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PubMed2006

Evaluation of Parkinson's disease in entrants on the Nebraska State Parkinson's Disease Registry.

We examined a sample of individuals in the Nebraska State Parkinson's Disease Registry (NSPDR) to determine what proportion meets standard criteria for Parkinson's disease (PD). The NSPDR was established in 1996 in an effort to understand the high prevalence of PD in Nebraska. Only minimal demographic data are included for each entrant. Subjects enter the NSPDR by means of diagnosing physicians, pharmacists dispensing anti-PD medications and the patients themselves. A series of 356 registrants diagnosed between 1997 and 2001 were contacted and invited to participate in a case-control study. Medical records were reviewed by a single abstractor in a standard manner. When patients consented, history was filled in by interview. A subset of patients were examined by a movement disorders specialist, who assigned all patients a probability of PD. Where sufficient information was available, 78% of registrants were confirmed to have PD (i.e., percent probability > 50%), including 83% of the patients previously diagnosed by a neurologist. Tremor was an initial symptom in 72% of confirmed versus 39% of excluded cases, and resting tremor was present in 86% of those that were confirmed. The most frequent reasons for exclusion were drug-induced Parkinsonism, multiple systems atrophy, vascular disease, and essential tremor. Use of the NSPDR for epidemiologic study requires careful review of the data set before assignment of cases. When histories are compiled in a standardized, comprehensive manner, the necessity for actual patient examinations can be minimized.

Case-Control Studies↗

PubMed1995

Striated anal sphincter denervation in patients with progressive supranuclear palsy.

Anal sphincter electromyography may contribute to the differential diagnosis between Parkinson's disease (PD) and other parkinsonisms featuring autonomic dysfunction, such as multiple system atrophy (MSA). Although patients with progressive supranuclear palsy (PSP) do not normally exhibit clinical signs of autonomic dysfunction, a few may be first seen with urinary and fecal incontinence. We performed an electromyographic study of the anal sphincter in 12 patients with clinical criteria of probable or definite PSP, two of them with clinical manifestations of vesical and anal sphincter dysfunction. The results have been compared with those obtained from six patients with PD and six patients with MSA. An abnormal anal sphincter examination was present in five of 12 PSP patients (41.6%). The abnormal motor units of these patients were indistinguishable from those observed in patients with MSA. Patients with MSA had the largest, and patients with PD had the lowest, proportion of abnormal motor units. We conclude that some patients with PSP may have electromyographic signs of denervation in the anal sphincter, which make them indistinguishable by using this test alone from patients with MSA.

Adult↗

PubMed1996

Reversal of behavioural abnormalities by fetal allografts in a novel rat model of striatonigral degeneration.

We have developed a rodent model of striatonigral degeneration, one of the core pathologies underlying the disease multiple system atrophy (MSA). 6-Hydroxydopamine (6-OHDA) was administered into the left medial forebrain bundle of male Wistar rats, followed 3-4 weeks later by intrastriatal injection of quinolinic acid into the ipsilateral striatum. The 6-OHDA lesion resulted in ipsilateral rotation to (+)-amphetamine and contralateral rotation to apomorphine. Following the subsequent striatal lesion, amphetamine-induced ipsilateral rotation persisted, but apomorphine-induced contralateral rotation was reduced or abolished. Subsequently, the lesioned striatum was implanted with fetal CNS allografts consisting of cell suspensions derived from striatal primordium alone or combined with cografts of ventral mesencephalon. Cografted rats showed a reduction or reversal of amphetamine-induced rotation. This was not observed in animals receiving striatal grafts alone. Apomorphine-induced contralateral rotation was restored after striatal grafts alone, but only partially in animals receiving sham or cografts. Tyrosine hydroxylase (TH) and dopamine- and cyclic adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP 32) immunocytochemistry showed mesencephalic and striatal graft survival in most animals. However, dopaminergic outgrowth was restricted to the graft deposit. The latter was surrounded by a markedly gliotic glial fibrillary acidic protein-positive capsule continuous with corpus callosum. Dopaminergic reinnervation of denervated and lesioned adult striatum itself was absent, suggesting that rotational recovery was due to diffuse dopamine release. The study shows that combined unilateral lesioning of rodent medial forebrain bundle and striatum results in a characteristic drug-induced rotational response that can be partly restored by mesencephalic/striatal cografts.

Amphetamines↗

PubMed1997

Freezing phenomenon in patients with parkinsonian syndromes.

Freezing is a common symptom in parkinsonian syndromes, but its association with different causes of parkinsonism as well as with other symptoms has never been investigated. We conducted a database survey of the occurrence of freezing in parkinsonism. Of 347 patients with a clinical diagnosis of parkinsonism other than idiopathic Parkinson's disease and with specific data regarding freezing, 158 patients had freezing (46%). Freezing was significantly associated with progression of the disease as rated on the Hoehn & Yahr scale [odds ratio (OR), 1.69; p < 0.004]. Gender was not a risk factor for the development of freezing. Patients with drug-induced parkinsonism were at a very low risk for developing freezing (p < 0.00001; OR, 0.1). Freezing was found in a high frequency in patients with vascular parkinsonism (57%), normal-pressure hydrocephalus (56%), and generally in the group of patients who had parkinsonism resulting from neurodegenerative diseases (progressive supranuclear palsy, multiple system atrophy, and corticobasal ganglionic degeneration; 45%). Freezing was significantly associated with the presence of dementia, incontinence, and tachyphemia (OR, 2.01, 1.7, and 5.09, respectively).

Dementia↗

PubMed1997

Urinary disturbances in striatonigral degeneration and Parkinson's disease: clinical and urodynamic aspects.

Although urinary disturbances are more frequent in multiple system atrophy (MSA) than in Parkinson's disease (PD), the striatonigral degeneration (SND) type of MSA is difficult to distinguish from PD, especially when the latter is associated with orthostatic hypotension or urinary symptoms. The pattern of urinary symptoms and urodynamic dysfunction was analyzed in 15 SND and 35 PD patients with urinary complaints. In SND, dysuria with or without chronic retention, frequently associated with a hypoactive detrusor and low urethral pressure, permitted early and reliable diagnosis. In PD, urgency to void, with or without difficulty voiding, but without chronic retention, associated with detrusor hyperreflexia and normal urethral sphincter function, predominated. In clinical practice, the study of urinary symptoms and bladder function may help to distinguish SND from PD in patients with urinary disturbances.

Aged↗

PubMed1997

Proton magnetic resonance spectroscopy in Parkinson's disease and atypical parkinsonian disorders.

Proton magnetic resonance spectroscopy (1H-MRS), localized to the lentiform nucleus, was carried out in 12 patients with idiopathic Parkinson's disease (IPD), seven patients with multiple-system atrophy (MSA), seven patients with progressive supranuclear palsy (PSP), and 10 healthy age-matched controls. The study assessed the level of N-acetylaspartate (NAA), creatine-phosphocreatine (Cr), and choline (Cho) in the putamen and globus pallidus of these patients. NAA/Cho and NAA/Cr ratios were significantly reduced in MSA and PSP patients. No significant difference was found between IPD patients and controls. These results suggest an NAA deficit, due to neuronal loss, in the lentiform nucleus of MSA and PSP patients. 1H-MRS is a noninvasive technique that can provide useful information regarding striatal neuronal loss in basal ganglia of patients with atypical parkinsonian disorders and represents a potential tool for diagnosing these disorders.

Aged↗

PubMed1998

123I-IBZM binding compared with long-term clinical follow up in patients with de novo parkinsonism.

We performed a prospective clinical follow up (mean follow up, 36 months; range, 24-56 months) of 65 patients with de novo parkinsonism in whom imaging of dopamine D2 receptors was performed before the initiation of dopaminomimetic therapy by means of 123I-iodobenzamide-single-photon-emission computed tomography (IBZM-SPECT). The results of IBZM-SPECT were compared with the long-term response to dopaminomimetic drugs, the development of motor fluctuations, and the development of clinical signs incompatible with Parkinson's disease (PD). A total of 55 patients had normal and 10 patients had reduced IBZM binding; 45 patients showed a good response to levodopa (L-dopa), 11 showed an equivocal response, and nine did not respond; 31 patients developed a fluctuating response to dopaminomimetic drugs and seven patients developed clinical signs indicative of multiple-system atrophy (n = 5), progressive supranuclear palsy (n = 1), or corticobasal ganglionic degeneration (n = 1). Chi-squared analysis showed a significant correlation of the results of IBZM-SPECT with the long-term response to dopaminomimetic therapy (p < 0.0001) and the development of motor fluctuations (p < 0.001) or clinical signs incompatible with PD (p < 0.0001). We conclude that IBZM-SPECT can help to differentiate between patients who will show a good response to L-dopa and will develop motor fluctuations (most likely patients with PD) and those patients who will not respond to L-dopa and might develop clinical signs compatible with another hypokinetic disorder of the basal ganglia.

Adult↗

PubMed1998

Young-onset Parkinson's disease revisited--clinical features, natural history, and mortality.

The authors report on clinical features and mortality rates in a group of 149 patients with apparent idiopathic parkinsonism starting before the age of 40 years. Ten had juvenile parkinsonism (JP; onset before age 21 years) and 139 had young-onset Parkinson's disease (YOPD; onset at age 21 to 40 years). Included were 60 patients originally reported 10 years ago. Fifty percent of the JP group had a positive family history of parkinsonism in a first-degree relative, and clinical presentation was heterogeneous. Mortality risk was threefold that of the normal population. In the YOPD group, the mortality risk was double that of the normal population. Poor initial response to L-dopa was a risk factor for early death. In two previously reported patients, the diagnosis had been changed to multiple system atrophy and Machado-Joseph disease. After a median disease duration of 18 years, cognitive impairment was found in only 19% of YOPD patients (13% of those younger than 60 years and 43% of those 60 years or older). Age was the most important factor for development of dementia, but female sex and positive family history of parkinsonism also had more modest predictive value. After a disease duration of 10 years or less, only 5% of patients were experiencing falls and 30% freezing, but all patients had developed L-dopa-related fluctuations and dyskinesias. The authors conclude that the mortality rate in parkinsonism starting before the age of 40 is increased in comparison to the normal population and is similar to the general Parkinson's disease population. Intellectual function and postural reflexes are usually well preserved for many years despite a long history of parkinsonism and the early and frequent occurrence of treatment complications, provided the patients remain biologically and chronologically young.

Adolescent↗

PubMed2007

Update on the neurology of Parkinson's disease.

The differential diagnosis of a patient with apparent Parkinson's Disease (PD) and bladder symptoms is considered and the bladder dysfunction of Multiple System Atrophy (MSA) is reviewed. Recent insights into the progression of the neuropathology of PD have enabled thinking about the stage of the disease at which bladder dysfunction is likely to occur and the expected clinical context of the problem. Bladder symptoms of neurological origin are likely in a patient who has had treated motor symptoms for some years and in whom the ongoing neuropathology has progressed beyond involvement of the basal ganglia, so that symptoms due to cortical dysfunction as well as the adverse effects of dopaminergic medication are also confounding factors. Bladder symptoms in a man with lesser neurological disability should be investigated to exclude underlying outflow obstruction. Possible management options are considered.

Humans↗

PubMed2002

Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment.

alpha-Synuclein (alphaS), a presynaptic nerve terminal protein, is now known to be a major component of neuronal and glial cytoplasmic inclusions in alpha-synucleinopathies (Lewy body disease and multiple system atrophy). However, alphaS has not been identified in either neuronal or glial cytoplasm in formalin-fixed, paraffin-embedded tissue sections from the normal human brain. Previous studies have shown that pretreatment with either proteinase K or formic acid enhances alphaS immunoreactivity. The aim of the present study was, therefore, to study the effects of pretreatment with proteinase K and formic acid on alphaS immunoreactivity in vibratome sections of brain tissue taken from normal human subjects. In addition to presynaptic staining, alphaS immunostaining was recognized in neuronal perikarya in the pretreated sections; this immunoreactivity was more intense in sections taken from the deeper layers of the cerebral neocortex, the CA2/3 region of the hippocampus, and the substantia nigra. This pattern of alphaS expression coincides with the distribution of intraneuronal inclusions in alphaS transgenic animals as well as in human autopsy tissue taken from patients with Lewy body disease. Furthermore, intense immunoreactivity was also found in the cytoplasm of astrocytes and oligodendrocytes throughout the brain. These findings suggest that a significant amount of alphaS is also present in the neuronal and glial cytoplasm in the normal human brain.

Aged↗

PubMed2006

The discovery of the pressor effect of DOPS and its blunting by decarboxylase inhibitors.

In the 1950s it was found that an artificial aminoacid, 3,4-threo-dihydroxyphenylserine (DOPS), was converted to norepinephrine (NE) in a single step by the enzyme L-aromatic amino acid decarboxylase (AADC), bypassing the need for the rate limiting enzyme dopamine beta hydroxylase. Trying to replicate the success of dihydroxyphenylalanine (DOPA) in the treatment of Parkinson disease, treatment with DOPS was attempted in patients with autonomic failure who have impaired NE release. DOPS improved orthostatic hypotension in patients with familial amyloid polyneuropathy, congenital deficiency of dopamine beta hydroxylase, pure autonomic failure and multiple system atrophy. DOPS pressor effect is due to its conversion to NE outside the central nervous system because concomitant administration of carbidopa, an inhibitor of AADC that does not cross the blood-brain barrier, blunted both the increase in plasma NE and the pressor response. DOPS pressor response is not dependent on intact sympathetic terminals because its conversion to NE also occurs in non-neuronal tissues.

Animals↗

PubMed2000

Subcellular localization of alpha-synuclein in primary neuronal cultures: effect of missense mutations.

Numerous recent observations have implicated alpha-synuclein in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies and multiple-system atrophy. Two missense mutations in the gene for alpha-synuclein have been identified in some cases of familial Parkinson's disease and it is thought that these may disrupt the normal structure of the protein and thus promote aggregation into Lewy body filaments. Here, we examine the subcellular localization of alpha-synuclein in primary cortical neurons maintained in a monolayer culture. The protein has widespread expression throughout neurons, including the nucleus, and has a discete localization in the neurites of more mature neurons, reminiscent of synaptic specializations. Interestingly, in a subpopulation of cortical neurons transfected at 13 days in vitro, we find that alpha-synuclein appears to aggregate into distinct punctate inclusions in the cytoplasm and proximal neurites. Unlike Lewy bodies, these structures are not ubiquitin positive. These regions of alpha-synuclein accumulation are observed following transfections with wild-type, Ala30Pro or Ala53Thr alpha-synuclein; neither mutation alters their frequency.

Animals↗

PubMed2000

Mechanisms of cell death in neurodegenerative disorders.

OBJECTIVE: Progressive cell loss in specific neuronal populations is the prominent pathological hallmark of neurodegenerative diseases, but its molecular basis remains unresolved. Apoptotic cell death has been implicated as a general mechanism in Alzheimer disease (AD) and other neurodegenerative disorders. However, DNA fragmention in neurons is too frequent to account for the continuous loss in these slowly progressive diseases. MATERIAL AND METHODS: In 9 cases of morphologically confirmed AD (CERAD criteria, Braak stages 5 or 6), 5 cases of Parkinson disease (PD) and 3 cases each of Dementia with Lewy bodies (DLB), Progressive Supranuclear Palsy (PSP), and Multiple System Atrophy (MSA), and 7 age-matched controls, the TUNEL method was used to detect DNA fragmentation, and immunohistochemistry for an array of apoptosis-related proteins (ARP), protooncogenes, and activated caspase-3 were performed. RESULTS: In AD, a considerable number of hippocampal neurons showed DNA fragmentation with a 3 to 5.7 fold increase related to neurofibrillary tangles and amyloid deposits, but only exceptional neurons displayed apoptotic morphology (1 in 1100-5000) and cytoplasmic immunoreactivity for ARPs and activated caspase-3 (1 in 2600 to 5650 hippocampal neurons), whereas no neurons were labeled in age-matched controls. Caspase-3 immunoreactivity was seen in granules of granulovacuolar degeneration, only rarely colocalized with tau-immunoreactivity. In PD, DLB, and MSA, TUNEL positivity and expression of ARPs or activated caspase-3 was only seen in microglia, rare astrocytes and in oligodendroglia with cytoplasmic inclusions in MSA, but not in nigral or other neurons with or without Lewy bodies. In PSP, only single neurons but oligodendrocytes, some with tau deposits, in brainstem tegmentum and pontine nuclei were TUNEL-positive and expressed both ARPs and activated caspase-3. CONCLUSIONS: These data provide evidence for extremely rare apoptotic neuronal death in AD compatible with the progression of neuronal degeneration in this chronic disease. In other neurodegenerative disorders, apoptosis mainly involves microglia and oligodendroglia, while alternative mechanisms of neuronal death may occur. Susceptible cell populations in a proapoptotic environment show increased vulnerability towards metabolic and other pathogenic factors, with autophagy as a possible protective mechanism in early stages of programmed cell death. The intracellular cascade leading to cell death still awaits elucidation.

Amyloid↗

PubMed1990

Phosphorylated high molecular weight neurofilament protein in lower motor neurons in amyotrophic lateral sclerosis and other neurodegenerative diseases involving ventral horn cells.

Lower motor neurons of the spinal cord of patients with amyotrophic lateral sclerosis (ALS), Werdnig-Hoffmann's disease (WH), X-linked recessive bulbospinal neuronopathy (X-BSNP) and multiple system atrophy (MSA), all of which were known to involve the lower motor neurons, were immunohistochemically examined by using a monoclonal antibody (Ta-51) specific to phosphorylated epitopes of high molecular weight subunits of neurofilaments. The incidence of Ta-51-positive neurons was significantly increased in ALS, WH and MSA, but not in X-BSNP. Ta-51-positive neurons showed a wide variety of morphological appearances, including neurons with normal appearance, central chromatolysis, simple atrophy and neurons containing massive neurofilamentous accumulation. In aged-control cases, similar Ta-51-positive neurons were observed, although to a much lesser extent. In ALS, spheroids and globules, which were strongly positive for Ta-51, were also significantly increased. Ta-51-positive motor neurons, spheroids and globules appeared in proportional to the number of remaining large motor neurons in ALS.

Adolescent↗

PubMed1989

Degenerative neurological disorders associated with deficiency of glutamate dehydrogenase.

The activity of glutamate dehydrogenase, the enzyme of glutamate degradation, was measured in platelets of 27 healthy controls and 85 patients with different degenerative cerebellar and/or basal ganglia disorders. A group of 7 patients was selected with slowly progressive multiple-system atrophy, in whom a clinical diagnosis of olivopontocerebellar atrophy appeared tenable, with decreased activity of glutamate dehydrogenase (38% of the mean control value). In 4 patients data on inheritance were compatible with the genetic pattern of autosomal recessive inheritance, while 3 patients were sporadic cases. In an effort to define this group of patients more precisely, it is suggested that decreased activity of glutamate dehydrogenase induces an increase in extracellular glutamate levels in the central nervous system with subsequent development of excitotoxicity.

Adult↗

PubMed1994

Alcohol ingestion lowers supine blood pressure, causes splanchnic vasodilatation and worsens postural hypotension in primary autonomic failure.

Patients with pure autonomic failure (PAF) and multiple system atrophy (MSA) may complain of feeling light-headed after alcohol ingestion particularly on assumption of the upright posture. The reasons for this have not been investigated. We therefore studied the effects of oral alcohol (40% vodka in sugar-free orange juice) and placebo (juice only) on the systemic and regional (including superior mesenteric artery, SMA) blood flow in nine patients with PAF and six patients with MSA. After alcohol, there was a fall in supine blood pressure (BP) and vasodilatation in the SMA but no change in cardiac output, or forearm muscle and cutaneous blood flow in either PAF or MSA; BP fell further during head-up tilt with no changes in levels of plasma catecholamines. After placebo, there were no changes while supine. We conclude that alcohol lowers supine BP and dilates the SMA with no change in muscle or cutaneous blood flow. Alcohol also enhances the fall in BP during head-up tilt. This may explain the symptoms experienced by PAF and MSA patients after alcohol.

Adult↗

PubMed1991

Sleep patterns and blood pressure variability in patients with pure autonomic failure.

Sleep patterns and 24-h blood pressure variability were studied in four female patients (age range: 56-82 years) with pure autonomic failure. All patients had severe symptomatic postural hypotension, without neurological deficits. In these patients the following patterns were observed: (i) a reversed diurnal blood pressure pattern, with the highest values observed at sleep onset; (ii) a prolonged sleep latency and increased amount of stage 3 sleep; (iii) difficulty with getting up after awakening in the morning, due to severe postural hypotension; (iv) an absence of prominent respiratory abnormalities during sleep; and (v) a dissociation between respiratory and haemodynamic findings. It is concluded that isolated deficiency of presumed postganglionic autonomic function influences sleep architecture, probably through absence of buffering of diurnal haemodynamic alterations, such as by postural hypotension and its consequences for body fluid volume regulation. This may be of relevance when sleep patterns are studied in other types of autonomic failure with postural hypotension involving central or preganglionic lesions, as in patients with the Shy-Drager syndrome or multiple system atrophy.

Aged↗

PubMed1995

Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure.

Anemia is a common complication of autonomic failure and reduced red blood cell mass may contribute to the orthostatic hypotension of these patients. We investigated whether treatment with recombinant erythropoietin improves anemia and increases blood pressure in patients with primary autonomic failure. Three patients with multiple system atrophy and autonomic failure and one with pure autonomic failure were studied. All patients had normocytic normochromic anemia and low (n = 2) or normal (n = 2) serum levels of erythropoietin. Treatment with erythropoietin, 4000 U subcutaneously biweekly for 6 weeks, increased hematocrit and blood pressure in all patients. Hematocrit increased from 33.9 +/- 0.7 to 44.3 +/- 1.4%, blood pressure in supine position increased from 150 +/- 8/87 +/- 8 (systolic/diastolic; mean +/- SD) to 166 +/- 25/92 +/- 12 mmHg, and after 3 min in the head-up tilt position from 86 +/- 21/47 +/- 15 to 102 +/- 23/63 +/- 12 mmHg, (p < 0.05). All patients reported improvement in orthostatic symptoms and increased tolerance to standing. The study shows that treatment with erythropoietin improves anemia, increases blood pressure and ameliorates orthostatic hypotension in patients with primary autonomic failure.

Aged↗