A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson's disease left untreated at diagnosis.

BACKGROUND: The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a "wait and watch" policy. The effect of the latter policy on the self reported health status of people with PD is unknown. AIMS: To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ-39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow-up. METHODS: A multicentre, prospective, "real life" observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details. RESULTS: 198 untreated PD were assessed over a mean period of 18 months. During two follow-up assessments, the self reported health status scores in all eight domains of the PDQ-39 and the overall PDQ-39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started. CONCLUSIONS: This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re-evaluation of the policy to delay treatment in newly diagnosed patients with PD.

Inhibition of hypothalamic thyrotropin-releasing hormone messenger ribonucleic acid during food deprivation.

Food deprivation in laboratory rats induces profound changes in the neuroendocrine system. We have investigated the hypothalamic and pituitary responses of the hypothalamo-pituitary thyroid axis to 48-h food deprivation in Sprague-Dawley rats. Peripheral T3 and hypophysial portal TRH were measured by RIA, and TSH beta, PRL, and pro-TRH mRNA were measured using in situ hybridization histochemistry. Peripheral total T3 was greatly reduced in food-deprived rats. Hypothalamic portal blood TRH levels declined significantly with time in control animals. The initial level of TRH in the portal blood of food-deprived rats was significantly reduced compared to that in controls, but did not fall further with time. In situ hybridization histochemistry revealed significantly lower pro-TRH mRNA in the paraventricular nucleus of food-deprived animals, while pro-TRH mRNA in the reticular nucleus remained unaltered. Furthermore, in the anterior pituitary, TSH beta mRNA decreased significantly in food-deprived animals, while PRL mRNA was unaltered. We conclude that the reduction in circulating T3 after food deprivation appears to be due primarily to decreased hypothalamic TRH synthesis and release.

Preproenkephalin and preprotachykinin messenger RNA expression in normal human basal ganglia and in Parkinson's disease.

Striatal expression of preproenkephalin and preprotachykinin messenger RNA was studied in normal controls and in patients with Parkinson's disease using in situ hybridization histochemistry. In controls, preproenkephalin messenger RNA was expressed in a population of medium-sized neurons of mean cross-sectional area 165 microns 2, accounting for 66% of striatal medium-sized neurons, whereas preprotachykinin messenger RNA was expressed in a population of medium-sized neurons of mean cross-sectional area 204 microns 2 (23% larger than those expressing enkephalin, P < 0.05), accounting for 58% of medium-sized striatal neurons. Much lower levels of both preproenkephalin messenger RNA and preprotachykinin messenger RNA were expressed by large neurons in the globus pallidus and substantia nigra reticulata. In addition, preproenkephalin messenger RNA was expressed at low levels by neurons in the subthalamic nucleus. In Parkinson's disease cases, there was a statistically significant increase in preproenkephalin messenger RNA expression in the body of the caudate (109% increase, P < 0.05) and in the intermediolateral putamen (55% increase, P < 0.05) due to an increase in the level of gene expression per neuron rather than an increase in the number of neurons expressing preproenkephalin messenger RNA. Similar increases were observed in other putaminal subregions and in the putamen as a whole, but these did not reach statistical significance. No change in preprotachykinin messenger RNA expression was detected. These findings demonstrate selective up-regulation of a striatal neuropeptide system in Parkinson's disease compatible with increased activity of the "indirect" striatopallidal pathway, which is thought to play a crucial role in the pathophysiology of akinesia and rigidity in this condition.

Glutamate decarboxylase-67 messenger RNA expression in normal human basal ganglia and in Parkinson's disease.

Expression of glutamate decarboxylase-67 messenger RNA was examined in the basal ganglia of normal controls and of cases of Parkinson's disease using in situ hybridization histochemistry in human post mortem material. In controls glutamate decarboxylase-67 messenger RNA expression was detected in all large neurons in both segments of the globus pallidus and in three neuronal subpopulations in the striatum as well as in substantia nigra reticulata neurons and in a small sub-population of subthalamic neurons. In Parkinson's disease, there was a statistically significant decrease of 50.7% in glutamate decarboxylase-67 messenger RNA expression per neuron in the lateral segment of the globus pallidus (controls: mean 72.8 microns2 +/- S.E.M. 8.7 of silver grain/neuron, n = 12; Parkinson's disease: mean 35.9 microns2 +/- S.E.M. 9.7 of silver grain/neuron, n = 9, P = 0.01, Student's t-test). In the medial segment of the globus pallidus, there was a small, but non-significant decrease of glutamate decarboxylase-67 messenger RNA expression in Parkinson's disease (controls: mean 100.6 microns2 +/- S.E.M. 7.2 of silver grain/neuron, n = 11; Parkinson's disease: mean 84.8 microns2 +/- S.E.M. 13.0 of silver grain/neuron, n = 7, P = 0.1, Student's t-test). No significant differences in glutamate decarboxylase-67 messenger RNA were detected in striatal neuronal sub-populations between Parkinson's disease cases and controls. These results are the first direct evidence in humans that there is increased inhibitory drive to the lateral segment of the globus pallidus in Parkinson's disease, as suggested by data from animal models. We therefore provide theoretical support for current experimental neurosurgical approaches to Parkinson's disease.

Effect of food deprivation and altered thyroid status on the hypothalamic-pituitary-thyroid axis in the rat.

Propylthiouracil (PTU) was administered to rats for different lengths of time with or without food deprivation on the last 2 days. Within 4 days of PTU treatment peripheral 3,5,3'-tri-iodothyronine (T3) fell to low levels and beta-subunit of thyroid-stimulating hormone (beta-TSH) mRNA increased significantly in the anterior pituitary. Pro-thyrotrophin-releasing hormone (pro-TRH) mRNA in the hypothalamic paraventricular nucleus (PVN) increased significantly in the control group of animals by 8 days and in the food-deprived group by day 12; the increment of pro-TRH mRNA in the food-deprived group on day 12 was significantly less than that in the control group. In a second study, animals were treated with intraperitoneal injections of T3 with or without the food deprivation. After 4 days of T3 treatment, peripheral T3 levels were markedly increased and pro-TRH mRNA in the PVN and beta-TSH mRNA in the anterior pituitary were significantly reduced. Food deprivation had no additional suppressive effect. These studies confirm that the predominant effect of food deprivation on the thyroid axis is at the hypothalamic or suprahypothalamic level and that it can, at least in part, overcome the increase in TRH mRNA due to diminished T3 feedback.

Up-regulation of tyrosine hydroxylase mRNA in a sub-population of A10 dopamine neurons in Parkinson's disease.

Neuronal injury has been consistently found in A10 midbrain dopamine neurons in Parkinson's disease (PD). To assess changes in neurotransmitter-related gene transcription, in these neurons in PD, tyrosine hydroxylase (TH) mRNA expression was examined in the ventral tegmental area (VTA) of seven PD cases and seven control subjects, using in situ hybridization histochemistry (ISHH). In controls, TH mRNA expression was found in both melanised and non-melanised neurons in the VTA. Neither population expressed dopamine beta-hydroxylase (DBH). Of the melanised neurons, 99% were TH mRNA positive. The level of the TH mRNA signal (expressed as grain density per cell) was similar in the two populations (melanised: 0.129+/-0.004 (mean+/-S.E.M.), n=142 vs. non-melanised: 0.138+/-0.006, n=89, P>0.05, Student's t-Test). In PD cases there was no significant change in TH mRNA expression in melanised neurons (0.138+/-0.003, n=196), and the proportion of positively labeled melanised neurons was 98%. However, non-melanised neurons showed significantly higher TH mRNA (0.163+/-0.006, n=87) than non-melanised neurons in control subjects (P<0.005) and melanised neurons in the PD cases (P<0.0005). This up-regulation of TH mRNA expression in non-melanised neurons may suggest the existence of a compensatory mechanism at presynaptic level.

Dopamine transporter (Dat) and synaptic vesicle amine transporter (VMAT2) gene expression in the substantia nigra of control and Parkinson's disease.

The cellular expression of DAT mRNA and VMAT2 mRNA was investigated in sections of the human post-mortem substantia nigra in control and Parkinson's disease tissue using in situ hybridisation techniques. Short synthetic oligodeoxynucleotides were used to detect these gene transcripts at the cellular level. In the control human nigra, high levels of expression were seen in all sub-divisions of the substantia nigra, especially within medial regions. By contrast, the level of expression of both DAT mRNA and VMAT2 mRNA was markedly reduced in Parkinson's disease; these reductions in hybridisation signal were associated with (i) a marked loss of dopamine-containing cells in the substantia nigra, and (ii) a reduction in both DAT and VMAT2 signal per cell in the remaining pigmented neurones. These disease-related decreases in the cellular abundance of both DAT and VMAT2 gene transcripts in the surviving cells of the parkinsonian nigra may reflect compensatory changes in catecholamine signalling or may be a consequence of neuronal dysfunction.

Nitric oxide synthase mRNA expression in human subthalamic nucleus, striatum and globus pallidus: implications for basal ganglia function.

The distribution of NOS mRNA within human basal ganglia was investigated using in situ hybridisation histochemistry (ISHH). Greater than 95% of subthalamic nucleus neurons were NOS mRNA-positive, between 1.5% and 2% of striatal neurons were positive and scattered NOS mRNA-positive neurons were detected in the medial, but not lateral globus pallidus. Levels of NOS mRNA expression per neuron were considerably higher in the striatum than in the pallidum or subthalamus. These findings have implications for basal ganglia function and disease states.

Selective increase in somatostatin mRNA expression in human basal ganglia in Parkinson's disease.

Levels of the neurotransmitter somatostatin (SS) have previously been shown to be reduced in the cortex and hippocampus of demented parkinsonian patients and patients with Alzheimer's disease. In situ hybridisation histochemistry (ISHH) was performed with an 35S tail-labelled oligonucleotide DNA probe to human SS mRNA, to examine its expression within the striatum, medial medullary lamina (MML) and reticular thalamic nucleus in Parkinson's disease (PD) and in matched controls. A chronic unilaterally MPTP-lesioned L-DOPA-naive primate model was also examined for comparison of SS mRNA expression with that in human L-DOPA treated PD subjects. Quantitation of SS mRNA expression on emulsion dipped sections revealed a significant increase (82%) in the MML of the globus pallidus in PD (56.5 microm2 of silver grain/cell, n = 9 cases) compared to controls (26.3 microm2/cell, n = 13 cases, p < 0.01, Student's t-test), paralleling the increase previously observed by this group for NOS mRNA. SS mRNA expression was higher in the dorsolateral than ventromedial putamen in controls (p < 0.001; DL: 24.89 +/- SEM 1.35; VM: 17.96 +/- SEM 2.63; n = 14) but this gradient was lost in PD cases (p > 0.05; DL: 22.68 +/- 1.94; VM: 22.17 +/- 2.94; n = 10). These findings suggest specific modification of basal ganglia SS-ergic pathways in PD.

Basal ganglia neuronal nitric oxide synthase mRNA expression in Parkinson's disease.

Expression of nitric oxide synthase (NOS) mRNA in post mortem brain was studied in putamen, globus pallidus and subthalamic nucleus (STN) of neurologically normal control subjects and patients with Parkinson's disease (PD) using in situ hybridization histochemistry. In PD, a significant increase in NOS mRNA expression was observed in the dorsal two-thirds of the STN with respect to the ventral one-third of the STN. A significant increase in NOS mRNA expression per cell in the medial medullary lamina of the globus pallidus was also observed in PD. NOS mRNA expression was significantly reduced in PD putamen. These findings provide evidence of increased activity of STN neurotransmitter systems in PD and demonstrate for the first time in any species that basal ganglia nitric oxide systems can be selectively regulated in response to changes in dopaminergic input.

Tissue pH as an indicator of mRNA preservation in human post-mortem brain.

The relationship between pH and mRNA preservation in post-mortem human brain was examined using in situ hybridization histochemistry and Northern hybridization with oligonucleotide probes in a large group of human subjects, including control and neuropathological cases. Tissue pH was found to correlate strongly with preservation of four mRNA species in three brain areas. Tissue with low pH, assumed to result from prolonged terminal hypoxia, contained reduced or absent mRNA, while tissue with higher pH was found to contain quantifiable amounts, the values for pathological brain samples being comparable to those for control material of similar pH. Measurement of tissue pH provides a simple means to screen post-mortem brain for mRNA preservation and is suggested as a means to match material in case-control studies of human neurodegenerative disease.

Deficits in a tricarboxylic acid cycle enzyme in brains from patients with Parkinson's disease.

Parkinson's disease (PD) is associated with mitochondrial dysfunction, specifically a deficiency of complex I of the electron transport chain. Most, although not all, studies indicate that this deficiency is limited to brain regions with neurodegeneration. The current studies tested for deficiencies in other mitochondrial components in PD brain in a neuropathologically unaffected region where the abnormality cannot be attributed to secondary effects of neurodegeneration. The activity of a key (and arguably rate-limiting) tricarboxylic acid cycle enzyme, the alpha-ketoglutarate dehydrogenase complex (KGDHC), was measured in the cerebellum of patients with PD. Activity in 19 PD brains was 50.5% of that in 18 controls matched for age, sex, post-mortem interval, and method of preservation (P<0.0019). The protein subunits of KGDHC were present in normal amounts in PD brains, indicating a relatively discrete abnormality in the enzyme. The activities of another mitochondrial enzyme, glutamate dehydrogenase (GDH), were normal in PD brains. These results demonstrate that specific reductions in KGDHC occur even in pathologically unaffected areas in PD, where the decline is unlikely to be a non-specific result of neurodegeneration. Reductions in the activity of this enzyme, if widespread in the brain, may predispose vulnerable regions to further damage.

Microglial activation in multiple system atrophy: a potential role for NF-kappaB/rel proteins.

Microglial activation is a prominent feature of affected brain areas in multiple system atrophy. Microglia express proinflammatory peptides, which may be a result of activation of nuclear factor-KB. We investigated the nuclear presence of RelA, the 65 kDa subunit of the NF-KB/RelA family in striatum and brain stem of patients with multiple system atrophy. Affected brain areas of patients with multiple system atrophy showed a marked immunoreactivity for nuclear Rel A p65, which was almost exclusively localized in activated microglia. Interestingly nuclear translocation of Rel A was not detected in striatal tissue of controls and Parkinson disease patients. Thus, NF-kappaB/Rel A complexes may play a role in mediating microglial activation in multiple system atrophy.

Central nervous system sarcoidosis--diagnosis and management.

A series of 68 patients with neurosarcoidosis is reported, with particular emphasis on clinical aspects, diagnosis and treatment. A classification system based on clinical diagnostic probability is proposed, consisting of probable and definite disease, the latter being dependent on finding sarcoid granulomas on nervous system histology, which was obtained in 12 patients (18%). The role of investigations, including magnetic resonance imaging (MRI), chest radiography, Kveim skin test, Gallium 67 isotope scanning and cerebrospinal fluid (CSF) studies, is considered. Sixty-two percent of patients presented with nervous system disease, most commonly affecting the optic nerve and chiasm. Other common presentations included cranial nerve palsies, spinal cord and brainstem manifestations. Investigations yielding most diagnostic information included the Kveim test (41/48, 85% positive), raised CSF protein and/or cells (50/62, 81%) and gallium 67 scan (14/31, 45%). Eleven out of 29 patients (38%) patients showed meningeal enhancement on MRI scanning and 43% of scans demonstrated multiple white-matter lesions. Mean follow-up for the group was 4.6 years. Forty-seven patients were seen for > 18 months, and over half of these patients progressed despite corticosteroid and other immunosuppressive therapies. The benefit of a large patient database prospectively studied, with extended follow-up is discussed in order to learn more about prognosis and advance therapy in neurosarcoidosis.

Neuropeptide Y and tyrosine hydroxylase mRNA levels in the locus coeruleus show similar increases after reserpine treatment.

In situ hybridisation histochemistry was used to study the effect of intra-peritoneal reserpine administration on messenger RNA (mRNA) levels in the locus coeruleus (LC) of the rat. 48h after injection, levels of mRNA encoding tyrosine hydroxylase (TH) and neuropeptide Y (NPY) in the LC increased to approximately 250% of control values (p less than 0.05). The level of beta-tubulin mRNA was unaffected by reserpine administration. The similar and selective increase in TH and NPY mRNA in the LC following reserpine administration suggests that NPY may play a role in the neurotransmitter function of this catecholaminergic nucleus.

A simplified and rapid procedure for in situ hybridization on human, flash-frozen, post-mortem brain and its combination with immunohistochemistry.

A simplified and rapid method is described for in situ hybridization (ISHH) studies of human post-mortem brain. Brain tissue was dissected into slices and was flash-frozen at -70 degrees C for storage. ISHH was carried out on 12 microns cryostat sections, post-fixed in 4% paraformaldehyde. The histology of human brain tissue prepared by this technique rivalled that of formalin-fixed, wax-embedded tissue. In ISHH studies, flash-frozen tissue gave superior results to those obtained following long-term fixation of tissue in 10% formalin with subsequent wax-embedding, or short-term prefixation in 4% paraformaldehyde. A systematic evaluation of commonly employed preparative procedures for ISHH was carried out on flash-frozen brain and a simplified protocol, consisting only of fixation and dehydration, was developed as a result of these studies. Specific hybridization of probes to a number of mRNA species was demonstrable in neurons in different brain regions. Using 0.5% glutaraldehyde/4% paraformaldehyde post-fixation, immunohistochemical labelling of TH-positive cortical catecholaminergic neurons and striatal dopaminergic terminals was successfully demonstrated in flash-frozen tissue. The same fixation technique also allowed combination of ISHH and immunohistochemistry for the simultaneous demonstration of tyrosine hydroxylase mRNA and peptide in neurons of human brain stem and cortex. mRNA and peptides in flash-frozen tissue were found to be stable for more than 3 years. ISHH could be readily performed on relatively large brain structures. In addition to permitting excellent ISHH and immunohistochemistry, alone or in combination, flash-freezing allows the maximum versatility of tissue use and does not compromise its study by other neuroscience techniques.

Raised intracranial pressure and visual complications in AIDS patients with cryptococcal meningitis.

The clinical course of cryptococcal meningitis in AIDS shows some important differences from the features of the illness in non-AIDS patients. Complications such as raised intracranial pressure and visual impairment that are recognised in non-AIDS patients may be less frequent in those with AIDS. Persistent intracranial hypertension should be managed actively to prevent visual impairment. In AIDS patients, in whom ventriculo-peritoneal shunts carry additional risks, acetazolamide can be used successfully to lower the CSF pressure and prevent visual loss.

PIP: 2 AIDS patients are described who had cryptococcal meningitis accompanied by increased intracranial pressure (ICP) and visual complications, a finding thought to be relatively rare in AIDS. Of the 2-6% of AIDS patients who develop cryptococcal meningitis, many have disseminated and recurrent infections. The 1st case was a 45-year old Ugandan woman who presented with stiff neck, and right VIth cranial nerve palsy. She was treated with amphotericin B and flucytosine with some improvement, but on the 9th day she awoke with headache, drowsiness, and total blindness, although no papilledema. Her CSF pressure was 40 cm H20. She recovered after a month of intravenous chemotherapy and acetazolamide, but remained blind. Her sudden blindness was thought to be due to bilateral optic nerve infarction. The 2nd case was a 32-year old male homosexual, admitted with headache, vomiting, confusion, and drowsiness. He had stiff neck, and a CSF of 40 cm containing Cryptococcus neoformans. He was given amphotericin B, flucytosine, and has CSF drained every other day. On day 21 papilledema was seen in the right eye, and acetazolamide was started to lower CSF pressure. This patient recovered without loss of vision. 3 published series of cryptococcus meningitis in AIDS patients remarked about the low incidence of raised ICP, while 1 reported 9 of 27 with neurological and ophthalmic complications. The visual complications and increased ICP in these patients was thought to be due to inflammatory arachnoiditis or direct cryptococcal infiltration.

Algoneurodystrophy following herpes zoster.

Algoneurodystrophy frequently follows an identifiable triggering event. It is not widely recognized that herpes zoster can precipitate algoneurodystrophy and three such cases are described here. In one, the affected dermatome did not correspond to the limb involved by the algoneurodystrophy.

Syrinx associated with intramedullary metastasis.

Two cases are reported of syrinx associated with an intramedullary metastasis. The first presented with hyperaesthesia in the right arm and bilateral pyramidal leg weakness, the second with a partial right sided Brown Sequard syndrome with a sensory level at D6. A possible pathological mechanism for the development of such syrinxes is discussed.