Early hematopoietic stem cell transplantation in a patient with severe mucopolysaccharidosis II: A 7 years follow-up.

Mucopolysaccharidosis type II (MPS II - Hunter syndrome) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2 sulfatase (I2S), leading to the accumulation of the glycosaminoglycans, affecting multiple organs and systems. Enzyme replacement therapy does not cross the blood brain barrier, limiting results in neurological forms of the disease. Another option of treatment for severe MPS, hematopoietic stem cell transplantation (HSCT) has become the treatment of choice for the severe form of MPS type I, since it can preserve neurocognition when performed early in the course of the disease. To date, only few studies have examined the long-term outcomes of HSCT in patients with MPS II. We describe the seven-year follow-up of a prenatally diagnosed MPS II boy with positive family history of severe MPS form, submitted to HSCT with umbilical cord blood cells at 70 days of age. Engraftment after 30 days revealed mixed chimerism with 79% donor cells; after 7 years engraftment remains at 80%. I2S activity 30 days post-transplant was low in plasma and normal in leukocytes and the same pattern is observed to date. At age 7 years growth charts are normal and he is very healthy, although mild signs of dysostosis multiplex are present, as well as hearing loss. The neuropsychological evaluation (Wechsler Intelligence Scale for Children - Fourth Edition - WISC-IV), disclosed an IQ of 47. Despite this low measured IQ, the patient continues to show improvements in cognitive, language and motor skills, being quite functional. We believe that HSCT is a therapeutic option for MPS II patients with the severe phenotype, as it could preserve neurocognition or even halt neurodegeneration, provided strict selection criteria are followed.

Evidence of a breakdown of corticostriatal connections in Parkinson's disease.

Dendritic spines are important structures which receive synaptic inputs in many regions of the CNS. The goal of this study was to test the hypothesis that numbers of dendritic spines are significantly reduced on spiny neurones in basal ganglia regions in Parkinson's disease as we had shown them to be in a rat model of the disease [Exp Brain Res 93 (1993) 17]. Postmortem tissue from the caudate and putamen of patients suffering from Parkinson's disease was compared with that from people of a similar age who had no neurological damage. The morphology of Golgi-impregnated projection neurones (medium-sized spiny neurones) was examined quantitatively. The numerical density of dendritic spines on dendrites was reduced by about 27% in both nuclei. The size of the dendritic trees of these neurones was also significantly reduced in the caudate nucleus from the brains of PD cases and their complexity was changed in both the caudate nucleus and the putamen. Dendritic spines receive crucial excitatory input from the cerebral cortex. Reduction in both the density of spines and the total length of the remaining dendrites is likely to have a grave impact on the ability of these neurones to function normally and may partly explain the symptoms of the disorder.

The L-dopa response in vascular parkinsonism.

OBJECTIVE: To determine whether a positive L-dopa response in vascular parkinsonism (VP) is correlated with the presence of nigrostriatal pathology due to either vascular damage or neuronal cell loss. METHODS: Seventeen patients with pathologically confirmed VP were selected from the pathological collection of the Queen Square Brain Bank for Neurological Disorders, and their L-dopa response during life was compared with the presence of macroscopic vascular damage in the nigrostriatal pathway and microscopic substantia nigra cell loss. RESULTS: Ten of the twelve patients with a good or excellent response had macroscopic infarcts or lacunae caused by enlarged perivascular spaces in the basal ganglia or microscopic neuronal cell loss in the substantia nigra. In contrast, only one of the five patients with a moderate or no response had lacunae in the putamen, and none had lacunar infarcts or substantia nigra cell loss. CONCLUSION: These results suggest that a substantial number of patients with clinically suspected VP may respond with benefit to dopaminergic therapy, especially those with lesions in or close to the nigrostriatal pathway.

Do published criteria improve clinical diagnostic accuracy in multiple system atrophy?

OBJECTIVE: To assess the accuracy of a clinical diagnosis of multiple system atrophy (MSA) and compare it to the Quinn and Consensus criteria for MSA using neuropathologically examined cases from the Queen Square Brain Bank for Neurological Disorders. METHODS: Fifty-nine cases with a neurologic diagnosis of MSA when last assessed prior to death were studied. RESULTS: In 51 (86%) of these cases, the diagnosis of MSA was confirmed pathologically. False positive diagnoses included PD (n = 6), progressive supranuclear palsy (n = 1), and cerebrovascular disease (n = 1). When applying either set of diagnostic criteria, a diagnosis of probable MSA gave lower sensitivity but higher positive predictive value than one of possible MSA. Application of either set of diagnostic criteria was superior to actual clinical diagnosis made early in the disease, but there was little difference by the last clinic visit. CONCLUSIONS: This study shows a high diagnostic accuracy for the clinical diagnosis of MSA by neurologists, with PD accounting for most of the false positive diagnoses. Application of either Quinn or Consensus criteria was superior to actual clinical diagnosis made early in the disease, but there was little difference by last clinic visit.

Pathological, clinical and genetic heterogeneity in progressive supranuclear palsy.

We have identified two groups of patients with clinically typical and atypical, pathologically diagnosed progressive supranuclear palsy (PSP), and investigated their genetic and molecular pathological characteristics. Those with clinically typical PSP are more likely to have the PSP susceptibility genotype and to have the deposition of PSP-type hyperphosphorylated tau protein. The clinically atypical PSP group contains a number of different clinical syndromes, including an L-dopa unresponsive bradykinetic syndrome and a clinical syndrome closely resembling idiopathic Parkinson's disease. The clinically atypical PSP group are less likely to have the PSP susceptibility genotype and often have the deposition of Alzheimer's disease paired helical filament type hyperphosphorylated tau. This study suggests that the tau PSP susceptibility genotype is most strongly associated with clinically typical PSP. Neurofibrillary tangle parkinsonian disorders, which pathologically resemble PSP but involve the deposition of Alzheimer's disease-type tau often without involvement of the tau susceptibility genotype, need to be distinguished for diagnostic and research purposes.

Sequence analysis of tau in familial and sporadic progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a tau deposition neurodegenerative disorder which usually occurs in sporadic form and is associated with a common variant of the tau gene. Rare familial forms of PSP have been described. Recently familial frontotemporal dementia linked to chromosome 17 (FTDP-17) has been shown to be due to mutations in tau and there may be a clinical and pathological overlap between PSP and FTDP-17. In this study we have analysed the tau sequence in two small families with PSP, and a number of clinically typical and atypical sporadic cases with pathological confirmation of the diagnosis. The tau mutations described in FTDP-17 were not found in the most clinically diagnosed patients with PSP. This suggests that usually FTDP-17 and PSP, including the rare familial form of PSP, are likely to be separate conditions and that usually PSP and typical PSP-like syndromes are not due to mutations in tau.

Two large British kindreds with familial Parkinson's disease: a clinico-pathological and genetic study.

We present the findings of a study of two large unrelated kindreds with autosomal dominant Parkinson's disease. The affected members were assessed clinically and with [(18)F]6-fluorodopa-PET and were indistinguishable from patients with the sporadic form of Parkinson's disease. In one kindred, an affected member was examined subsequently at autopsy and Lewy bodies were present in a distribution typical of sporadic Parkinson's disease. These kindreds are distinct from other Parkinsonian kindreds with identified genetic loci (PARK1-4) and provide further evidence for genetic heterogeneity in familial Parkinson's disease.

Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease.

The authors studied the accuracy of clinical diagnosis of idiopathic PD (IPD) in 100 consecutive clinically diagnosed cases that came to neuropathological examination. Ninety fulfilled pathologic criteria for IPD. Ten were misdiagnosed: multiple system atrophy (six), progressive supranuclear palsy (two), post-encephalitic parkinsonism (one), and vascular parkinsonism (one). Assessment of the clinical features suggests that an accuracy of 90% may be the highest that can be expected using current diagnostic criteria.

A clinical and pathological study of motor neurone disease on Guam.

Despite over 40 years of intensive study, the cause of the high incidence of motor neurone disease (MND) on Guam, and the relationship between this disease and MND seen in the rest of the world are still uncertain. We present a series of 45 cases of Guamanian MND, which reaffirm the clinical similarity between this disease and MND seen in other countries. However, the occurrence of MND among the indigenous Chamorros of Guam is distinguished by four factors: (i) high prevalence; (ii) frequent familial occurrence; (iii) co-occurrence with the parkinsonism-dementia complex (PDC); and (iv) association with an unusual and distinctive linear retinopathy termed Guam retinal pigment epitheliopathy (GRPE). These distinguishing factors were not present in four non-Chamorros who resided on Guam when their MND symptoms occurred. Pathologically, the classical features of MND were seen in Guamanian Chamorro cases including ubiquitin inclusions. Neurofibrillary tangles were frequently seen. The neurofibrillary tangles appeared in the same distribution as described in the PDC but, unlike classical PDC, they were not usually associated with cell loss and occurred less frequently. While neurofibrillary tangle formation and the clinicopathological syndrome of MND may occur in parallel, observations from this series suggest that pathologically classical MND on Guam may occur independently of neurofibrillary degeneration and the clinical features of PDC.

Characterisation of isolated alpha-synuclein filaments from substantia nigra of Parkinson's disease brain.

The defining neuropathological deposits of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are strongly immunoreactive for alpha-synuclein. We have shown previously that isolated filaments from dementia with Lewy bodies and multiple system atrophy brains are labelled in a characteristic fashion by a number of alpha-synuclein antibodies. Here we have extracted filaments from substantia nigra of patients with idiopathic Parkinson's disease. Antibodies directed against the carboxy-terminal region of alpha-synuclein labelled isolated filaments along their entire lengths. By contrast, an antibody directed against the amino-terminal region of alpha-synuclein only labelled one filament end. These characteristics were identical to those of filaments extracted from brains of patients with dementia with Lewy bodies and multiple system atrophy.

Neuronal intranuclear inclusion disease and juvenile parkinsonism.

Juvenile parkinsonism (onset age <20 yrs) is uncommon and few cases with neuropathologic confirmation have been reported. We present the case of a 17-year-old boy who presented with asymmetric arm tremor and bulbar symptoms. His paternal great aunt had parkinsonism with onset at age 22 years. Examination revealed parkinsonism in the absence of additional neurologic signs except for delayed pupillary responses to light. He responded well to levodopa but developed motor fluctuations and disabling dyskinesias after 3 years of treatment. Following attempted withdrawal of levodopa at age 24 years, he developed severe aspiration pneumonia complicated by cardiorepiratory arrests and he died 6 months later. At autopsy, the dominant histologic feature was wide-spread neuronal hyaline intranuclear inclusions. Neuronal depletion was observed in the substantia nigra, locus ceruleus, and, to a lesser extent, in the frontal cortex, and inclusions were particularly prominent in these areas. Inclusions were immunoreactive for ubiquitin and were typical of those seen in neuronal intranuclear inclusion disease (NIID), a rare, multisytem neurodegenerative disease. NIID should be considered in the differential diagnosis of juvenile parkinsonism. A link between NIID and hereditary neurodegenerative disorders characterized by expanded polyglutamine tracts is supported by the similar appearance of intranuclear inclusions in both conditions and by a family history in some cases of NIID.

Apolipoprotein E epsilon4 allele has no effect on age at onset or duration of disease in cases of frontotemporal dementia with pick- or microvacuolar-type histology.

Frontotemporal dementia (FTD) is the second most common cause of presenile dementia. Here we have investigated the frequency of the epsilon4 allele of the Apolipoprotein (APOE) gene in FTD and in other non-Alzheimer forms of dementia related to FTD such as Motor Neurone disease dementia, semantic dementia, progressive aphasia, progressive supranuclear palsy, and corticobasal degeneration. In none of these diagnostic groups did we find a significant increase in the APOE epsilon4 allelic frequency, compared to population values. Neither did we observe any affects of the epsilon4 allele upon age at onset or duration of disease. We conclude therefore that polymorphic variations in the APOE gene do not modulate either the occurrence or progression of these non-Alzheimer forms of dementia.

What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson's disease?

OBJECTIVES: Few studies have attempted to identify what premortem features best differentiate multiple system atrophy (MSA) from Parkinson's disease (PD). These studies are limited by small sample size, clinical heterogeneity, or lack of postmortem validation. We evaluated the sensitivity and specificity of different clinical features in distinguishing pathologically established MSA from PD. METHODS: One hundred consecutive cases of pathologically confirmed PD and 38 cases of pathologically confirmed MSA in one Parkinson's disease brain bank were included. All cases had their clinical notes reviewed by one observer (AH). Clinical features were divided into two groups: those occurring up to 5 years after onset of disease and those occurring up to death. Statistical analysis comprised multivariate logistic regression analysis to choose and weight key variables for the optimum predictive model. RESULTS: The selected early features and their weightings were: autonomic features (2), poor initial levodopa response (2), early motor fluctuations (2), and initial rigidity (2). A cut off of 4 or more on the ROC curve resulted in a sensitivity of 87.1% and specificity of 70.5%. A better predictive model occurred if the following features up to death were included: poor response to levodopa (2), autonomic features (2), speech or bulbar dysfunction (3), absence of dementia (2), absence of levodopa induced confusion (4), and falls (4). The resulting ROC curve based on individual scores showed a best cut off score of at least 11 of 17 (sensitivity 90.3%, specificity 92.6%). CONCLUSIONS: Predictive models may help differentiate MSA and PD premortem. Hitherto poorly recognised features, suggestive of MSA, included preserved cognitive function and absence of psychiatric effects from antiparkinsonian medication. Diagnostic accuracy was higher in those models taking into account all clinical features occurring up to death. Further studies need to be based on new incident cohorts of parkinsonian patients with subsequent neuropathological evaluation.

Organochlorine insecticides in substantia nigra in Parkinson's disease.

The concentrations of organochlorine (OC) compounds in the substantia nigra (SN) were compared in Parkinson's disease (PD) with concentrations in brain from cortical Lewy body dementia (CLBD), Alzheimer's disease (AD), and nondemented nonparkinsonian controls (CON). The levels of the gamma isomer of hexachlorocyclohexane (gammaHCH, lindane) were significantly higher in PD tissues (mean +/- SD: 0.56 +/- 0.434 microg/g lipid) than in the other three groups (CLBD 0.052 +/- 0.101 microg/g lipid; AD none detected; CON 0.125 +/- 0.195; all differences from PD significant at p < .05, Mann-Whitney U-test). Dieldrin (HEOD) was higher in PD brain than in AD or control brain, while 1,1'-(2,2-dichloroethenyl diene)-bis(4-chlorobenzene) (p,p-DDE) and total Aroclor-matched polychlorinated biphenyls (matched PCBs) were only higher in PD substantia nigra when these concentrations were compared with those of CLBD. These findings are not inconsistent with the hypothesis derived from epidemiological work and animal studies that organochlorine insecticides produce a direct toxic action on the dopaminergic tracts of the substantia nigra and may contribute to the development of PD in those rendered susceptible by virtue of cytochrome P-450 polymorphism, excessive exposure, or other factors.

The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases.

Progressive supranuclear palsy is characterised pathologically by the deposition of neurofibrillary tangles consisting of tau protein. Patients with the disease have been reported to have a more frequent occurrence of one allele of an intronic polymorphism of the tau gene. Other diseases which may involve tau deposition include frontotemporal dementia and corticobasal degeneration. This polymorphism has been studied in a series of subjects with progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, idiopathic Parkinson's disease, and normal controls to (1) confirm this association in a large series and (2) to investigate a possible role for this association in other disorders which involve tau deposition. The results confirm the finding of an overrepresentation of the A0 allele and the A0/A0 genotype in patients with progressive supranuclear palsy, in the largest series reported to date. The A0 allele was found in 91% of patients with progressive supranuclear palsy as opposed to 73% of controls (p<0.001) and the A0/A0 genotype was seen in 84% of patients as compared with 53% of controls (p<0.01). There was no significant difference between patients with Parkinson's disease, frontotemporal dementia, or corticobasal degeneration, and controls. The A0 allele may have a direct effect on tau isoform expression in progressive supranuclear palsy or it may be in linkage disequilibrium with an adjacent determinant of tau gene expression. The explanation for this difference between a predisposition factor to progressive supranuclear palsy and the other conditions may lie in the molecular pathology of these diseases.

Is Parkinson's disease a primary olfactory disorder?

It has been known for over 30 years that olfactory function is disordered in idiopathic Parkinson's disease (IPD). The severity and partial specificity of anosmia was not realized until recently, with the advent of more detailed analysis and sophisticated measurement. The olfactory vector hypothesis suggests that the causative agent for IPD enters the brain via the nasal route, but the reason for olfactory dysfunction may be more subtle. Evidence for olfactory disturbance is reviewed from pathological, psychological, neurophysiological and genetic stand-points. It is proposed that the initial causative event in IPD may start in the rhinencephalon (olfactory brain) prior to damage in the basal ganglia.

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.

Conjugates of catecholamines with cysteine and GSH in Parkinson's disease: possible mechanisms of formation involving reactive oxygen species.

Oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine (DA) to generate semiquinones/quinones, oxygen radicals, and other reactive oxygen species may play a role in neuronal cell death in Parkinson's disease (PD). In particular, semiquinones/quinones can form conjugates with thiol compounds such as GSH and cysteine. Exposure of L-DOPA, DA, and other catecholamines to a system generating O2.- radical led to O2(.-)-dependent depletion of added GSH (or cysteine), accompanied by the formation of thiol-DA or -DOPA adducts as detected by HPLC. Superoxide could additionally cause destruction of these adducts. Iron or copper ions could also promote conjugate formation between GSH or cysteine and DA and L-DOPA, especially if H2O2 was present. We applied HPLC to measure glutathionyl and cysteinyl conjugates of L-DOPA, DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) in postmortem brain samples from PD patients and normal control subjects. Conjugates were detected in most brain areas examined, but levels were highest in the substantia nigra and putamen. In most regions, adduct levels were lower in PD, but there were significant increases in cysteinyl adducts of L-DOPA, DA, and DOPAC in PD substantia nigra, suggesting that acceleration of L-DOPA/DA oxidation occurs in PD, although we cannot say if this is a primary feature of the disease or if it is related to therapy with L-DOPA. In vitro, conjugate formation could be inhibited by the dithiol dihydrolipoate but not by its oxidised form, lipoic acid.