Culturally adapted psychosocial interventions (CaPSI) for early psychosis in a low-resource setting: study protocol for a large multi-center RCT.

BACKGROUND: Psychosis treatment guidelines recommend cognitive behaviour therapy (CBT) and family intervention (FI), for all patients with first episode psychosis (FEP), though guidance borrows heavily from literature in adults from high income countries. To our knowledge, there are few randomized controlled trials (RCTs) examining the comparative effect of these commonly endorsed psychosocial interventions in individuals with early psychosis from high-income countries and no such trials from low and middle-income countries (LMICs). The present study aims to confirm the clinical-efficacy and cost-effectiveness of delivering culturally adapted CBT (CaCBT) and culturally adapted FI (CulFI) to individuals with FEP in Pakistan. METHOD: A multi-centre, three-arm RCT of CaCBT, CulFI, and treatment as usual (TAU) for individuals with FEP (n = 390), recruited from major centres across Pakistan. Reducing overall symptoms of FEP will be the primary outcome. Additional aims will include improving patient and carer outcomes and estimating the economic impact of delivering culturally appropriate psychosocial interventions in low-resource settings. This trial will assess the clinical-efficacy and cost-effectiveness of CaCBT and CulFI compared with TAU in improving patient (positive and negative symptoms of psychosis, general psychopathology, depressive symptoms, quality of life, cognition, general functioning, and insight) and carer related outcomes (carer experience, wellbeing, illness attitudes and symptoms of depression and anxiety). CONCLUSIONS: A successful trial may inform the rapid scale up of these interventions not only in Pakistan but other low-resource settings, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority groups with FEP. TRIAL REGISTRATION: NCT05814913.

Identification of FUS p.R377W in essential tremor.

BACKGROUND AND PURPOSE: Exome sequencing analysis has recently identified a nonsense mutation in fused in sarcoma (FUS) segregating with essential tremor (ET) within a large French-Canadian family. Further characterization of FUS resulted in the identification of additional mutations in ET patients; however, their pathogenicity still remains to be confirmed. The role of FUS in an independent cohort of ET patients from Canada was evaluated. METHODS: The entire coding sequence of FUS in 217 patients diagnosed with ET was analyzed and two missense variants in 219 healthy controls were genotyped by Sanger sequencing. RESULTS: Sequencing of FUS identified a previously reported non-pathogenic mutation p.G174_G175del in one ET patient and two healthy controls, and a novel p.R377W in one patient with family history of disease. This mutation is highly conserved and strongly predicted to be damaging by in silico analysis. CONCLUSION: This study has identified a novel FUS p.R377W substitution in ET patients. Additional genotyping studies in a large number of ET patients and controls are necessary to conclusively define its pathogenicity.

Gamma-aminobutyric acid (GABA)-B receptor 1 in cerebellar cortex of essential tremor.

Some reports suggest cerebellar dysfunction as the basis of essential tremor (ET). Several drugs with the action of gamma-aminobutyric acid (GABA) are known to improve ET. Autopsy studies were performed on brains from nine former patients followed at the Movement Disorders Clinic Saskatchewan, Canada, and compared with five normal control brains. We aimed to measure the concentration of GABA B receptor 1 (GBR1) in the brains of patients who had had ET and to compare them to the GABA concentration in brains of controls. Western blot was used to determine the expression of GBR1 in cerebellar cortex tissue. We found that compared to the controls, the ET brains had three different patterns of GBR1 protein concentration--two with high, four comparable, and three with marginally low levels. There was no association between the age of onset, severity or duration of tremor, the response to alcohol or other drugs and GBR1 level. Thus, we conclude that our study does not support that GBR1 is involved in ET. Further studies are needed to verify these results.

Essential tremor is not dependent upon cerebellar Purkinje cell loss.

UNLABELLED: The pathophysiology of essential tremor (ET) is unknown but recent studies report that the majority of ET cases has cerebellar Purkinje cell (PC) degeneration and its sequelae. OBJECTIVE: To perform PC counts in ET, and normal and Parkinson's disease (PD) controls to determine the relationship of PC loss to ET. METHODS: All ET cases and PD controls were followed at our clinic. Normal controls had no history of neurological disease and had normal standard neuropathological studies. The PC counts were done by a neuropathologist who was blinded to the clinical diagnosis. Three different methods were used for counting PC; section through any part of the PC, through any part of the PC nucleus, and through any part of PC nucleolus. The counts were done in five non-contiguous microscopic fields. RESULTS: 59 brains were studied. These included 12 ET, 41 PD controls, and six normal controls. The mean age at death was 82.7 in ET, 79.1 in PD, and 75.7 years in the normal controls. The mean duration of symptoms was 34 years in ET and 15.7 years in the PD cases. The mean PC counts through any part of the neuron were 64.8 in ET, 56.2 in PD, and 58.0 in normal controls. Differences were not significant. CONCLUSION: Cerebellar PC loss does not distinguish ET from controls. It is concluded that PC loss is neither a pathological basis for, nor the distinctive feature of ET.

Death-associated protein kinase 1 variation and Parkinson's disease.

BACKGROUND AND PURPOSE: Mutations of the LRRK2 gene are now recognized as major risk factors for Parkinson's disease. The Lrrk2 protein is a member of the ROCO family, which also includes Lrrk1 and Dapk1. Functional genetic variants of the DAPK1 gene (rs4877365 and rs4878104) have been previously associated with Alzheimer's disease. METHODS: Herein, we assessed the role of DAPK1 variants (rs4877365 and rs4878104) in risk of Parkinson's disease with Sequenom iPLEX genotyping, employing one Taiwanese series (391 patients with Parkinson's disease, 344 controls) and five separate Caucasian series' (combined sample size 1962 Parkinson's disease patients, 1900 controls). RESULTS: We observed no evidence of association for rs4877365 and rs4878104 and risk of Parkinson's disease in any of the individual series or in the combined Caucasian series under either an additive or recessive model. CONCLUSION: These specific DAPK1 intronic variants do not increase the risk of Parkinson's disease. However, further functional studies are required to elucidate the potential therapeutic implications with the dimerization of the Dapk1 and Lrrk2 proteins.

Significance of cerebellar Purkinje cell loss to pathogenesis of essential tremor.

UNLABELLED: Some recent studies indicate that most essential tremor (ET) cases have cerebellar pathology characterized by Purkinje cell (PC) loss and its sequelae. OBJECTIVE: To assess the role of PC degeneration in ET symptomatology. METHODS: We studied seven ET, six tremor dominant Parkinson's disease controls and two normal control brains. Cerebellar PC counts were done in all cases by a neuropathologist using three different methods to identify PC. RESULTS: There were individual differences in PC counts in all subgroups. There was no difference between ET and controls of the same age. The PC count in ET was not related to: onset site of ET, severity of symptoms, or any other clinical features that we studied but there was a trend to a reduced number of PC with age in all groups. CONCLUSION: There is no evidence in our study or in the literature to date indicating that PC loss is the pathological basis of ET. Further studies are needed to determine the pathophysiology of ET.

Cerebellar Purkinje cell loss is not pathognomonic of essential tremor.

BACKGROUND: Most of the literature on pathology of essential tremor (ET) has reported no consistent abnormalities. Some recent studies however indicate that cerebellar Purkinje cell (PC) loss is the pathological basis of ET in most patients. OBJECTIVE: To compare cerebellar PC loss in ET, with normal and tremor dominant Parkinson's disease [PD] control brains. METHODS: Cerebellar PC counts were performed in seven ET, six PD and two normal control brains. Three different counting methods - sectioned through nucleolus, through nucleus and through any part of PC body, were used to count the PC. RESULTS: There were individual differences in the PC counts both in the ET and the PD cases. In all three subgroups, there was a reduction in the number of PC with advancing age. When the individuals of comparable age in the three subgroups were considered, there was no clear distinction between ET, PD and normal control subjects. There was no association between the degree of PC loss and the severity or the duration of ET. CONCLUSION: Our study militates against the hypothesis that PC loss is pathognomonic of ET.

Course in Parkinson disease subtypes: A 39-year clinicopathologic study.

BACKGROUND: Individual variations in the course of Lewy body Parkinson disease (PD) are well known. Patients have been classified into different clinical subtypes to identify differences in the course among the subgroups. Several studies indicate that the outcome is more favorable in tremor dominant (TD) cases but others report no difference. A majority of progression studies are based on cross-sectional single point data or short-term clinical observations. The lack of longitudinally followed autopsy-confirmed PD cohort remains a major weakness in the literature. Biochemical studies of brain indicate most pronounced abnormalities in akinetic/rigid (AR) and the least in TD cases. We postulate that PD course in these subtypes is concordant with the biochemical findings. OBJECTIVE: To compare the course in TD, mixed (MX), and AR subtypes of PD. METHODS: Longitudinal clinical follow-up and autopsy studies were performed on 166 patients with PD over 39 years (1968-2006). Patients were classified into TD, AR, and MX based on the entire clinical course. Only the pathologically confirmed PD cases were included. RESULTS: Sixty-six percent of cases had MX, 26% AR, and 8% TD profile. The age at onset was younger (p < 0.001) and progression to Hoehn & Yahr stage 4 was slower (p = 0.016) in the TD cases. Dementia was most common in AR (p = 0.039) and the least common in TD. In general, the course was most favorable in TD, followed by MX and AR subgroups. CONCLUSION: The three subtypes of Parkinson disease have different courses which are concordant with the differences in brain biochemical abnormalities.

Vascular pathology in male Lewis rats following short-term, low-dose rotenone administration.

The long-term administration of low doses of rotenone has been used to produce a model of Parkinson disease (PD) in rats. However, only about 50% of similarly treated rats develop the PD-like syndrome, with many dying during the first few days of treatment. The lesions in male Lewis rats that became moribund or died after short-term, low-dose rotenone administration are described. Dosed rats had fibrinoid change and acute hemorrhage involving small arteries and arterioles of the brain and lungs. The thalamus, hypothalamus, and medulla oblongata were most frequently and severely affected. Blood vessels in the brain of some male Lewis rats appeared acutely susceptible to the effects of rotenone. Understanding the selective nature of the fibrinoid change and hemorrhage might explain how rotenone produces PD-like signs and lesions in rats, and it might also provide the basis for a model of intraparenchymal hemorrhagic cerebrovascular disease (i.e., hemorrhagic strokes) in humans.

Globus pallidus dopamine and Parkinson motor subtypes: clinical and brain biochemical correlation.

BACKGROUND: Patients with Parkinson disease (PD) may be akinetic/rigid, be tremor dominant, or have comparable severity of these motor symptoms (classic). The pathophysiologic basis of different PD phenotypes is unknown. This study assessed pallidal and striatal dopamine level patterns in different motor subgroups of PD and normal control brains. METHODS: Globus pallidus and striatum dopamine (DA) levels were measured with high performance liquid chromatography in eight autopsy confirmed PD and five control frozen brains. RESULTS: DA levels in the external globus pallidus (GPe) of normal brains were nearly six times greater than in the internal pallidum (GPi). In PD, the mean loss of DA was marked (-82%) in GPe and moderate (-51%) in GPi. DA loss of variable degree was seen in different subdivisions of GPe and GPi in PD; however, DA levels were near normal in the ventral (rostral and caudal) GPi of PD cases with prominent tremor. There was marked loss of DA (-89%) in the caudate and severe loss (-98.4%) in the putamen in PD. The pattern of pallidal DA loss did not match the putaminal DA loss. CONCLUSION: There is sufficient loss of dopamine (DA) in external globus pallidus and the internal globus pallidum (GPi) as may contribute to the motor manifestations of Parkinson disease (PD). The possible functional disequilibrium between GABAergic and DAergic influences in favor of DA in the caudoventral parts of the GPi may contribute to resting tremor in tremor dominant and classic PD cases.

Brain aconitase activity is not decreased in progressive supranuclear palsy.

The novel finding of decreased activity of aconitase, a key Krebs cycle enzyme highly sensitive to oxidative damage, in cybrid cell lines using mitochondrial DNA from patients with progressive supranuclear palsy (PSP) implies an enzyme abnormality in brain. However, the authors found that postmortem brain aconitase activity is normal in PSP. This suggests that patients with PSP do not have systemic aconitase deficiency and that data derived from cybrid cell models of neurodegenerative disorders might not always predict similar changes in human brain.

Elevated levels of DeltaFosB and RGS9 in striatum in Parkinson's disease.

INTRODUCTION: In the present study, we determined whether certain proteins known to mediate dopamine signaling in striatum show abnormal levels in Parkinson's disease. METHODS: Protein levels were assayed by western blotting in samples of caudate nucleus and putamen obtained at autopsy from patients with Parkinson's disease and from control subjects. Levels of several markers of dopaminergic function were also assayed. RESULTS: Levels of the transcription factor DeltaFosB and of the G protein modulatory protein RGS9 were both increased in caudate and putamen from patients with Parkinson's disease. Levels of several other proteins were not affected. Interestingly, levels of both DeltaFosB and RGS9 correlated inversely with putamen levels of dopamine, dopamine metabolites, and the dopamine transporter. CONCLUSIONS: These findings are consistent with observations in laboratory animals, which have demonstrated elevated levels of DeltaFosB in striatum after denervation of the midbrain dopamine system, and confirm that similar adaptations in DeltaFosB and RGS9 occur in humans with Parkinson's disease. Knowledge of these adaptations can help us understand the changes in striatal function associated with Parkinson's disease and assist in the development of novel treatments.

The protective role of levodopa in the human substantia nigra.

Laboratory studies and studies of animal models of parkinsonism have produced contradictory evidence, but there is no evidence that LD is toxic to normal substantia nigra in animals. We have studied human subjects longitudinally to address that issue. A cumulative LD dose up to 24 kg was not toxic in one autopsied essential tremor (ET) case. Two other ET patients did not develop parkinsonism on 8.5 kg and 21 kg cumulative LD dose, respectively. One DOPA-responsive dystonia (DRD) case has no evidence of parkinsonism after 29 years and more than 17 kg of LD. A DRD patient who received 3 kg over 11 years had normal SN neuronal complement at autopsy. One patient who has clinical and laboratory evidence of nigral pathology as the basis of parkinsonism when untreated for 18 years had progressive disability. While on LD he has excellent symptomatic benefit and virtual cessation of progression of the disease. Epidemiologic studies indicate that those prescribed LD at an early stage of illness and hence given larger cumulative lifetime doses have longer survival than those in whom LD is started late and who receive smaller total doses. Our observations and the available literature support that levodopa is not toxic to normal or diseased substantia nigra in human beings. Evidence presented here indicates that levodopa has a protective effect on the human substantia nigra neurons.

Levodopa prolongs life expectancy and is non-toxic to substantia nigra.

The primary objective of the study was to determine the effect of levodopa (LD) on human substantia nigra. The study included patients seen at the Movement Disorder Clinic, Saskatoon over a 32 year period. The evidence provided is based on epidemiological observations of 934 consecutive Parkinson syndrome (PS) patients assessed during 22 years and detailed studies of six patients including two autopsies. Life expectancy increased significantly with LD therapy. The prolonged survival was evident when the patients were treated during early stage of the illness. One parkinsonian patient with substantia nigra (SN) pathology who was extensively studied for 30 years, revealed significant slowing of the disease progression while on LD. Three essential tremor patients who received 24 kg (26 years), 22 kg (21.5 years), and 8.5 kg (12.5 years) LD respectively, had no evidence of PS and one autopsy revealed normal SN. Two dopa-responsive dystonia patients who received LD 3 kg (11 years) and 17 kg (29 years) each had no evidence of PS and one autopsy revealed normal number of SN neurons. These observations indicate that LD is not toxic to human SN and are consistent with salutary effect of the drug on the SN in Parkinson's disease.

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Elevated activity of phospholipid biosynthetic enzymes in substantia nigra of patients with Parkinson's disease.

We reported that the activities of phospholipase A2, phosphocholine cytidylyltransferase and phosphoethanolamine cytidylyltransferase, key phospholipid metabolic enzymes, are low in substantia nigra of normal human brain and that this might reduce the ability of nigral neurons to repair damage to cell membranes. To determine whether adaptive changes in nigral phospholipid metabolism can occur in idiopathic Parkinson's disease we compared activities of 11 catabolic and anabolic enzymes in autopsied brain of 10 patients with Parkinson's disease to those in control subjects. Nigral activity of the catabolic enzyme phospholipase A2 was normal in the Parkinson's disease group, whereas that of the biosynthetic enzymes phosphoethanolamine cytidylyltransferase, phosphocholine cytidylyltransferase, and phosphatidylserine synthase were elevated 193, 48 and 38%, respectively, possibly representing a compensatory response to repair membrane phospholipids. Enzyme activities were normal in all other brain areas with the exception of increased (+26%) activity of calcium-stimulated phospholipase A2 in putamen, a change which could be consequent to either decreased dopaminergic striatal input or to a dopamine nerve terminal degenerative process. Our data indicate that the normally low rate of membrane phospholipid synthesis in the substantia nigra, the primary area of neurodegeneration in Parkinson's disease, is increased during the course of the disorder. We suggest that pharmacotherapies which augment this compensatory response might have utility as a treatment for Parkinson's disease.

Progressive supranuclear palsy: clinical features, pathophysiology and management.

Progressive supranuclear palsy (PSP) is a degenerative condition of unknown aetiology that produces an akinetic-rigid form of parkinsonism characterised by early falls and abnormalities of extraocular movements. Mean age of onset is approximately 63 years, and mean survival from symptom onset is 9 years. Men are much more frequently affected than women. The classic clinical finding is supranuclear ophthalmoplegia, which may not present until late in the illness, if at all. The clinical diagnosis of PSP can be difficult to make, as the sites of pathology are heterogeneous. Structural and functional neuroimaging studies, although not specific for PSP, may be of some assistance in making the diagnosis. The definitive diagnosis of PSP requires the presence of both clinical and neuropathological evidence. Multiple anatomical sites are affected in PSP. The most consistently involved are the subthalamic nucleus, globus pallidus interna and externa, pontine nuclei, periaqueductal grey matter and the substantia nigra. The location of the pathology accounts for the clinical features. The histological hallmark of PSP is the presence of globose neurofibrillary tangles in the affected subcortical nuclei. Neurofibrillary tangles are composed of abnormally phosphorylated tau, a microtubule-associated protein that is involved in maintenance of the cytoskeleton. Abnormalities near or in the gene coding for tau are implicated in the pathogenesis of PSP. The multiple neurotransmitter abnormalities, including those affecting dopamine, acetylcholine, gamma-aminobutyric acid and norepinephrine (noradrenaline) systems and pathways, as well as both pre- and post-synaptic pathology, make pharmacological therapy of PSP a challenge. Although an individual patient may respond to a drug, in general patients with PSP have a minimal response and a short duration of sustained benefit.