CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts.

BACKGROUND: Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a genetically heterogeneous disease characterized by a combination of systemic bone cysts and dementia. OBJECTIVE: The authors present a neurologic, neuroradiologic, and neuropathologic analysis of a series of PLOSL patients in which the diagnosis has been confirmed by molecular genetic methods. METHODS: Clinical, neurophysiologic, and imaging follow-up data on eight patients as well as autopsy samples of three patients were analyzed in this study. All eight patients were homozygous for a loss-of-function mutation in the DAP12 gene. RESULTS: In most patients, the disease debuted with pain in ankles and wrists after strain during the third decade, followed by fractures caused by cystic lesions in the bones of the extremities. Frontal lobe syndrome and dementia began to develop by age 30, leading to death by age 40. Neuroimaging disclosed abnormally high and progressively increasing bicaudate ratios and calcifications in the basal ganglia as well as increased signal intensities of the white matter on T2-weighted MR images even before the appearance of clinical neurologic symptoms. Three patients who had undergone autopsies showed an advanced sclerosing leukoencephalopathy with frontal accentuation, widespread activation of microglia, and microvascular changes. CONCLUSIONS: Although PLOSL in most patients manifests by bone fractures, some patients do not show any osseous symptoms and signs before the onset of neurologic manifestations. Consequently, patients with frontal-type dementia of unknown origin should be investigated by x-ray of ankles and wrists. The current results suggest early basal ganglia involvement in PLOSL.

Psychopathy and the posterior hippocampus.

Neurobiology of psychopathy is of interest, not only because neural underpinnings of psychopathy remain obscure, but also because psychopaths may provide a model to study violent behavior, neurology of morals and impaired decision-making. Medial temporal lobe pathology has been suggested to be a part of the neural systems dysfunction which manifests as violent and psychopathic behavior. Yet, so far no sound evidence of neuroanatomical correlates for psychopathic behavior has been found. In this study regional hippocampal volumes were measured using magnetic resonance imaging in 18 habitually violent offenders with antisocial personality disorder and type 2 alcoholism (derived from forensic psychiatric evaluation). The regional volumes along the anteroposterior axis of the hippocampus were correlated with the subjects' degree of psychopathy as evaluated by the Psychopathy Checklist-Revised. Strong negative correlations, up to -0.79, were observed, among the study subjects, between the psychopathy scores and the posterior half of the hippocampi bilaterally. These data are in accordance with experimental studies proposing that lesions of the dorsal hippocampus impair acquisition of conditioned fear, and with theories on psychopathology according to which one of the central features in the birth of psychopathy is a deficit in acquisition of conditioned fear.

Physical activity and bone mineral acquisition in peripubertal girls.

The association of the amount and type of physical activity with bone mineral acquisition was studied in 191 peripubertal Caucasian girls aged 9-16 years (66 gymnasts, 65 runners, and 60 nonathletic controls). Weight, height, stage of puberty, the amount of leisure-time physical activity, and years of training were recorded, and dietary calcium and vitamin D were assessed by a semi-quantitative questionnaire. The bone area, the bone mineral density (BMD), and the bone mineral content (BMC) of the femoral neck, lumbar spine and antebrachium were measured by dual-energy x-ray absorptiometry. The unadjusted mean values of BMD at the femoral neck were 15.2% higher in the pubertal gymnasts than in the controls (P<0.001). Compared with the controls, the mean BMC adjusted for bone area of the pubertal gymnasts at the femoral neck and lumbar spine was 16.4% and 10.8% higher, respectively. When comparing the association of the type of physical activity among the pubertal athletics by multiple regression analysis, height, physical activity, gymnastics, and Tanner stage emerged as significant variables and accounted for 54.7% and 63.4% of the total variation in BMD of the femoral neck and lumbar spine, respectively. These results indicate that physical activity is associated with bone mineral acquisition in peripubertal girls and that high-impact weight-bearing exercise seems to be particularly associated with the increase of the BMD at the femoral neck.

Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

Aging and homicide rates.

There are no published studies concerning the effect of mortality rate on the rate of homicide by habitually violent offenders. On the basis of nation-wide statistics in Finland, the frequency of homicide is 61% lower among 50-year old males than among 30-year old males. However, when the 4.9-fold mortality of habitually violent offenders is taken into account, the homicide rate is only 43% lower among 50-year old males than among 30-year old males. This is an important issue in forensic psychiatry and that requires further attention, as age is used a predictive factor when assessing the risk of violent behavior.

Vitamin D intake is low and hypovitaminosis D common in healthy 9- to 15-year-old Finnish girls.

OBJECTIVES: To study the prevalence of hypovitaminosis D, the effect of vitamin D supplementation on serum 25-hydroxyvitamin D [S-25(OH)D], and the intakes of vitamin D and calcium in Finnish 9- to 15-year-old athletic and nonathletic girls. DESIGN: 1-year follow-up study (February 1997-March 1998) with three months of vitamin D supplementation (10 microg/d) from October to January. SETTING: Turku University Central Hospital, Finland. SUBJECTS: 191 female volunteers aged 9-15 y (131 athletes and 60 controls). METHODS: Vitamin D and calcium intakes were estimated by a four-day food recording and a semi-quantitative food frequency questionnaire (FFQ). S-25(OH)D was followed by radioimmunoassay (RIA). RESULTS: At baseline the mean S-25(OH)D concentration was 33.9 nmol/l among all girls. In winter severe hypovitaminosis D (S-25(OH)D < 20 nmol/l) occurred in 13.4% of the participants and in 67.7% S-25(OH)D was below 37.5 nmol/l. By the next summer the mean S-25(OH)D concentration was 62.9 nmol/l and in 1.6% of the subjects it was below 37.5 nmol/l. The prevalence of severe hypovitaminosis D was not significantly reduced by three months of vitamin D (10 microg/d) supplementation. At baseline, the mean intake of vitamin D was 2.9 microg/d by food recording and 4.3 microg/d by FFQ. The mean calcium intake was 1256 mg/d and 1580 mg/d, respectively. The intakes of vitamin D and calcium remained unchanged during the follow-up period. The athletes consumed more calcium than nonathletic controls, whereas the intake of vitamin D was quite similar among both groups. The vitamin D intake by FFQ correlated with the S-25(OH)D concentration in wintertime (r = 0.28, P < 0.01). CONCLUSION: Hypovitaminosis D is fairly common in growing Finnish girls in the wintertime, and three months of vitamin D supplementation with 10 microg/d was insufficient in preventing hypovitaminosis D. The daily dietary vitamin D intake was insufficient (< 5 microg/d) in the majority of participants, while the calcium intake was usually sufficient.

Mortality among habitually violent offenders.

There are no published studies about mortality among habitually violent offenders, although it would be essential to take into account the possibly higher mortality rate of this population, when the incidence of committing violent offenders is calculated as a function of age. We studied mortality during the age range 30-50 years among 102 habitually violent male offenders, who were considered to be dangerous to the lives of other people, during the 24.5-year period 1971-1995 (in the range 3.5 months-24.5 years, the average prison time was 6 years, 7 months and 11 days). In Finland, the death rate in the group of men aged 30-50 years is 3.7/1000/year, but among these habitually violent male criminals, the mortality rate was observed to be 18.1/1000/year. Therefore, the relative risk for dying in this age group was 4.9-fold when compared with the normal male population aged 30-50 years. A finding of this magnitude has a substantial effect, when the real incidence of committing homicides or other violent offenses is calculated as a function of age. This is an important issue in forensic psychiatry, since it is generally believed that the incidence of committing violent crimes is decreased between the ages of 30 and 50 years, and age is used as one predictive factor when the risk of forthcoming violent behavior is assessed.

Fine-scale mapping of a novel dementia gene, PLOSL, by linkage disequilibrium.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770) is a rare hereditary cause of presenile dementia with autosomal recessive inheritance. Its unique feature is the cystic bone lesions that accompany the dementia. About 160 cases have been reported to date, mostly in Finland and Japan. The etiology and pathogenesis of PLOSL are unknown. We recently assigned the locus for PLOSL in the Finnish population to chromosome 19q13.1 (P. Pekkarinen et al., 1998, Am. J. Hum. Genet. 62, 362-272). In the present study, we restrict the critical region for PLOSL to 153 kb by linkage-disequilibrium mapping. First, three new microsatellite markers were revealed in the PLOSL critical region. These and three other markers spanning the critical region were analyzed in Finnish PLOSL families. Strong linkage disequilibrium (multipoint P value < 10(-47)) was detected between the markers and PLOSL, and for two markers, D19S1176 and D19S610, all the PLOSL chromosomes shared identical 171- and 218-bp alleles, respectively. Haplotype analysis revealed five different haplotypes in the Finnish PLOSL chromosomes. But all of them shared the region between markers D19S1175 and D19S608 that could be traced to one ancestor haplotype by single recombination events, thus defining the critical region as 153 kb. Multipoint association analysis also assigned the most likely location of the PLOSL locus within this interval to the immediate vicinity of marker D19S610. A promising positional candidate for PLOSL, an amyloid precursor-like protein, was studied by sequencing, but no mutations were detected. These results lay the basis for the cloning of this novel dementia gene and for diagnostics in the Finnish population using haplotype analysis.

Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2-adrenoceptor antagonist atipamezole: a pharmacodynamic and kinetic study in healthy volunteers.

BACKGROUND: Specific and selective alpha2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because alpha2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with atipamezole, an alpha2-antagonist, in healthy persons. METHODS: The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of atipamezole to reverse the sedative effects of 2.5 microg/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of atipamezole (15, 50, and 150 microg/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h. RESULTS: The mean +/- SD atipamezole dose needed in part 1 was 104+/-44 microg/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 microg/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 microg/kg dose of atipamezole. The pharmacokinetics of atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine. CONCLUSIONS: The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous atipamezole. The applied infusion rate (75 microg x kg(-1) x min(-1)) for the highest atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Similar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.

Assignment of the locus for PLO-SL, a frontal-lobe dementia with bone cysts, to 19q13.

PLO-SL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile frontal-lobe dementia, resulting in death at <50 years of age. Since the 1960s, approximately 160 cases have been reported, mainly in Japan and Finland. The pathogenesis of the disease is unknown. In this article, we report the assignment of the locus for PLO-SL, by random genome screening using a modification of the haplotype-sharing method, in patients from a genetically isolated population. By screening five patient samples from 2 Finnish families, followed by linkage analysis of 12 Finnish families, 3 Swedish families, and 1 Norwegian family, we were able to assign the PLO-SL locus to a 9-cM interval between markers D19S191 and D19S420 on chromosome 19q13. The critical region was further restricted, to approximately 1.8 Mb, by linkage-disequilibrium analysis of the Finnish families. According to the haplotype analysis, one Swedish and one Norwegian PLO-SL family are not linked to the chromosome 19 locus, suggesting that PLO-SL is a heterogeneous disease. In this chromosomal region, one potential candidate gene for PLO-SL, the gene encoding amyloid precursor-like protein 1, was analyzed, but no mutations were detected in the coding region.

Single-photon emission tomography imaging of monoamine transporters in impulsive violent behaviour.

Several studies have shown that impulsive violent and suicidal behaviour is associated with a central serotonin deficit, but until now it has not been possible to use laboratory tests with high sensitivity and specificity to study this kind of deficit or to localize the sites of serotonergic abnormalities in the living human brain. The aim of this study was to test the hypothesis that monoamine transporter density in brain is decreased in subjects with impulsive violent behaviour. We studied serotonin (5-HT) and dopamine (DA) transporter specific binding in 52 subjects (21 impulsive violent offenders, 21 age- and sex-matched healthy controls, and ten non-violent alcoholic controls) with single-photon emission tomography (SPET) using iodine-123-labelled 2beta-carbomethoxy-3beta(4-iodophenyl)tropane ([123I]beta-CIT) as the tracer. The blind quantitative analysis revealed that the 5-HT specific binding of [123I]beta-CIT in the midbrain of violent offenders was lower than that in the healthy control subjects (P<0. 005; t test) or the non-violent alcoholics (P<0.05). The results imply that habitual impulsive aggressive behaviour in man is associated with a decrease in the 5-HT transporter density.

Psychiatric disorders and violent behavior.

Until recently, many researchers have been sceptical about any relationship between psychiatric disorders and violence. Since public opinion has always been prejudiced against the mentally ill, professionals in the field of psychiatry have been very cautious about further stigmatizing individuals with psychiatric illnesses. The authors have reviewed studies of mental disorders and violence, particularly the most recent, and find that there is increasing evidence for an association between psychiatric disorders and violence. Recent data suggest that the combination of previous violent behavior, alcoholism and antisocial personality disorder markedly increases the risk of future violent behavior. Schizophrenia, personality disorders and alcoholism per se do not increase the risk of violent behavior as much as do the above factors, but the risk among these diagnostic groups is, however, notably higher than that in the general population. The authors emphasize that only a minority of patients with mental disorders are violent. Future research is needed to better identify and treat these potentially violent patients.

Mental disorders and homicidal behavior in Finland.

BACKGROUND: Owing to the fact that Finnish police have been able to solve about 95% of all homicides during recent decades and because most homicide offenders are subjected to an intensive psychiatric evaluation, it was possible to examine data on 693 of 994 homicide offenders during an 8-year period. METHODS: The prevalences of mental disorders of the homicide offenders were used to calculate odds ratios (ORs) for the statistical increase in risk associated with specific mental disorders. RESULTS: The results indicate that schizophrenia increases the OR of homicidal violence by about 8-fold in men and 6.5-fold in women. Antisocial personality disorder increases the OR over 10-fold in men and over 50-fold in women. Affective disorders, anxiety disorders, dysthymia, and mental retardation did not elevate the OR to any significant extent (OR < 5.0). CONCLUSION: Homicidal behavior in a country with a relatively low crime rate appears to have a statistical association with some specific mental disorders classified according to DSM-III-R classifications.

Risk of homicidal behavior among discharged forensic psychiatric patients.

We studied the risk of homicidal behavior among 281 released male forensic psychiatric patients during the 14-year period 1978-1991. Released patients were about 300 times more likely to commit a homicide than the general male population during the first year outside hospital, and the corresponding risk was 53-fold during a mean follow-up period of 7.8 years. The odds ratio for committing a homicide among all Finnish schizophrenics during the 12-year period 1980-1991 was 9.7, which indicates that previous criminality associated with schizophrenia also increases the risk of homicidal behavior remarkably when compared with schizophrenia per se. We believe that this kind of epidemiological approach is a useful method of identifying and classifying factors associated with very high risk of homicidal behavior and preventing homicidal behavior among high-risk populations.

Factors associated with homicide recidivism in a 13-year sample of homicide offenders in Finland.

OBJECTIVE: Data on persons known to have committed homicide during a 13-year period were studied to determine factors associated with increased risk of repeating homicide. METHODS: Between 1981 and 1993, a total of 1,649 homicides were committed in Finland. In 1,089 cases (66 percent), the offenders received an exhaustive forensic psychiatric examination. Data from reports of these examinations were analyzed to determine whether mental disorder and other factors were associated with homicide recidivism. RESULTS: Thirty-six homicide recidivists were identified. Twenty-four were alcoholics, 23 had a personality disorder, in most cases combined with alcoholism, four had schizophrenia, and two had major depression. Homicidal behavior was ten times more likely in men who had committed a previous homicide than in the general male population. Alcoholism increased the odds ratio of additional homicidal behavior in male homicide offenders about 13 times, and schizophrenia increased the odds ratio more than 25 times. During their first year after release from prison, male homicide offenders were about 250 times more likely to commit homicide than members of the general male population. CONCLUSIONS: The data suggest that mentally abnormal offenders are overrepresented among homicide recidivists in Finland. The risk of repeat homicide appears to be very high during the first year after release from prison.

Schizophrenia and homicidal behavior.

It is generally thought that schizophrenia does not predispose subjects to homicidal behavior. However, many previous studies have suffered from notable methodological weaknesses. In particular, obtaining comprehensive study groups of violent offenders has been difficult. Finnish police have been able to solve about 97 percent of homicides during the last few decades. Because most homicide offenders are subjected to intensive forensic psychiatric examination, we were able to obtain data for 93 homicide offenders with schizophrenia among 1,423 arrested during a 12-year period. Calculations of the odds ratios revealed that the risk of committing a homicide was about 10 times greater for schizophrenia patients of both genders than it was for the general population. Schizophrenia without alcoholism increased the odds ratio more than 7 times; schizophrenia with coexisting alcoholism more than 17 times males.

Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics.

Animal studies suggest that development of substance dependence is associated with dopaminergic activity in striatum and the limbic system. Several genetic studies indicate that allele A1 is associated with both D2 receptor density and alcoholism, although these findings have remained controversial. We studied striatal dopamine (DA) re-uptake site densities in 48 subjects (19 healthy controls, 19 habitually impulsive violent alcoholics, and 10 non-violent alcoholics) with single photon emission computed tomography (SPECT) using iodine-123-labelled 2 beta-carbomethoxy-3 beta(4-iodophenyl)tropane, (beta-CIT) as a tracer. Blind quantitative analysis revealed that the striatal DA transporter density was markedly lower in non-violent alcoholics than in healthy controls (P < 0.001), while violent alcoholics had slightly higher DA transporter densities than controls (P < 0.10). The results indicate that both types of alcoholics have alterations in striatal dopaminergic system, though these occur in opposite directions.