Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and α-synuclein pathology

Alzheimers disease (AD), Picks disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or -synuclein. In AD, -amyloid (A)-associated caspase activation and cleavage of tau at Asp⁴²¹ (Tau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether Tau accumulates in other diseases not characterized by extracellular A accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied Tau accumulation in DLB cases associated with intracellular -synuclein. Tau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of Tau may represent a common pathway associated with abnormal accumulation of intracellular tau or -synuclein and may be relatively less dependent on the extracellular accumulation of A in non-AD dementias.     

Unconscious Confusion

Abstract Background Imprecise definitions of syncope and related conditions appear common in the medical literature. To investigate the scope of the problem we systematically searched for definitions in high-ranking medical journals. Methods Literature review of articles on syncope, neurocardiogenic syncope, neurally mediated syncope, orthostatic intolerance, and orthostatic hypotension with these keywords in the title, mainly published in the ten journals with the highest impact in the fields of cardiology, internal medicine, and neurology. Results Syncope, neurocardiogenic syncope, neurally mediated syncope, orthostatic intolerance, and orthostatic hypotension were defined in only 41%, 34%, 26%, 38%, and 48% of papers respectively. Definitions, when given, differed considerably among papers. Orthostatic hypotension was most frequently defined, with an increase in number and consistency of definitions after publication of a consensus in 1996. Conclusions Syncope and related conditions proved to be infrequently and inconsistently defined in current medical literature. The lack of consistent terminology is likely to harm medical education, research, and patient care. There is a strong need for a systematic terminology for syncope and related conditions.     

Temperamental factors in children and adolescents with obsessive-compulsive disorder (OCD) and in normal controls

Abstract We studied parent-rated temperamental traits in patients (n=83) with obsessive-compulsive disorder (OCD) as compared with children and adolescents matched for age and gender (n=85) using the EAS (Emotionality, Activity, Sociability) questionnaire. Specifically, two hypotheses of OCD were studied: (1) the presence of behavioural inhibition (BI) and (2) of high levels of emotionality utilising ANOVA analyses, controlling for gender and age group (children vs. adolescents). The presence of BI in OCD patients was confirmed in that they scored higher than controls on Shyness [F (df=7)=2.69, p<0.012] but lower on Activity [F (df=7)=3.01, p<0.005]. Also, our second hypothesis was corroborated in that OCD patients scored higher than controls on Emotionality [F (df=7)=3.59, p<0.001]. A third hypothesis, the presence of temperamental heterogeneity in OCD, was likewise confirmed. We found, using hierarchical cluster analyses, two subgroups of about equal size, an Inhibited/Shy group (n=44), high in Shyness and low in Emotionality, Sociability and Activity, and an Uninhibited group (n=32) that was high in Emotionality, Sociability and Activity, but low in Shyness. However, the temperamental subgroups gave no clear picture with regard to the most common symptom patterns.     

Estimation of noradrenaline concentrations in the axoplasm of noradrenergic neurones in man

The plasma concentrations of noradrenaline (NA) and its primary neuronal metabolite, dihydroxyphenylglycol (DOPEG), were examined during graded orthostasis and NA infusion in 13 healthy subjects to estimate the NA concentration difference between the site of neuronal DOPEG formation and that in plasma.Stimulation of NA release by graded orthostasis resulted in similar absolute increments in plasma NA and DOPEG with both plasma concentrations being dependent on the degree of orthostasis. The mean value of the DOPEG/NA ratio amounted to 0.999 (0.745; 1.341). NA was infused i.v. during two consecutive 30-min periods at constant rates of 0.43 and 0.86 nmol kg^–1 min^–1, respectively. This infusion resulted in a DOPEG/NA ratio of 0.048 (0.036; 0.064) for the first and 0.078 (0.067; 0.090) for the second infusion period (p < 0.01).For each individual subject, the factor quantifying the NA concentration difference between the site of neuronal DOPEG formation and plasma was calculated from the square root of the ratio of DOPEG/NA during orthostasis to DOPEG/NA during the low rate of NA infusion. The average NA concentration at the site of neuronal DOPEG formation (i.e. the axoplasm of noradrenergic neurones) was found to be 4.6-fold higher than that in plasma.     

Vergleich veränderter Bewußtseinszustände unter den Halluzinogenen (−)-Δ9-trans-Tetrahydrocannabinol (Δ9-THC) und N,N-Dimethyltryptamin (DMT)

Zusammenfassung Die Untersuchung vergleicht unter Verwendung zweier Placebo-Kontrollgruppen veränderte Bewußtseinszustände, die unter den Halluzinogenen (–)⁹-trans-Tetrahydrocannabinol (⁹-THC) und N,N-Dimethyltryptamin (DMT) auftreten. 24 Probanden erhielten 250g ⁹-THC p.o. pro kg Körpergewicht, und 26 Probänden wurde 250g DMT pro Körpergewicht i.m. appliziert. Die Placebogruppe bestand aus insgesamt 24 Probanden. Die Effekte wurden retrospektiv mit einem Fragebogen erfaßt, dessen Items nach inhaltlichen und testtheoretischen Gesichtspunkten zu den folgenden 8 Skalen zusammengefaßt wurden: Optische Sinnestäuschungen, akustische Sinnestäuschungen, Konzentrations- und Gedächtnisstörungen, Derealisationserscheinungen, Depersonalisationserscheinungen, Leiberlebensveränderungen, euphorisches Zustandsbild und dysphorisches Zustandsbild.In allen acht Syndromen unterschieden sich die beiden Halluzinogene signifikant von Placebo. Zwischen den Halluzinogenen konnte jedoch keine signifikante Differenz nachgewiesen werden. In der Skala optische Sinnestäuschungen zeigte sich als Tendenz, daß DMT hier eine stärkere Wirkung als ⁹-THC entfaltet.Methodische Probleme des Vergleichs verschiedener Halluzinogene werden diskutiert.     

Fainting in animals

Fainting (syncope) is unconsciousness due to insufficient cerebral circulation in the context of a temporary failure of the systemic circulation. This paper firstly aims to discuss fainting in animals, and secondly to discuss animal physiology to broaden the understanding of human fainting.Of the three major syncope types (cardiac, orthostatic and reflex syncope), only cardiac syncope occurs in animals as in man, through arrhythmia or output failure.Mans orthostatic fainting tendency has been blamed on his upright posture. A comparison with animals shows that giraffes, treeclimbing snakes, and animals that quickly raise and lower their heads face more serious gravitational circulatory challenges than man, but do not appear to faint. Merely carrying the brain above the heart does not explain a fainting tendency, as the human heart-to-brain height is smaller than that of many mammals with similar blood pressure. Two evolutionary novelties may be to blame: the proportion of cardiac output going upwards to the brain is much larger than in apes, and mans large legs suggest that the volume lost to venous pooling is also larger.Emotional factors play a role in many reflex syncope events. Tonic immobility (feigning death,playing possum) is not a good model, as it concerns immobility as a survival strategy of an attentive brain, rather than unconsciousness due to circulatory breakdown. Whether orienting and defense responses form a valid model remains to be proven. Emotional fainting may be uniquely human; how mental processes can shut down the circulation and thereby the brain needs serious study, as it may hold the key to syncope prevention.     

Life events and syndromes of depression in the general population

Summary Brown and Harris (1978) contend that life events have causal significance for both psychotic and neurotic depression. This contradicts the psychiatric tradition. Neurotic depression has been regarded as a consequence of life-stress, while psychotic depression has been regarded as a consequence of processes intrinsic to the organism. Empirical evidence is presented to support the view that life events have a differential effect, within the general population. It is argued that Brown and Harris's (1978) conclusion follows from an inappropriate approach to classification. It is argued further that their data lend support to the traditional view. It is noted that their approach may inhibit the development of explanatory models linking life-stress, vulnerability factors and depression.     

The dexamethasone suppression test and thyroid stimulating hormone response to TRH in RDC schizoaffective patients

Summary The dexamethasone suppression test (DST) brought to light significantly more non-suppression of cortisol secretion in RDC schizoaffectives of the depressed (89%) and of the manic type (67%) than in RDC schizophrenia (25%). However, only in the RDC endogenous depressives, whose pathological DST rate was 57%, was the thyroid stimulating hormone (TSH) response to thyrotrophin releasing hormone (TRH) found to be significantly blunted. It is suggested that the DST results can be interpreted as partially validating DSM-III's wide major affective disorder since this concept also encompasses all cases with mood-incongruent psychotic features. Furthermore, it is hypothesized that the coupling of DST non-suppression and TSH blunting may be important for defining a valid depressive subgroup within these extended clinical boundaries for affective illness.     

The effect of oxidative stress on amyloid precursor protein processing in cells engaged in β-amyloidosis is related to apolipoprotein E genotype

The reduced antioxidative defense in allele 4 carriers is suggested to contribute to -amyloidosis in Alzheimers disease and Downs syndrome. We studied the effect of oxidative stress on accumulation of amyloid- peptide (A) in vascular smooth muscle cells (SMCs) that are engaged in production of amyloid- in vivo. Previously, we found that oxidative stress caused by ferrous ions induced accumulation of A-apolipoprotein E deposits in lysosomes and was associated with a greater oxidative protein damage in 4 carriers. Here, we demonstrate that ferrous ions induce formation of A deposits also in vascular tunica media in organotypic cultures of whole brain vessels, suggesting the role of oxidative stress in development of vascular -amyloidosis. Cellular accumulation of A in SMCs treated with ferrous ions was associated with a greater accumulation of C-terminal amyloid precursor protein (APP) fragments in 4/4 than in 3/3 myocytes and reduced the amount of soluble APP in 3/3, but not 4/4, cultures. Antioxidant vitamin E prevented these effects, and, when applied alone, diminished the amount of APP C-terminal fragments and increased the amount of secreted APP in 3/3, but not 4/4, cells. C-terminal APP-immunoreactive material was accumulated in lysosomes partly with A- and N-terminal APP immunoreactivities. These results suggest that the increased accumulation of APP and its fragments in lysosomes may yield additional amounts of cellular A, particularly in 4 carriers. We hypothesize that the altered processing of APP in SMCs locally exposed to oxidative stress facilitates cellular deposition of A and contribute to the increased risk of development of -amyloidosis in 4/4 carriers.     

GABA binding sites: their density,their affinity to muscimol and their behaviour against neuroactive steroids in human gliomas of different degrees of malignancy

Summary The aim of the present investigation was to answer the question if there exists a relation between the equipment of human gliomas with GABA binding sites and the degree of malignancy of these tumours diagnostically characterized according to WHO classification. The following parameters were assessed: the density, the affinity and the sensitivity to the modulating steroids 3 -hydroxy-5 -pregnane-20-one (3 OH-DHP) and 3 ,21dihydroxy-5 -pregnane-20-one (THDOC). Scatchard analysis and non linear computerization revealed that the occurrence of GABA sites was directly related to the degree of tumour malignancy: GABA sites were only detectable in lower malignant gliomas of WHO grade II but not in the very malignant glioblastomas. However, irrespective of the individual density to be detected all glioma GABA sites were sensitive to 3 -hydroxy-5 -pregnane-20-one (3 OH-DHP) and 3 ,21dihydroxy-5 -pregnane-20-one (THDOC) without exception. The effects of THDOC were due to increases in the number of binding sites whereas in the presence of 3 OH-DHP a decrease in affinity was noted, additionally. These findings support the view of a normal functional integrity of GABA receptors in gliomas.     

Mental Hygiene of the Special Schools Teachers in Kerman,Iran

The goal of this research is to identify and study the mental hygiene and its related factors (individual, family, organizational) in the Kerman special schools teachers. 266 teachers of the special schools of the cities of the province Kerman were chosen as the research sample. The necessary data were obtained by questionnaire which its validity and reliability were determined. The statistical analysis of the research findings (by Spearman coefficient test) Man-Whithey and Kruskal wallis tests showed that there was a positive and meaningful relationship between Level of education, service of record the number of the members of teachers family, income, dwelling-place, economic power, acceptance of the teachers job in their family, leadership style, suitable educational possibilities, suitable educational space, job satisfaction with the mental hygiene of the teachers. The results of the research also showed that the Kerman special schools teachers enjoyed a relatively desirable mental hygiene.     

On areas of transition between entorhinal allocortex and temporal isocortex in the human brain. Normal morphology and lamina-specific pathology in Alzheimer's disease

Summary The allocortical entorhinal region does not gradually transform into the temporal isocortex. Instead, there is an extended stretch of transentorhinal cortex with interdigitation of allocortical and isocortical laminae. The main feature of this transition zone is that the superficial layer of large multipolar nerve cells (Pre-) of the entorhinal region gradually sweeps downward and follows an oblique course through the outer layers. During this course the starshaped nerve cells of Pre- are transformed into pyramidal cells.The layer Pre- projection cells are particularly prone to the development of neurofibrillary changes of the Alzheimer type. In cases of presenile and senile dementia almost all of the layer Pre- projection neurons are changed pathologically. The isocortical pyramidal cells of layers II to IV are far less inclined to develop neurofibrillary changes. In the transentorhinal cortex, the tangle-bearing neurons follow an oblique course through the superficial laminae and are finally located between the isocortical layers III and IV, findings that confirm the assumption that these neurons are constituents of the allocortical layer Pre-.Layer-specific pathology of the profound stratum as well confirms the transentorhinal region as being formed by interdigitating allocortical and isocortical layers.Supported by grants from the Deutsche Forschungsgemeinschaft     

A process analysis of Bender Gestalt Test performance in childhood emotional disorder: A single-case study

This study involves an analysis of the Bender Gestalt Test performance of a young, severely disturbed boy emphasizing the origins of and processes mediating the emergence of deviant responses. Deviant responses are considered to reflect a conflict between primitive motor impulses and an emergent, visually-mediated organization of the designs, corresponding to the several stages of sensory-motor adaptation. The manner of the resolution of visuo-motor conflict may prefigure later dispositional trends significantly embedded within aspects of childhood emotional disorder. Finally, analogy is drawn between specific aspects of performance and the boy's behavioral organization.     

Depression: Demographic factors in the distribution of different syndromes in the general population

Summary Epidemiologists attempt to identify the causes of disorders by examining their demographic distribution. Psychiatric epidemiologists have frequently used measures ofgeneralized psychological disturbance. It is argued that the epidemiologist's purpose is better served by the use of measures ofspecific psychological syndromes. Four depressive syndromes, that were derived by Principal Components Analysis and called Anxiety-Depression, Cognitive-Depression, Vegetative-Depression, and Classic-endogenous Depression, were considered. Their relationship with age, sex, marital status, employment status and social class were out-lined and the variability in their demographic distribution was highlighted. It was concluded that the use of general rather than specific measures of depressive disorder may account for some of the disparities in the relevant epidemiological literature.     

Coping with stress as a theme in teaching psychopathology to medical students

In an era when non-psychiatric physicians are increasingly aware of their need for at least a rudimentary knowledge of psychology, medical schools are making belated attempts to remedy the situation.The effort described here succeeded because the students did not seem to view the course as one about crazy people. Thus, they did not distance themselves from the course material and patients.... One student said, This was a course about everybody—about what people have to do to live in the world.     

Sympathetic cardiovascular dysfunction in long-standing idiopathic Parkinson's disease

Standard autonomic tests (heart rate response to deep breathing-HR _db , heart rate and systolic blood pressure response to tilt-HR and SBP) and spectral analysis of heart rate and arterial blood pressure and their transfer function (for the mid-frequency band a measure of baroreflex sensitivity) were performed in 20 patients with idiopathic Parkinson's disease (IPD) and 20 age-matched controls. Patients showed significantly diminished SBP, and reduced sympathetic vasomotor and cardiomotor outflow (diminished Mayer waves), consistent with an alteration of the efferent arc of the baroreflex. These results were only significant in long-standing IPD (IPD-1, >5 years), whereas patients with short disease duration (IPD-s, <5 years) showed values comparable to controls. Respiratory-related heart rate variability was slightly reduced in IPD-1 but this was mainly due to diminished respiratory effort, indicated by low respiratoryrelated blood pressure variability. We conclude that autonomic abnormalities are only present in long-standing IPD and consist in reduced sympathetic vasomotor and cardiomotor outflow.     

A disease-specific psychosocial questionnaire for Parkinson’s disease caregivers

Abstract. Objective: To evaluate the Belastungsfragebogen Parkinson Angehörigen—kurzversion (BELA-A-k), a questionnaire for measuring psychosocial problems and need for help in Parkinsons disease (PD) caregivers. Methods: The Belastungsfragebogen Parkinson Angehörigen—kurzversion was translated into Dutch. It consists of 15 items with a Bothered by (Bb) and a Need for Help (NfH) score. The BELA-A-k was tested for cultural differences, relevance and feasibility in a pilot (n = 10). We determined the psychometric properties in a validation study (n = 50) and compared the BELA-A-k with the Sickness Impact Profile, the COOP/WONCA Functional Health Assessment Charts and the Loneliness Questionnaire (de Jong-Gierveld). All questionnaires were administered in person at home, in a prescribed order. Results: The BELA-A-k was completed by 60 PD-caregivers. The internal-consistency reliability coefficients for the total Bothered by (0.90) and Need for Help (0.92) scales were excellent. The internal consistency of the subscales exceeded the 0.70 standard except for the Bothered by and Need for Help Social functioning scale (Bb = 0.62; NfH = 0.65) and the Partner-bonding/Family scale (NfH = 0.69). Almost all BELA-A-k subscales correlated highly (P < 0.001) with the corresponding scales of the standard quality of life indices. Conclusion: The BELA-A-k is a relevant, reliable and valid measure for assessing psychosocial problems and need for help of PDcaregivers.     

Electrophysiological evidence for visuocognitive dysfunction in younger non caucasian patients with Parkinson's disease

Summary A study of primary (VEPs) and cognitive (ERPs) visual evoked potentials was carried out in a group of non-demented Afro-American Parkinson's disease (PD) patients. Current studies suggest that differences exist in the clinical manifestations of PD in Caucasian and non-Caucasian populations. Two horizontal sinusoidal gratings differing in spatial frequency, i.e., 1 and 4 cycles per degree (cpd), were presented in an oddball paradigm to 17 patients with PD and 17 age-matched control subjects. While the 1 cpd stimulus, is not expected to reveal retinal dopaminergic deficency, but only visuocognitive deficits, the 4 cpd may give direct information of both retinal and cognitive visual deficits. We measured the latencies and amplitudes of N70, P100 and P300 components, and derived the normalized measures of P300-N70 latency difference (Central Processing Time-CPT70), the P300-P100 latency difference (CPT100) and the P300 amplitude responses normalized to either N70 and P100 amplitude (Amplitude Ratios AR70 and AR100). Our results do show that cognitive electrophysiological deficits in younger PD patients exist in non-Caucasians, perhaps to an even greater degree than in Caucasians, and confirm that absolute and normalized ERP amplitude and latency abnormalities are a distinguishing feature of younger PD patients from controls. In particular P300 measures are abnormal for 1 cpd pattern. A negative correlation exists between P300 amplitude and the motor score. By comparing the results for 1 and 4 cpd stimuli it can be concluded that primary and cognitive visual abnormalities are independently affected in PD, implying that visuo-cognitive abnormalities are not passively determined by retinal dopaminergic deficiency.     

Aspects of aggression in formerly depressed patients and in healthy controls

Summary Thirty former inpatients (14 male and 16 female) who had suffered from a nonpsychotic depressive syndrome were investigated by means of a new personality inventory—the KSP—when they had recovered from the depressive disorder, and their results were contrasted to those obtained from 53 healthy controls (19 male, 34 female). Attention was focused on the subscales of the KSP which refer to aspects of aggression. Former patients scored significantly higher than controls in the variables irritability, suspicion, guilt, and inhibition of aggression. The findings suggest a particular personality makeup for at least one subgroup of depression-prone subjects and closely resemble classical concepts of hostility and depression.Supported in part by a grant from the Swedish Medical Research Council (Grant No. 21X-5244)     

An epidemiological study of minor psychiatric disturbances

Summary A representative epidemiological field study of minor mental disturbances among 19- to 20-year-old persons in Zurich (Switzerland) is reported. Respondents had completed two selfreport inventories; SCL-90R by Derogatis and a Syndrome List concerning psychosomatic and neurotic syndromes. There is a high prevalence rate of such disturbances. Usually, however, they do not lead to treatment-seeking behaviour. Females show higher prevalence figures on nearly all scales and syndromes. The syndromes of anxiety and depression are most prominent among females. Unexpectedly, there are few differences in prevalence rates between different socio-demographic groups. There are, however, three high-risk groups: (1) persons without occupational training; (2) persons without religious affiliation and (3) persons whose parents or siblings had psychiatric problems. Reasons for the lack of clearcut associations between social status and psychiatric syndromes are discussed.This research is supported by the Swiss National Science Foundation, grant no. 3.804-0.76.