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K Markopoulou

Publications and source records attributed to K Markopoulou.

17 recordsLinked to original sources
PubMed2006

A comparison of the effects of imposed extension and flexion movements on Parkinsonian rigidity.

OBJECTIVE: To test a hypothesis that Parkinsonian rigidity is more pronounced in imposed extension than flexion movement. METHODS: Twelve Parkinsonian subjects (both "Off" and "On" medication states) and seven control subjects participated in the protocol, in which a servomotor imposed wrist flexion and extension. Rigidity was quantitatively evaluated by the rectified torque integral with time, i.e., temporal score, and by the torque integral with joint angle, i.e., work score, for extension and flexion, respectively. RESULTS: In the "Off" state, the imposed extension induced a significantly higher resistance than did flexion. Dopaminergic medication significantly reduced the temporal score associated with imposed extension, and significantly decreased the work score of both movements. Compared with controls, the scores were higher for patients in the "On" state. CONCLUSIONS: Rigidity is more readily elicited in extension movement. The distinction is not evident in clinical practice, whereas it can be clearly revealed with the application of biomechanical analyses. SIGNIFICANCE: This distinction may prove to be a standard feature of rigidity. The procedures may be helpful in diagnosis and useful in evaluating new treatments and developing rehabilitation programs.

Aged↗
PubMed2001

Positron emission tomography of dopamine pathways in familial Parkinsonian syndromes.

Positron emission tomography (PET) scan is considered to be the most useful tool with which to assess the integrity of nigrostriatal function in the living brain. Recently, different genetic defects have been associated with a variety of familial parkinsonian syndromes, the clinical phenotypes of which have varying degrees of similarities to idiopathic parkinsonism (IP), (sporadic Parkinson's disease). This review summarizes: (1) the PET scan findings (fluorodopa uptake and raclopride binding) in both familial parkinsonian syndromes and IP; and (2) the similarities and differences of the clinical and PET features between familial parkinsonian syndromes and IP. This analysis demonstrates that more similarities than differences exist in PET scan findings in the different familial parkinsonian syndromes with the exception of pallido-ponto-nigral degeneration (PPND), that is perhaps best considered as multisystem degeneration. As a result of this analysis, we believe that while different genetic defects may underlie different mechanisms of nigrostriatal degeneration, the final pattern of nigrostriatal dysfunction is essentially similar to that of IP. 'Parkinson's disease', therefore, may not represent a single disease entity, but rather the final manifestation of different pathogenetic mechanisms-mediated by genetic or environmental factors, or an interaction of genetic and environmental factors.

Dopamine↗
PubMed1999

PET studies of parkinsonism associated with mutation in the alpha-synuclein gene.

OBJECTIVE: To assess the pattern of dopaminergic abnormalities in a Greek-American kindred (family H) with autosomal dominantly inherited, levodopa-responsive parkinsonism caused by a mutation of the gene encoding alpha-synuclein. BACKGROUND: Mutations of alpha-synuclein have been associated recently with dominantly inherited, levodopa-responsive parkinsonism. The pattern of dopamine deficiency and status of postsynaptic dopamine receptors in this condition have not been reported previously. The authors followed a large, six-generation family in whom the affected members carry the recently reported G209A mutation in the gene encoding alpha-synuclein. METHODS: The authors studied four affected and two clinically unaffected gene-negative members of family H using [18F]-6-fluoro-L-dopa (FD) and [11C]-raclopride (RAC) PET to assess presynaptic dopaminergic function and dopamine D2 receptors. The results were compared with normal subjects and patients with sporadic, idiopathic PD (IP). RESULTS: In affected individuals, FD uptake was reduced in both the caudate and the putamen, but the putamen was affected more severely than the caudate, as seen in IP. RAC binding was within the normal range, but the ratio of RAC binding in the putamen to that in the caudate was increased in affected members of family H. This pattern is similar to that seen in IP. CONCLUSIONS: PET of the nigrostriatal system in parkinsonism associated with a mutation in the ac-synuclein gene indicates that it results in a pattern of dopamine deficiency, with preserved D2 binding, indistinguishable from IP.

Adult↗
PubMed1999

Reduced expression of the G209A alpha-synuclein allele in familial Parkinsonism.

Missense mutations at the alpha-synuclein gene have been associated with familial parkinsonism. We report that the phenotype of a kindred (Family H) with autosomal dominant, levodopa-responsive parkinsonism maps to chromosomal region 4q21-23 and that affected members of this kindred harbor a previously reported mutation (G209A) in exon 4 of the alpha-synuclein gene. We assessed the expression of the G209A allele in lymphoblastoid cell lines established from 12 individuals heterozygous for the G209A allele. The expression of this allele is either absent or significantly reduced in 7 affected heterozygotes and in 3 asymptomatic heterozygotes who are older than the mean age at disease diagnosis for their generation. In contrast, it is expressed in 1 affected and 1 unaffected heterozygote. The unaffected heterozygote is younger than the mean age at disease diagnosis for their generation. The lack of or significantly reduced expression of the G209A allele in affected heterozygotes suggests that the timing of reduced expression may be critical for disease onset. If so, the parkinsonian phenotype may arise from haploinsufficiency at the alpha-synuclein gene at a time point before symptom onset. In conclusion, reduced alpha-synuclein gene expression may be important in the pathogenesis of parkinsonism.

Alleles↗
PubMed1998

Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17.

Pallido-ponto-nigral degeneration (PPND) is one of the most well characterized familial neurodegenerative disorders linked to chromosome 17q21-22. These hereditary disorders are known collectively as frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17). Although the clinical features and associated regional variations in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The microtubule associated protein (tau) gene is located on chromosome 17q21-22. For these reasons, we investigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the tau gene. Two missense mutations in exon 10 of the tau gene that segregate with disease, Asn279(Lys) in the PPND kindred and Pro301(Leu) in four other FTDP-17 kindreds, were found. A third mutation was found in the intron adjacent to the 3' splice site of exon 10 in patients from another FTDP-17 family. Transcripts that contain exon 10 encode tau isoforms with four microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with three MT-binding repeats (3Rtau). The insoluble tau aggregates isolated from brains of patients with each mutation were analyzed by immunoblotting using tau-specific antibodies. For each of three mutations, abnormal tau with an apparent Mr of 64 and 69 was observed. The dephosphorylated material comigrated with tau isoforms containing exon 10 having four MT-binding repeats but not with 3Rtau. Thus, the brains of patients with both the missense mutations and the splice junction mutation contain aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.

Adult↗
PubMed1998

Olfactory dysfunction in Parkinson's disease.

The olfactory system is one of the nonmotor systems severely affected in Parkinson's disease (PD). Olfactory dysfunction occurs early in the disease process, is independent of disease stage, duration, and treatment. However, olfactory dysfunction appears to be dependent on disease subtype. Olfaction is mildly impaired or preserved in most of the parkinsonism-plus syndromes (PPS). This provides a means of differential diagnosis between typical PD and PPS. Olfactory function is impaired also in familial forms of parkinsonism in which the genetic defect is known. In familial parkinsonism, olfactory function is impaired in both typical PD and PPS phenotypes. Olfactory dysfunction does not appear to be a manifestation of dopamine deficiency. Olfactory dysfunction is also associated with other neurodegenerative diseases such as Alzheimer's disease (AD), Huntington's disease (HD), as well as with normal aging. The neuropathological changes observed in the olfactory system in PD and other neurodegenerative diseases appear to be disease-specific, raising the possibility that olfactory dysfunction may be the result of a central rather than a peripheral process. The cellular and molecular mechanisms underlying olfactory dysfunction in PD and other neurodegenerative diseases remain unknown.

Humans↗
PubMed1997

Olfactory dysfunction in familial parkinsonism.

Impaired olfactory function is commonly observed in idiopathic Parkinson's disease (IPD). However, it is unknown whether it is also found in familial parkinsonism. To address this issue we administered a smell test to 12 affected, three monosymptomatic, and 12 at-risk individuals from six large parkinsonian kindreds. Three kindreds exhibited an IPD phenotype and three exhibited a parkinsonism-plus syndrome (PPS) phenotype. All but one of the affected individuals had impaired olfactory function. In contrast, only five of the 12 at-risk individuals had impaired olfactory function. The degree of olfactory impairment in the at-risk individuals was less severe than in the affected individuals. The difference in the degree of olfactory impairment in individuals exhibiting the IPD and the PPS phenotypes was not statistically significant. These findings suggest that olfactory dysfunction is a phenotypic characteristic of familial parkinsonism and that it is independent of the kindred phenotype. The appearance of olfactory dysfunction soon after disease onset raises the possibility that it is part of the neurodegenerative disease process.

Adult↗
PubMed1996

Drug-induced parkinsonism after allogeneic bone marrow transplantation.

We report a severe case of drug-induced parkinsonism (DIP) after allogeneic BMT successfully treated with levodopa. BMT patients typically receive numerous medications which can cause DIP, and mild cases of DIP may remain unrecognized or be misdiagnosed. Physicians should be aware of DIP as a potential neurological complication after BMT to avoid further administration of drugs that could aggravate symptoms.

Adult↗
PubMed1995

A Greek-American kindred with autosomal dominant, levodopa-responsive parkinsonism and anticipation.

Interest is increasing concerning the role of genetic factors in the etiology of Parkinson's disease. We report the analysis of a Greek-American kindred with levodopa-responsive parkinsonism. Of the 98 individuals present in six generations of this pedigree, 16 individuals in three successive generations have developed parkinsonism. Affected members were examined both in Greece and in the United States. The clinical presentation consisted of asymmetric rigidity, resting tremor, bradykinesia, and postural instability, and symptoms were responsive to levodopa. The disease appears to be inherited in an autosomal dominant manner. The inheritance pattern and the development of parkinsonism in successive generations on two continents challenges environmental factors as the primary cause in the pathogenesis of parkinsonism in this kindred. Anticipation is present in this pedigree. The affected members in the third generation developed symptoms at ages 50 to 71, in the fourth at ages 40 to 55, and in the fifth at age 31 years. This is another example of a neurodegenerative disease with autosomal dominant inheritance and anticipation. A molecular genetic analysis of this pedigree is in progress.

Adult↗
PubMed1995

Effects of breathing patterns on mechanically ventilated patients with chronic obstructive pulmonary disease and dynamic hyperinflation.

OBJECTIVE: To examine the circulatory and respiratory effects of breathing pattern in patients with chronic obstructive pulmonary disease (COPD) and dynamic hyperinflation (DH) during controlled mechanical ventilation. DESIGN: Prospective, controlled, randomized, non-blinded study. SETTING: Respiratory intensive care unit of a university hospital. PATIENTS: Nine patients with acute respiratory failure and DH due to acute exacerbations of COPD. INTERVENTIONS: Keeping tidal volume and total breath duration (TTOT) constant, patients were ventilated at six different values of expiratory time (TE). TE changes were randomly induced by alterations of constant inspiratory flow (VI) and/or end-inspiratory pause (EIP). Patients were studied at three levels of VI(0.93 +/- 0.08, 0.72 +/- 0.06 and 0.55 +/- 0.04 l/s, mean +/- SE), with and without EIP (10% of TTOT). MEASUREMENTS AND RESULTS: Lung volumes, airflows, airways pressures, oxygenation indices and dead space were measured. Alveolar pressure and airway resistance (Rmin), as well as the additional resistance (delta R) due to viscoelastic pressure dissipation and time-constant inequalities, were estimated by rapid airway occlusion during inflation. In seven out of nine patients, right-heart catheterization was performed and hemodynamic parameters were obtained at each value of TE. A significant decrease of intrinsic positive end-expiratory pressure (PEEPi), end-inspiratory static and mean (mPaw) airway pressures, end-expiratory lung volume above passive FRC (Vtrap), delta R and venous admixture and a significant increase of peak airway pressure, Rmin, stroke volume index and mixed venous PO2 (PvO2) were observed when VI increased. At each VI, the addition of EIP significantly decreased iso-volume expiratory flows and PvO2 and increased Vtrap and mPaw. CONCLUSIONS: We conclude that in mechanically ventilated patients with COPD, the pattern of lung inflation and TE alteration have a significant impact on respiratory system mechanics, gas exchange and hemodynamics. Addition of EIP in patients with COPD may be detrimental.

Acute Disease↗
PubMed1995

Ventilatory post-stimulus potentiation in patients with brain damage.

In normal humans when a brief hypoxic ventilatory stimulus is terminated abruptly by breathing 100% O2, ventilation during hyperoxia gradually declines to baseline prehypoxic levels without an undershoot. This has been interpreted as evidence of decay of short-term potentiation (STP), a mechanism located in the brainstem and not dependent upon higher center inputs. STP decay may be important in preventing periodic breathing by damping ventilatory responses to cyclic stimuli. Patients with brain damage commonly have periodic breathing that may be caused partly by impairment of STP activation. To test this 12 tracheostomized patients with severe brain damage (Glasgow score 9.9 +/- 0.6) were studied. Breathing stability was estimated by at least 6 h of capnography and from these records apnea index (AI, episodes/hour) and cyclic changes of end-tidal CO2 (c-PETCO2, cycles/hour) were derived. STP activation was examined by brief exposure to hypoxia (45 s, end-tidal O2 = 50 mm Hg) followed by hyperoxia. Forty-four hypoxic-hyperoxic runs were analyzed and compared with 19 normoxic-hyperoxic trials. At the end of the hypoxia ventilation (VI) increased 39.5 +/- 5.8% and PETCO2 decreased 2.7 +/- 0.6 mm Hg to 91.5 +/- 2.2% of baseline value. When hypoxia was terminated abruptly by hyperoxia VI dropped immediately to 63.2 +/- 7.2% of baseline, remaining for 35 s significantly lower than the corresponding values acquired during hyperoxia after normoxia. After hypoxia, apneas occurred in 19 of 44 hyperoxic runs. There was a negative relationship between nadir hyperoxic ventilation after hypoxia and both AI and c-PETCO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Developmental analysis of the facets, a group of intronic mutations at the Notch locus of Drosophila melanogaster that affect postembryonic development.

The activity of the Notch locus of Drosophila melanogaster during embryogenesis is necessary for the correct segregation of neural from epidermal lineages. The action of Notch is not confined to embryogenesis but is also essential for normal development during the postembryonic stages. Its action is pleiotropic, as revealed by the existence of several classes of mutations which affect various imaginal structures. Here, we examine a group of six recessive mutations, the facets (fa, fa3, fag, fag-2, fafx and fasw), which affect eye and optic lobe morphology and have been previously shown to be associated with the insertion of transposable elements into an intronic region of Notch. Using both somatic recombination and gynandromorph analysis, we find that their behavior in a mosaic analysis is not identical. While in the majority of alleles abnormal Notch function in the retina is sufficient to induce optic lobe abnormalities, in the case of fag-2, a considerable number of individuals having mosaic retinas exhibit normal optic lobe structure. All the facet alleles appear to behave in a cell-autonomous manner. A developmental analysis of the eye and optic lobe defects associated with the facet mutations support the contention that Notch may be involved not only in the formation of certain structures but also in their maintenance.

Alleles↗
PubMed1989

Phenotypic and molecular analysis of the facets, a group of intronic mutations at the Notch locus of Drosophila melanogaster which affect postembryonic development.

The function of the Notch locus of Drosophila melanogaster is essential for normal development both during embryogenesis and during postembryonic stages. In the embryo its function is necessary for the correct segregation of neural from epidermal lineages. During postembryonic stages Notch exhibits pleiotropic effects that are both tissue- and stage-specific. Here, we examine a group of six recessive mutations, the facets (fa, fa3, fag, fag-2, fafx and fasw), which affect eye morphology and have been previously shown to be associated with the insertion of transposable elements in an intronic region of Notch. The analysis of revertants has shown that the mutant phenotype depends on the presence of the transposable element and that the disruption of the wild-type sequence organization per se is not its cause. Four of these alleles, even though they are associated with the insertion of the same transposable element, display considerably different phenotypes. Therefore, no simple correlation exists between the mutant phenotype and the type of inserted element. A comparison of the tissue localization of the Notch and the transposable element transcripts revealed that in the third larval instar the elements are transcribed in both orientations in tissues in which Notch is also transcriptionally active. The complexity of the defects associated with the facet alleles, as well as the findings of the transcriptional analysis, indicate that a mutational mechanism based solely on transcriptional interference is not sufficient to explain the nature of the mutational event. It is likely that in these mutations alterations, in the temporal and/or spatial context caused by transcriptional and perhaps posttranscriptional interference mechanisms by the inserted elements, may be responsible for the mutant phenotype.

Alleles↗
PubMed1989

The expression of the neurogenic locus Notch during the postembryonic development of Drosophila melanogaster and its relationship to mitotic activity.

The molecular analysis of the Notch locus of Drosophila melanogaster demonstrated that it codes for a protein which shows homology to the epidermal growth factor as well as to the products of certain yeast genes involved in the control of the cell cycle (Wharton et al., 1985a; Breeden and Nasmyth, 1987). The structure of the protein suggests that Notch is involved in a cell interaction mechanism which controls the differentiation of several different tissues during development. Here we examine Notch expression during imaginal development using in situ hybridization to tissue sections and demonstrate that Notch is not expressed ubiquitously during the postembryonic stages, but rather is confined to specific tissues. During the larval and early pupal period Notch transcripts are predominantly localized in the imaginal discs and the central nervous system. In the middle and late pupal period the signal levels in these tissues drop dramatically and in the adult animal Notch transcripts are essentially detected only in the ovaries. In the larval stages the pattern of Notch expression appears to be closely correlated with mitotically active tissues, while in later stages this correlation appears less strict. The findings reported here indicate that there is a requirement for normal Notch function in a number of tissues at several developmental stages and that the pleiotropic phenotypic manifestation of Notch mutations is a context dependent developmental result. The observed association of Notch expression with mitotically active cell populations raises the possibility that Notch may play a role in the cell cycle.

Animals↗