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PubMed2004

Near-infrared spectrophotoscopy of finger venules in assessment of autonomic dysfunction.

The authors evaluated morphologic changes in the venules of the finger using near-infrared spectrophotoscopy in patients with autonomic dysfunction, such as familial amyloidotic polyneuropathy and multiple-system atrophy. Abnormalities of the venules, such as tortuosity, irregular venous caliber, and microaneurysm-like change, and a linear negative correlation between the degree of orthostatic hypotension and the degree of vasoconstriction of the venules were observed.

Adult↗

PubMed2006

Testing the validity of the PDQ-39 in patients with MSA.

We assessed the validity of the PDQ-39, a disease-specific health-related quality of life instrument for patients with Parkinson's disease, in patients with multiple system atrophy (MSA). Two hundred and seventy-nine patients completed the PDQ-39, the EQ-5D, the Hospital Anxiety and Depression Scale, and scales of life satisfaction and disease severity. Ceiling and floor effects were noted in some dimensions, and Mobility was skewed towards the severe end of the spectrum. Apart from the dimension of Social Support, all dimensions had high internal consistency. The factor structure of the PDQ-39 in MSA was stable, and convergent and divergent validity with other measures of quality of life and mental health were good. However, many of the specific features of MSA are not reflected in the PDQ-39. Higher order factor analysis did not support the use of a single summary index. We conclude that the PDQ-39 has only limited validity in patients with MSA.

Activities of Daily Living↗

PubMed2004

Laryngeal inputs in defensive airway reflexes in humans.

Stimulation of laryngeal receptors is the natural starting point of defensive airway reflexes including the cough reflex, expiration reflex, spasmodic panting, and apnoea with laryngospasm. Although several different types of laryngeal receptors have been reported, the laryngeal irritant receptors are considered to play the most essential role in elicitation of defensive airway reflexes. Based on the knowledge that the laryngeal irritant receptors are stimulated by water solutions lacking chloride anions, we have developed an experimental method to elicit defensive airway reflexes with a direct instillation of distilled water onto the laryngeal mucosa in humans. Using this experimental method, we studied the characteristics of defensive airway reflexes in lightly anaesthetized patients with multiple system atrophy (MSA). The reflex responses to water stimulation observed in these patients were characterized by apnoea with laryngospasm while the cough reflex was never elicited. Endoscopic images of the larynx in these patients were also characterized by laryngeal oedema. Considering the pathological changes occurring in the central nervous system and the laryngeal mucosa, it is possible that the defensive airway reflexes may be modified by central and/or peripheral mechanisms in patients with MSA.

Apnea↗

PubMed2006

Analysis of 14 LRRK2 mutations in Parkinson's plus syndromes and late-onset Parkinson's disease.

The pleomorphic pathology of postmortem LRRK2-positive patients and the frequent association with late-onset Parkinson's disease (LOPD) symptoms suggest that LRRK2 mutations may play a role in Parkinson's Plus disorders and LOPD. Published studies primarily focus on the common G2019S mutation. Analysis of a spectrum of LRRK2 mutations in Parkinson's Plus disorders has yet to be reported. We investigated 14 leucine-rich repeat kinase 2 (LRRK2) mutations in a cohort of Parkinson's Plus disorders and LOPD. A total of 458 patients with progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal ganglionic degeneration (CBGD), atypical Parkinsonism (AP), and LOPD were screened for 14 mutations that span exons 19 to 41 of the LRRK2 gene. Among the LOPD cases, 1 patient was found to harbor the R1441C mutation. He presented with typical features of PD at age of 58 years old and responded well to levodopa. We did not detect any of the 14 mutations in PSP, MSA, CBGD, and AP patients. We highlight the first case of LRRK2 R1441C mutation in late onset sporadic PD of non-European ancestry. Furthermore, extensive mutational screen found LRRK2 mutations to be rare among patients who presented with PSP, MSA, CBGD, and AP.

Age Factors↗

PubMed2006

Coexistence of PSP and MSA: a case report and review of the literature.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by Parkinsonism, vertical gaze palsy, and early falls. The neuropathology is characterized by neurofibrillary tangles, tufted astrocytes, and coiled bodies, but some brains show other pathologic processes. To investigate the frequency of alpha-synuclein pathology in PSP with immunohistochemistry and to report the clinical and pathological features of a case of PSP with concomitant Multiple system atrophy (MSA) (PSP/MSA), 290 cases of PSP were screened for alpha-synuclein pathology with immunohistochemistry. Double-labeling immunohistochemistry was performed on a case of PSP/MSA. Among the PSP cases screened for alpha-synuclein pathology, a single case of PSP/MSA was detected. The patient was an 86-year-old woman with clinical features consistent with PSP. She had no documented dysautonomia or cerebellar signs, and imaging studies were not diagnostic of MSA. Pathological examination showed tau-immunoreactive neuronal and glial lesions consistent with PSP as well as alpha-synuclein immunoreactive glial cytoplasmic inclusions diagnostic of MSA. Double-immunolabeling studies showed no co-localization of alpha-synuclein and tau in most neuronal and glial lesions. Based upon the findings in this case, the neuropathologic changes of PSP and MSA are distinct and independent processes, but they can occasionally coexist.

Aged, 80 and over↗

PubMed2001

Genotypes of catechol-O-methyltransferase and response to levodopa treatment in patients with Parkinson's disease.

A single nucleotide polymorphism at the nucleotide 1947 in the catechol-O-methyltransferase (COMT) gene encodes the high and low activity forms of the enzyme. We investigated COMT genotypes of 73 Korean patients with Parkinson's disease (PD), 29 with multiple system atrophy (MSA), and 49 controls, and analyzed the response to levodopa challenge in the PD patients. We found no significant difference in the distribution of the COMT genotypes among the three groups. The frequencies of the G- and A-alleles in the total population were 75 and 25%, respectively. The levodopa response was determined by a single oral levodopa challenge test with Sinemet (25/250 mg) in the patients with PD. The motor response evaluated by the time to peak response, the duration and magnitude of the response in the motor part of the Unified Parkinson's Disease Rating Scale; tapping or walking times showed no significant difference between the genotypes. Thus, pharmacokinetic or pharmacodynamic factors other than the investigated genetic variant of the COMT enzyme seem to determine the response to levodopa in PD.

Adult↗

PubMed2006

Neurofilament heavy-chain NfH(SMI35) in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes.

We aimed to evaluate the potential of the cerebrospinal fluid (CSF) axonal damage biomarker NfH(SMI35) in the laboratory-supported differential diagnosis of parkinsonian syndromes. Patients with idiopathic Parkinson's disease (PD; n = 22), multiple-system atrophy (MSA; n = 21), progressive supranuclear palsy (PSP; n = 21), corticobasal degeneration (CBD; n = 6), and age-matched controls (n = 45) were included. CSF levels of NfH(SMI35) were measured using ELISA. Levels of CSF NfH(SMI35) were elevated in PSP compared to PD and controls (P < 0.05 each). They were also significantly higher in MSA than in PD and controls (P < 0.05 each). NfH(SMI35) differentiated PD from PSP with a sensitivity of 76.5% and a specificity of 94.4%. Axonal damage as measured by CSF NfH(SMI35) is most prominent in the more rapidly progressive syndromes PSP and MSA as compared to PD or CBD. CSF NfH(SMI35) may therefore be of some value for the laboratory-supported differential diagnosis of atypical parkinsonian syndromes.

Adult↗

PubMed1998

Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease.

The cause and mechanism of neuronal cell death in the substantia nigra of patients with Parkinson's disease (PD) are unknown. There is also controversy about whether the cell death results from a single event followed by cell loss consistent with aging or whether there is an ongoing pathologic process. Using postmortem tissue obtained from the Parkinson's Disease Society Brain Tissue Bank in London, we have sought to establish whether apoptosis, or more specifically DNA fragmentation of neurons, is a prominent feature of nigral pathology. In addition, we have studied microglial activation in the substantia nigra as an indicator of ongoing pathology using the highly sensitive markers CR3/43 and EBM11. Reactive astrocytes have been assessed using immunostaining for glial fibrillary acidic protein (GFAP). Ten patients with pathologically proven PD were studied. In all cases, regardless of disease duration, severity, drug treatment, or age of the patient, there was no evidence of apoptosis in the substantia nigra as assessed by in situ end-labeling of DNA fragments using biotinylated dUTP and terminal deoxynucleotidyl transferase (TdT). In contrast, a case of multiple system atrophy (MSA) served as a positive control for the technique. In this case, positive DNA end-labeling could be found in neurons and non-neuronal cells in the brain stem. In the PD cases, there was, however, localized pathology in the substantia nigra as revealed by the CR3/ 43 and EBM11 markers for activated microglia. This process seemed independent of disease duration and was florid even in patients with severe neuronal loss. It remains to be determined to what extent the activation of glial cells reflects progressive nigral pathology, and whether those factors which are classically associated with prominent apoptotic neuronal cell death in vivo, such as neurotrophic factor deprivation, are prime causes of nigral neuronal loss in PD. Future studies should focus on recent-onset PD or incidental Lewy body disease to further address these questions.

Aged↗

PubMed2002

Mitochondrial DNA deletions/rearrangements in parkinson disease and related neurodegenerative disorders.

Inhibition of mitochondrial respiratory chain function may contribute to dopaminergic neurodegeneration in the substantia nigra (SN) of patients with Parkinson disease (PD). Since large-scale structural changes (e.g. deletions and rearrangements in mitochondrial DNA [mtDNA]) have been associated with mitochondrial dysfunction, we tested the hypothesis that increased total mtDNA deletions/rearrangements are associated with neurodegeneration in PD. This study employed a well-established technique, long-extension polymerase chain reaction (LX-PCR), to detect the multiple mtDNA deletions/rearrangements in the SN of patients with PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), Alzheimer disease (AD), and age-matched controls. We also compared the total mtDNA deletions/rearrangements in different brain regions of PD patients. The results demonstrated that both the number and variety of mtDNA deletions/rearrangements were selectively increased in the SN of PD patients compared to patients with other movement disorders as well as patients with AD and age-matched controls. In addition, increased mtDNA deletions/rearrangements were observed in other brain regions in PD patients, indicating that mitochondrial dysfunction is not just limited to the SN of PD patients. These data suggest that accumulation of total mtDNA deletions/rearrangements is a relatively specific characteristic of PD and may be one of the contributing factors leading to mitochondrial dysfunction and neurodegeneration in PD.

Aged↗

PubMed1999

The dropped head sign in parkinsonism.

We describe seven patients who exhibited the dropped head sign in parkinsonism. These included six females and one male between the ages of 53 and 74. Three patients were clinically diagnosed as probable Parkinson's disease and four were diagnosed with probable multiple system atrophy. None had weakness in the posterior neck muscles or spasms in the anterior neck muscles. When the patients attempted to extend the head voluntarily or passively muscle contraction that was not seen in the dropped-head condition appeared. Surface electromyography of the neck indicated that the anterior neck muscles had rigidity. A gamma-block of the SCM muscles reduced the muscle activity when the head was elevated and improved the dropped-head condition slightly. These findings seem to indicate that the dropped head sign in parkinsonism could be associated with anterior neck muscle rigidity. Although the severity of the dropped head condition was affected by medication or by the clinical course in three patients, there was no clear relationship between the severity of the dropped head condition and the parkinsonism. We suspected that unbalanced muscle rigidity between the anterior and the posterior neck muscles could cause the dropped head sign.

Aged↗

PubMed1999

Hydroxyl radical and superoxide dismutase in blood of patients with Parkinson's disease: relationship to clinical data.

Hydroxyl radical (.OH) levels in blood, superoxide dismutase (SOD) activity in plasma (plasma-SOD) and in red blood cells (RBC) relative to Cu,Zn-SOD (SOD1) protein (RBC-SOD/SOD1), SOD1 protein in RBC (SOD1/RBC) and plasma (SOD1/plasma), and Mn-SOD protein in plasma (SOD2/plasma) were measured in patients with Parkinson's disease (PD), multiple-system atrophy (MSA) with parkinsonism, and in control subjects. Patients with PD had significantly higher.OH and plasma-SOD values and significantly lower RBC-SOD/SOD1 and SOD1/RBC values than the corresponding MSA and control values. In PD, RBC-SOD/SOD1 values were significantly lower in older patients and were negatively correlated with age.OH levels were significantly higher in PD patients with early onset, a long period of illness or severe Yahr stage, and were negatively correlated with onset and positively correlated with duration of illness. RBC-SOD/SOD1 values in PD patients who received pergolide therapy were significantly higher than those in PD patients who received neither pergolide nor bromocriptine therapy. Therefore, the higher.OH level and the lower SOD1 activity may play a role in the onset and progression of PD, and pergolide may act neuroprotectively by inducing SOD1 activity.

Age Factors↗

PubMed1998

Increased basal ganglia iron in striatonigral degeneration: in vivo estimation with magnetic resonance.

BACKGROUND: As many as 20% of individuals with the clinical diagnosis of Parkinson's disease (PD) do not have the characteristic neuropathologic features of PD at post mortem. The striatonigral degeneration (SND) subtype of multiple system atrophy is one of the categories of pathology which may be incorrectly diagnosed as PD on the basis of clinical presentation. SND may be associated with increased iron deposition in the putamen which can be detected with magnetic resonance imaging. METHODS: We have estimated regional brain iron content in a patient with probable SND, using a novel imaging method developed in our laboratory, and have compared the results in this patient to those which we have previously reported in patients with PD and in age-matched controls. RESULTS: We observed that putamenal iron content was increased in our SND patient, beyond the 95% confidence limit for inclusion in the PD group, even when considering clinical severity. In contrast, pallidal and thalamic iron were within the PD range. CONCLUSIONS: The demonstration of increased putamenal iron content may be a useful adjunctive investigative procedure in patients with suspected SND.

Basal Ganglia↗

PubMed2002

An imaging study of parkinsonism among African-Caribbean and Indian London communities.

We previously reported on 131 parkinsonian patients of African-Caribbean and Indian origin attending movement disorders clinics in six London Hospitals, of whom approximately 20% manifested atypical parkinsonism with a late-onset, akinetic-rigid predominant syndrome, postural instability and minimal resting tremor refractory to levodopa therapy and dopamine agonists (see Hu et al., Neurology 2000;54[Suppl.3]: A188 and Hu et al., Mov Disord 2000;15[Suppl.3]:S212). To better elucidate the phenotype of these atypical patients (18)FDG/(18)F-dopa positron emission tomography (PET) were performed in a subgroup to look for cortical and striatal metabolic changes suggestive of multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or dementia with Lewy bodies. Magnetic resonance imaging (MRI) rating of cerebral vascular lesion load, putaminal atrophy, and neuropsychological testing were also performed. Discriminant function analysis of (18)F-dopa/(18)FDG striatal metabolism in 43 patients failed to separate atypical ethnic minority from typical Caucasian Parkinson's disease (PD) patients. Additionally, atypical Indian and African-Caribbean patients did not show cortical reductions in glucose metabolism suggestive of PSP, CBD, or DLB. Cerebral vascular lesion load rated in these patients did not differ between atypical and typical PD groups, and none of the atypical patients had MRI changes suggestive of MSA or PSP. Our results suggest the atypical parkinsonian phenotype seen in African-Caribbean and Indian patients represents a levodopa-refractory form of PD separate from MSA or PSP in most patients.

Adult↗

PubMed2007

Tracking the neurodegeneration of parkinsonian disorders--a pilot study.

The purpose of the study was to explore the possibilities of using diffusion tensor imaging (DTI) and tractography (DTT) for the differential diagnosis and monitoring of disease progression in idiopathic Parkinson's disease (IPD), compared with the atypical parkinsonian disorders multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A 3.0-T MR scanner was used. DTI was acquired using a single-shot EPI sequence with diffusion encoding in 32 directions and a voxel size of 2 x 2 x 2 mm3. DTI data were analysed and DTT was performed using the PRIDE fibre tracking tool supplied by the manufacturer. The fractional anisotropy (FA) and apparent diffusion coefficient (ADC) within each tract were determined. DTI and DTT images in patients with moderate to advanced MSA demonstrated degeneration of the middle cerebellar peduncles and pontine crossing tracts, with decreased FA and increased ADC. This accounted for most of the pontine and cerebellar atrophy characteristic of this disease. In contrast, patients with PSP showed a selective degeneration of the superior cerebellar peduncle. Three-dimensional images of whole-brain white matter tracts demonstrated a reduction of cortical projection fibres in all patients with PSP. Visualization of the selective degeneration of individual fibre tracts, using DTI and DTT, adds qualitative data facilitating the differential diagnosis of parkinsonian disorders. Repeated measurements of FA and ADC values in a whole fibre tract might be used for monitoring disease progression and studying the effect of treatment in neuroprotective trials. The results are preliminary considering the small number of subjects in the study.

Adult↗

PubMed2001

CSF-neurofilament and levodopa tests combined with discriminant analysis may contribute to the differential diagnosis of Parkinsonian syndromes.

The differentiation between Parkinson's disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is important for prognostic and therapeutic purposes. In order to evaluate the diagnostic capability of two tests reflecting these items, patients fulfilling strict clinical criteria for PD (n=35), MSA (n=36) and PSP (n=14), were consecutively included. An analysis of neurofilament protein (NFL), a marker of axonal degeneration in the cerebrospinal fluid (CSF) and a levodopa test, recorded with optoelectronic technique were performed. Using discriminant analyses, the test's abilities to predict the clinical PD or non-PD (MSA and PSP) diagnoses were compared. Whereas the CSF-NFL and levodopa tests predicted 79 and 85% correct diagnoses respectively, the combined test predicted 90% correct diagnoses. We conclude that the CSF-NFL and levodopa tests provide detailed information of clinical variables on which the clinical diagnostic criteria are based. As they are pathologically unrelated, the diagnostic precision increases compared to clinical diagnoses when they are combined.

Adult↗

PubMed1998

Direct genetic evidence for involvement of tau in progressive supranuclear palsy. European Study Group on Atypical Parkinsonism Consortium.

OBJECTIVE: To confirm whether a dinucleotide repeat sequence in an intron of the microtubule-associated protein tau is associated with progressive supranuclear palsy (PSP) in an independent study population and to establish an improved methodology for allelotyping. BACKGROUND: It has recently been reported that a genetic variant of tau, known as the A0 allele, was represented excessively in PSP patients when compared with control subjects. METHODS: In a multicenter study, the authors examined the allelic distribution of this dinucleotide repeat marker in a set of clinically ascertained PSP patients (n = 30), multiple system atrophy (MSA) patients (n = 35), and matched control subjects (n = 70). Individuals were allelotyped using automated analysis of fluorescently labeled PCR products. RESULTS: The A0 allele was significantly overrepresented in the PSP patients (93.3% versus 76.4%; p = 0.0067; odds ratio [OR] = 4.33; 95% confidence interval [CI], 1.36 to 13.60), but not in the MSA patients. Likewise, A0 homozygotes were overrepresented in the PSP group (86.7% versus 61.1%; p = 0.02; OR = 4.14; 95% CI, 1.19 to 14.48) compared with control subjects. CONCLUSIONS: The findings of this study, which is the largest to date, support those of a previous investigation that used pathologically confirmed PSP patients. These data provide additional strong evidence that genetic variation at or near the tau gene plays an important role in the pathogenesis of PSP.

Aged↗

PubMed2006

Growth hormone stimulation tests in the differential diagnosis of Parkinson's disease.

Idiopathic Parkinson's disease (IPD) is a common neurodegenerative disorder whose differential diagnosis from other forms of atypical parkinsonism, for instance multiple system atrophy (MSA) or progressive supranuclear palsy, may be difficult, especially in the early stages. Growth hormone stimulation tests have been recently reported to be useful in the differential diagnosis between IPD and MSA. Both clonidine, an alpha(2)-adrenoceptor agonist, and arginine, an amino acid activating the cholinergic system, have been used to assess growth hormone response in patients with IPD and MSA. This review summarizes the results of several studies and discusses the validity of these tests in the differential diagnosis of parkinsonisms.

Adrenergic alpha-Agonists↗

PubMed2006

Predictors of falls and fractures in bradykinetic rigid syndromes: a retrospective study.

BACKGROUND: Falls and fractures contribute to morbidity and mortality in bradykinetic rigid syndromes. METHODS: The authors performed a retrospective case notes review at the Queen Square Brain Bank for Neurological Disorders and systematically explored the relation between clinical features and falls and fractures in 782 pathologically diagnosed cases (474 with Parkinson's disease (PD); 127 progressive supranuclear palsy (PSP); 91 multiple system atrophy (MSA); 46 dementia with Lewy bodies (DLB); 27 vascular parkinsonism; nine Alzheimer's disease; eight corticobasal degeneration). RESULTS: Falls were recorded in 606 (77.5%) and fractures in 134 (17.1%). In PD, female gender, symmetrical onset, postural instability, and autonomic instability all independently predicted time to first fall. In PD, PSP, and MSA latency to first fall was shortest in those with older age of onset of disease. Median latency from disease onset to first fall was shortest in Richardson's syndrome (12 months), MSA (42), and PSP-parkinsonism (47), and longest in PD (108). In all patients fractures of the hip were more than twice as common as wrist and forearm fractures. Fractures of the skull, ribs, and vertebrae occurred more frequently in PSP than in other diseases. CONCLUSION: Measures to prevent the morbidity associated with falls and fractures in bradykinetic rigid syndromes may be best directed at patients with the risk factors identified in this study.

Accidental Falls↗