Psychological and physiological effects of caring for patients with treatment-resistant depression.

BACKGROUND: Carers of patients with psychiatric disorders show high levels of anxiety and depression, possibly mediated through disruption of the hypothalamo-pituitary-adrenal (HPA) axis. Among carers of patients with treatment-resistant depression (TRD), we set out to determine the psychological and physiological (HPA axis) consequences of caring, and the association of these consequences with long-term outcome in patients. METHOD: Thirty-five informal carers of patients with severe TRD requiring in-patient treatment were recruited and compared with 23 controls. HPA-axis activity was assessed by measuring post-awaking salivary cortisol. The Involvement Evaluation Questionnaire (IEQ) and the General Health Questionnaire-12 (GHQ-12) were administered to measure carer burden and psychiatric caseness respectively. Independent t tests were used to compare differences between carers and controls and a linear regression model was used to determine the association of post-awakening cortisol with carer status while controlling for confounding variables. Data on long-term patient outcome (12 to 83 months), measured using the Hamilton Depression Rating Scale (HAMD), were also obtained and linear regression was used to determine the association between cortisol output in carers and remission status in patients. RESULTS: Carers experienced high carer burden and high psychiatric caseness. Carers showed reduced cortisol output after awakening, calculated as the area under the curve with respect to ground (AUCg), which remained significant after controlling for potential confounders. In a linear regression model, non-remission in patients was associated with reduced cortisol output in carers. CONCLUSIONS: Caring for patients with TRD is associated with adverse psychological and physiological changes suggesting hypocortisolism post-awakening. These changes are associated with poor patient outcome.

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.

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.

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.

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.

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.

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.

Molecular genetics of familial parkinsonism.

Parkinson's disease (PD) is a progressive, neurodegenerative disorder associated with tremor, rigidity, bradykinesia, and postural instability. There exists a familial form of PD that is indistinguishable from the sporadic form. In addition, there exists a class of syndromes classified as parkinsonism-plus syndromes (PPS), in which parkinsonism is an essential but not the only phenotypic characteristic. The etiology of PD remains unclear. Both environmental and genetic factors contribute to the disease pathogenesis. Recent progress in the molecular genetics of parkinsonism has demonstrated that six different chromosomal regions are associated with forms of familial parkinsonism. Mutations in four candidate genes have been identified and include both point mutations and deletions. Both gain-of-function and loss-of-function mutational mechanisms have been implicated. The molecular genetic characterization has led to a new classification of PD and PPS based on the type of genetic defect. Understanding the mechanisms by which these mutations lead to disease should provide further insights into the etiology of parkinsonism.

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.

Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system.

Despite the evidence of an association between depression and increased inflammatory markers, still little is known in relation to the most severe cases of the disorder i.e., those who fail to respond to antidepressants. We have assessed the cytokine profile and cortisol levels in 21 healthy controls (HC) and 19 medicated patients with depression with treatment-resistance (TRD) moderately ill. As an initial exploratory analysis, we have also related cytokine profile to the patient's clinical treatment outcome after an inpatient admission. Cytokine profile was measured in the serum by the Cytokine Array I kit (Randox). Plasma cortisol was carried out using a commercially available for the IMMULITE system. When compared to healthy controls, depressed patients had higher levels of cortisol, IL-6, IL-10, but lower levels of IL-4 and VEGF. Our exploratory analysis showed subjects who did not go on to respond to the inpatient admission treatment package had lower levels of MCP-1, and a trend toward lower levels of VEGF. Taking together, these data suggest that lack of clinical therapeutic benefit of antidepressants is associated with overall activation of the inflammatory system.

Discrepancy between subjective and objective severity in treatment-resistant depression: prediction of treatment outcome.

OBJECTIVE: Identifying predictors of outcome among patients with treatment-resistant depression (TRD) is challenging. We hypothesised that discrepancy between self-rated and observer-rated scales may be a simple way of making such a prediction. METHOD: 102 patients were admitted to a unit specialising in the treatment of resistant depression and underwent fortnightly assessment with clinician-rated (Hamilton Depression Rating Scale-21, HAM-D) and self-rated (Beck Depression Inventory, BDI) measures. All patients had significant depressive symptoms that were treatment resistant, 70% as part of a major depressive disorder and the remainder as part of a bipolar or other disorder. A discrepancy score between the HAM-D and BDI was calculated on admission and its association with patient clinico-demographic factors was determined. A subset of 67 patients remained as inpatients for 40 weeks or until clinical response and were entered into a responder analysis, in which response was defined as ≥50% reduction in admission HAM-D score. The association of the admission BDI-HAM-D discrepancy score with subsequent patient response, was determined. RESULTS: The magnitude of BDI-HAM-D discrepancy was higher in those with co-morbid personality disorder, lower in those with psychosis and positively correlated with anxiety. High BDI-HAM-D discrepancy score predicted delayed treatment response (odds ratio 5.40, p = 0.005). CONCLUSION: Within TRD, higher discrepancy predicts slower response to treatment independent of objective illness severity; this may be mediated by underlying personality traits and co-morbid anxiety.

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson's disease. Variability in familial Parkinson's disease.

Individuals with familial Parkinson's disease (PD) due to a monogenic defect can show considerable clinical and neuropathological variability. To identify factors underlying this variability, histopathological analysis was performed in two clinically different A53T alpha-synuclein heterozygotes from Family H, a multigenerational alpha-synuclein A53T kindred. To determine whether additional genetic factors could contribute to phenotypic variability, Family H and another multigenerational A53T kindred were analyzed for parkin polymorphisms. We identified a previously described variant in parkin exon 4 associated with increased PD risk (S167N). The two A53T heterozygotes had markedly different neuropathology and different parkin genotypes: A N167 homozygote had early onset rapidly progressive disease, early dementia, myoclonus and sleep disorder, while a S167 homozygote had late onset, slowly progressive disease and late dementia. Both had brainstem, cortical, and intraneuritic Lewy bodies (LB). The N167 individual had widespread cortical neurofibrillary degeneration, while the S167 individual had only medial temporal lobe neurofibrillary degeneration. The N167 individual had severe neuronal loss in CA2 associated with Lewy neurites (LN), while the S167 individual had severe neuronal loss in CA1 associated with TDP-43 immunoreactive neuronal inclusions. These findings implicate TDP-43 in the pathology of familial PD and suggest that parkin may act as a modifier of the A53T alpha-synuclein phenotype of familial PD. Furthermore, they suggest a mechanism by which a rare genetic variant that is associated with a minor increase of PD risk in the heterozygous state may, in the homozygous state, exacerbate a disease phenotype associated with a highly penetrant dominant allele.

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.

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.

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.

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.

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.

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)