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Biomedical subjects

A J Lees

Publications and source records attributed to A J Lees.

At least 55 records · Page 3Linked to original sources
PubMed2002

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.

Adult↗
PubMed2002

The complex relationship between soluble and insoluble tau in tauopathies revealed by efficient dephosphorylation and specific antibodies.

Phosphorylated tau is deposited as insoluble inclusion bodies in the tauopathies. We have used a new efficient method to dephosphorylate tau extracted from control and tauopathy brain. In some tauopathies, including Alzheimer's disease and progressive supranuclear palsy, the pattern of insoluble tau isoforms reflected that of soluble tau. In contrast, in corticobasal degeneration, Pick's disease, and some forms of fronto-temporal dementia, specific tau isoforms were selectively sequestered into insoluble inclusion-forming tau. Therefore the overall expression of individual tau isoforms does not predict which tau isoforms are deposited in all tauopathies and different mechanisms must operate that result in the deposition of specific tau isoforms.

Amino Acid Sequence↗
PubMed2002

Analysis of tau haplotypes in Pick's disease.

Pick's disease (PiD) is characterized by the deposition of tau protein as three-repeat tau Pick bodies, whereas progressive supranuclear palsy (PSP) involves the deposition of four-repeat tau neurofibrillary tangles. PSP is associated with the tau H1 haplotype. The authors investigated a possible association between PiD and the tau H1 or H2 haplotype. There was no difference between the tau H2 haplotype or H2H2 genotype frequency in PiD cases and control subjects. No tau mutations were identified in pathologically typical cases of PiD, with antibody 12-E8-negative Pick bodies.

Aged↗
PubMed2002

Anti-basal ganglia antibodies in acute and persistent Sydenham's chorea.

OBJECTIVE: To determine the sensitivity and specificity of methods to detect anti-basal ganglia antibodies (ABGA) in Sydenham's chorea (SC). BACKGROUND: SC is a delayed manifestation of group Abeta hemolytic streptococcal infection typically associated with rheumatic fever (RHF). SC is characterized by chorea and motor and neuropsychiatric symptoms. Patients with SC produce antibodies that cross-react with streptococcal, caudate, and subthalamic nuclei antigens detected using an immunofluorescent (IF) method with inconsistent reports of positivity. METHODS: The authors developed ELISA and Western immunoblotting (WB) methods to detect ABGA and compared these assays to IF. They investigated samples from patients with acute SC (n = 20), persistent SC (n = 16), control samples from RHF (n = 16), and healthy pediatric volunteers (n = 11). RESULTS: ABGA ELISA had a sensitivity of 95% and specificity of 93% in acute SC. Both WB and IF had a sensitivity of 100% and specificity of 93%. In the persistent SC group, ABGA sensitivity dropped to 69% using WB and to 63% using IF. Three common basal ganglia antigens were identified by WB in both acute and persistent SC (40 kDa [n = 15], 45 kDa [n = 15], and 60 kDa [n = 13]). There was no antibody reactivity to cerebellum, cerebral cortex, or myelin antigen preparations in any group. CONCLUSIONS: These results support the hypothesis that Syndenham's chorea is an autoantibody-mediated disorder. Western immunoblotting and immunofluorescence are the best methods for detecting anti-basal ganglia antibodies, and reactivity to basal ganglia antigens of 40, 45, and 60 kDa were commonly seen in both acute and persistent cases of SC.

Acute Disease↗
PubMed2002

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.

Aged↗
PubMed2002

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.

Aged↗
PubMed2001

Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial.

BACKGROUND: The long-term effectiveness of three different initial drug regimes in patients with early, mild PD was evaluated by the PD Research Group of the United Kingdom (PDRGUK). In 1995, the selegiline arm of the trial was terminated following an interim analysis. METHOD: This was an open, randomized trial. Between 1985 and 1990, 782 patients with de-novo PD were recruited and randomized to one of three treatment arms: levodopa plus dopa decarboxylase inhibitor; levodopa plus decarboxylase inhibitor and selegiline; or bromocriptine. The main endpoints were mortality, disability, and adverse events. Intention-to-treat analysis was used. RESULTS: There was no significant difference in mortality between the bromocriptine and the levodopa arms (hazard ratio 1.15 [95% CI 0.90, 1.47]). Patients initially randomized to bromocriptine had slightly worse disability scores throughout follow-up. This difference was significant during the first years. Patients in the bromocriptine arm returned to pretreatment disability levels one year earlier than those in the levodopa arm. Patients randomized to bromocriptine had a significantly lower incidence of dyskinesias than those randomized to levodopa (rate ratio 0.73 [95% CI 0.57, 0.93]). However, this difference was not significant when only moderate to severe dyskinesias were considered. Patients in the bromocriptine arm had slightly lower rates of dystonias and on-off fluctuations, but moderate and severe forms were equally frequent in both arms. CONCLUSION: Starting treatment with the dopamine agonist bromocriptine does not reduce mortality in PD. A slightly lower incidence of motor complications is achieved at the expense of significantly worse disability scores throughout the first years of therapy.

Antiparkinson Agents↗
PubMed2001

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.

Adult↗
PubMed2001

Effect of ApoE and tau on age of onset of progressive supranuclear palsy and multiple system atrophy.

In addition to allelic association between genetic polymorphisms and diseases, modulation of age of onset is a well recognised effect of disease susceptibility genes. The ApoE epsilon4 allele is associated with an earlier age of onset of sporadic and familial Alzheimer's disease. It has been suggested that the tau genotype influences the age of onset of progressive supranuclear palsy (PSP), a form of atypical parkinsonism caused by tau neurofibrillary tangle deposition. We have therefore analysed the relationship between tau and ApoE genotypes and the age of onset of PSP and another form of atypical parkinsonism, multiple system atrophy (MSA). We have not found any effect of possession of the tau H1 haplotype or the ApoE epsilon4 allele on the age of onset of MSA or PSP.

Age of Onset↗
PubMed2001

Strong association of a novel Tau promoter haplotype in progressive supranuclear palsy.

The microtubule associated protein, tau, is found in fibrillar lesions that characterise progressive supranuclear palsy (PSP) and related tauopathies. Mutations in the tau gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and genetic association of the H1 haplotype of the tau gene with PSP has firmly established a direct role for tau in disease pathogenesis. However, the functional significance of the tau genetic association in PSP is unknown. We analysed the tau gene promoter sequence and identified two novel single nucleotide polymorphisms. Here we report the genetic association of a novel tau promoter haplotype with PSP which may influence tau transcription.

DNA Mutational Analysis↗
PubMed2001

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.

OBJECTIVE: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). BACKGROUND: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. METHODS: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. RESULTS: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). CONCLUSIONS: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Genotype↗
PubMed2001

Self-assembly organometallic squares with terpyridyl metal complexes as bridging ligands.

A series of novel heterometallic square complexes with the general molecular formulas [fac-Br(CO)(3)Re[mu-(pyterpy)(2)M]](4)(PF(6))(8) and [(dppf)Pd[mu-(pyterpy)(2)Ru]](4)(PF(6))(8)(OTf(8) (4), where M = Fe (1), Ru (2), or Os (3), pyterpy is 4'-(4' "-pyridyl)-2,2':6',2' '-terpyridine, dppf = 1,1'-bis(diphenylphosphino)ferrocene and OTf is trifluoromethanesulfonate, were prepared by self-assembly between BrRe(CO)(5) or (dppf)Pd(H(2)O)(2)(OTf)(2) and (pyterpy)(2)M(PF(6))(2). The obtained NMR spectra, IR spectra, electrospray ionization mass spectra, and elemental analyses are all consistent with the proposed square structures incorporating terpyridyl metal complexes as bridging ligands. Multiple redox processes were observed in all square complexes. All four complexes display strong visible absorptions in the region 400-600 nm, which are assigned as metal (Fe, Ru, or Os)-to-ligand (pyterpy) charge transfer (MLCT) bands. Square 3 exhibits an additional weak band at 676 nm, which is assigned to an Os-based (3)MLCT band. For each complex, the bands centered between 279 and 377 nm are assigned as pyterpy-based pi-pi bands and the Re-based MLCT band. Square 3 is luminescent in room-temperature solution, while squares 1, 2, and 4 do not have any detectable luminescence under identical experimental conditions.

Journal Article↗
PubMed2001

SPECT imaging of the dopamine transporter in juvenile-onset dystonia.

Juvenile-onset dystonia that improves after levodopa may occur in both dopa-responsive dystonia (DRD) and juvenile parkinsonism (JP), clinically similar conditions with different prognoses and management goals. The authors show normal striatal uptake of the dopamine transporter ligand FP-CIT with SPECT in a clinically atypical case of DRD, in contrast to the reduced uptake observed in JP.

Adolescent↗