient with orthostatic hypotension in IPD was 31.2% and not differed between groups (35.1% in MSA, 33.3% in DLB and 33.3% in PSP). But the systolic blood pressure dropped drastically after standing in patients with MSA and DLB than in patients with IPD and PSP.
Patients with degenerative parkinsonism showed widespread symptoms of autonomic dysfunctions. The severity of those symptoms in patients with PSP were comparing to that of MSA patients and worse than that of IPD.
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Status of the disease is the one of main concerns of clinicians, especially in the course of primary degenerative disorders. In Parkinson’s disease (PD), Unified Parkinson’s Disease Rating Scale (UPDRS) is an useful clinical score that can express severity of parkinsonian symptoms, but L-DOPA treatment and motor fluctuations can change the UPDRS scores. Even in the best ‘on’ state, there can be residual motor deficits, and it is very difficult to estimate the worst ‘off’ state due to long duration effect of L-DOPA.
To find relevant examination scores of ‘on’ or ‘off’ state of PD patients which correlates with clinical and demographic variables those can represents the status of Parkinson’s disease.
Sixty-four patients with PD (24 male, age 63.0±8.6 years, Hoehn and Yahr stage (HY) 2.8±0.5) were examined UPDRS at ‘on’ and practically defined ‘off’ (12 hours after last medication) state. We evaluated the association between the ‘on’ and ‘off’ scores of UPDRS and duration of disease and treatment, and equivalent L-DOPA dose of the patients. Patients were grouped according to the presence of motor fluctuation to find the differences in those associations.
There were significantly strong correlations between UPDRS ‘off’ scores and clinical variables such as duration of disease and treatment. In ‘on’ state, only complication part of UPDRS was correlated with duration of disease and treatment, but activity of daily living (ADL) and motor part of UPDRS were correlated well with age of the patients. Age at disease onset showed significant negative association with the difference between ‘off’ and ‘on’ state UPDRS scores. Thirty-one patients who had motor fluctuation (9 male, age 62.7±9.3 years, HY 3.0±0.6) showed significantly increased duration of the disease, duration of L-DOPA treatment and equivalent DOPA dose compared to those of 33 patients without motor fluctuation (15 male, age 63.3±8.1 years, HY 2.6±0.3). In patients without motor fluctuation, both ‘off’ and ‘on’ UPDRS showed association with duration of disease and treatment, but ‘off’ and ‘off’ – ‘on’ difference of UPDRS were better correlated with duration of disease and treatment in patients with motor fluctuation.
We found that the UPDRS scores of practically defined ‘off’ state significantly correlated with the duration of the disease and treatment. Patients with motor fluctuation revealed better responsiveness to medication than those without motor fluctuation. In patients without motor fluctuation, UPDRS scores of ‘on’ state can reflect the clinical presentation as much as those of ‘off’ state.
To determine the frequency of mild cognitive impairment (MCI) of Parkinson’s disease (PD, PDMCI) and its subtypes among non-demented PD patients, and to identify the influence of the age and presenting symptom on the development of PDMCI.
A total 141 non-demented PD patients underwent a comprehensive neuropsychological assessment including attention, language, visuospatial, memory and frontal functions. PDMCI was defined by neuropsychological testing and was classified into five subtypes. Patients were divided into two groups (tremor vs. akinetic-rigid type) for presenting symptom and three groups according to the age. Neuropsychological performance of patients was compared with normative data.
Almost half (49.6%) of non-demented PD patients had impairment in at least one domain and can be considered as having PDMCI. Executive type of PDMCI was the most frequent and amnestic, visuospatial, linguistic and attention types followed in the order of frequency. The population of PDMCI was increasing as the age of disease onset was higher. Whereas the frequency of executive and amnestic types of PDMCI was comparable in younger group, executive type was the most frequent in older group. The patients with tremor dominant type performed worse on tests, particularly on attention test.
MCI was common even in the early stage of PD and the subtype was diverse. Unlike MCI developing Alzheimer’s disease later, executive type of PDMCI was the most common. Age was an important risk factor for development of MCI in PD. The concept of MCI should be introduced in PD.
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