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Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral Abeta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Abeta40 and Abeta42. Abeta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Abeta42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of Abeta42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Abeta40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Abeta burden in a different fashion from APP717 mutations in their familial AD brains.

Certain psychosocial factors such as marriage and involvement with support groups can influence longevity by unknown cellular mechanisms. To determine whether social factors impact upon the phenotypic expression of neurodegenerative disorders, we organized a standardized database on 43 patients with familial Alzheimer's disease [(FAD) (n = 18)] and spinocerebellar ataxia (SCA) types one and three (n = 25). Variables including information on social factors (marital status, close friends, church attendance and group memberships) were correlated with genetic and clinical data. In the total population (n = 43) higher education was linearly related to a greater income. Social factors did not significantly affect the onset of symptoms in patients with FAD. Regardless of the number of CAG trinuceotide repeats, most SCA patients who regularly attended church related activities and social group activities had a later onset of disease symptoms compared to those individuals with less social interaction.

Cerebral presenilin-1 protein (PS-1) is normally composed of the amino-terminal fragment (NTF) with Mr 28 kDa and the carboxy-terminal fragment (CTF) with 18 kDa. We analyzed human PS-1 in brains with early-onset familial Alzheimer's disease (FAD) with and without PS-1 mutations to study whether mutated PS-1 was abnormally metabolized. Cerebral PS-1 were found to be cleaved into two fragments of NTF and CTF independently of the occurrence of PS-1 mutation in human brains. A small portion of PS-1 was recently found to suffer another processing by caspase-3, an apoptosis-related cysteine protease. In contrast to the recent finding that the Volga-German mutation on presenilin-2 (PS-2) affects the increasing caspase-3 PS-2 fragment, the PS-1 mutation did not cause a significant change in PS-1 fragmentation. We conclude that PS-1 fragmentation and other (probably caspase-3-mediated) digestion following apoptosis occur independently of PS-1 mutations.

We report the results of linkage analysis in a large American family of Czech descent with dominantly inherited "Pure" essential tremor (ET) and genetic anticipation. Genetic loci on chromosome 2p22‐p25 establish linkage to this region with a maximum LOD score (Zmax) = 5.92 for the locus, D2S272. Obligate recombinant events place the ETM gene in a 15‐cM candidate interval between the genetic loci D2S168 and D2S224. Repeat expansion detection analysis suggests that expanded CAG trinucleotide sequences are associated with ET. These findings will facilitate the search for an ETM gene and may further our understanding of the human motor system.

In the past few years, genetic characterization has assigned seven chromosomal loci-designated as spinocerebellar ataxia (SCA) types 1-5 (OMIM 164400, 183090, 183085, 600223, 600224), SCA type 7 (OMIM 164500), and dentatorubropallidoluysian atrophy (OMIM 125370)-to a group of dominantly inherited ataxias.1 The locus for a benign adult-onset form of dominantly inherited ataxia has been linked to the centromeric region of chromosome 11 in a family descended from the grandparents of President Abraham Lincoln.2 During our investigation of a family with dominantly inherited ataxia that has lived in Rockingham County, Virginia, since colonial times, we uncovered several interesting historical facts about President Lincoln's family that cast doubt that the SCA5 gene was inherited through the Lincoln lineage. As part of this investigation, we constructed a family pedigree of President Lincoln's ancestors based on several historical sources3-6(figure 1). Figure 1. A partial pedigree of President Abraham Lincoln's family. Nine generations and 29 individuals from the president's family are shown. The names of family members whose signatures are found infigures 2 and 3 are followed by an asterisk (*). The known birth and death years are below each individual's name. Males are squares and females are circles. The dark symbols represent individuals with ataxia as cited by Ranum et al.2 The gray symbol representing individual VI-10 denotes that she had evidence of a tremor in her handwritten line. Our 16th president's paternal grandfather, Captain Abraham Lincoln(individual VI-9, figure 1), was born in Berks County, Pennsylvania, on May 13, 1744, and later moved to northwest Virginia. Captain Lincoln was a wealthy landowner and a distinguished figure in the American militia during the Revolutionary War. His wife, Bathsheba (individual VI-10,figure 1), was born in Bridgewater, Virginia, …

We studied 60 patients with multiple system atrophy and autonomic failure and 60 control subjects matched for age, sex and race. Their psychosocial history, pedigree and occupation were obtained by personal interview. An inventory of autonomic and neurologic symptoms was obtained from 148 first-degree relatives of the patients and 80 controls by a self-administered questionnaire. Patients with multiple system atrophy had significantly more potential exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, and pesticides than the control population. The potential exposures were determined in most subjects by their reported usual occupation. Clinical symptoms of multiple system atrophy were reported by a significantly larger group of patients' relatives than controls. These findings are possibly consistent with the hypothesis that multiple system atrophy develops as a result of a genetically determined selective vulnerability in the nervous system. Specific neuronal systems may become targets for environmental insults or toxins, and the disease state may occur when ageing neuronal systems can no longer sustain functional capacity. This preliminary study supports the need to further explore possible environmental, occupational, and familial contributions to the aetiology of multiple system atrophy.

We compared hippocampal lesions in three pedigrees of Familial Alzheimer's Disease (FAD). In these pedigrees, the disease is inherited as an autosomal dominant disorder and has been linked to DNA markers on chromosome 21. In eight cases of FAD (four from one pedigree and two each from two others) we quantified neurofibrillary tangles (NFT) and senile plaques (SP) in hippocampal subdivision CA1-4, subiculum, presubiculum, and dentate gyrus. We observed consistent patterns of the distribution of lesions: The highest density of NFT and SP was present in CA1-2; virtually no SP or NFT were present in presubiculum; SP diameter was consistently greatest in CA4. We found no overall differences among pedigrees in total densities of NFT and SP, but statistical analyses disclosed that an uncommon type of SP was disproportionately present in two pedigrees. This type of SP was usually restricted to CA4, had a marked amyloid core devoid of argyrophilic neurites. These studies also disclosed inter- and intrafamilial heterogeneity of lesion distribution (including congophilic angiopathy and cerebellar plaques) in these three pedigrees.

Genetic counseling is a 2-way street between counselor and the counseled. In this article, both share experiences gained through more than 25 years of searching for the gene, finding the presenilin-1 Alzheimer's disease gene, and waiting for a cure. “Research Families” made research models a reality. Few family members requested presymptomatic testing.

Objective.This study compared the frequencies of genetic and functional coagulation abnormalities in children with arterial ischemic stroke or porencephaly with frequencies in previously published studies. Methods.A series of 59 children (age 0–18 years) with arterial ischemic stroke or porencephaly were referred to the National Institutes of Health. A blood sample, buccal smear sample, questionnaire, and pedigree were requested for each child. Blood samples were analyzed for protein C (PC); protein S; antithrombin (AT); activated PC resistance (APCR); lipoprotein (a) [Lp(a)]; lupus anticoagulant; anticardiolipin antibodies; and the methylenetetrahydrofolate reductase C677T (MTHFR), factor V G1619A, factor II G20210A (PT), plasminogen activator inhibitor-1 4G6755G, and tissue factor pathway inhibitor C536T mutations. The frequency of each coagulation abnormality was compared with published international pediatric stroke case and control rates. Results.At least 1 prothrombotic abnormality was identified in 63% (36 of 57) of children studied, including plasminogen activator inhibitor-1 4G6755G (15 of 56), MTHFR (12 of 56), elevated Lp(a) (12 of 59), APCR (11 of 58), factor V G1619A (5 of 57), PT (3 of 57), PC deficiency (1 of 59), and AT deficiency (1 of 59). The MTHFR mutation, elevated Lp(a), the PT mutation, and AT deficiency rates were similar to rates in cases and more common than control subjects in previously published studies. The rate of children with APCR or multiple abnormalities was higher than in previous pediatric stroke studies. A family history of early thrombosis was identified in one third of the children with a prothrombotic abnormality. Conclusions.Two thirds of children in this study had at least 1 of the prothrombotic risk factors tested, and several children had multiple risk factors. These results provide additional evidence that prothrombotic abnormalities are common among children with AIS or porencephaly.

Although genetic testing is available for some degenerative diseases, in most types of dementia, both genetic and environmental factors are involved. Overall, dementing diseases can be either sporadic or inherited, and in general, the earlier the onset, the more likely a disease is to be inherited. Before genetic testing is performed, the ethical issues, such as the effect the tests might have on asymptomatic children, should be considered. The ethical use of DNA samples in research is another genetic testing issue to be considered.

Objective: To identify the genetic mutation responsible for autosomal dominant spastic paraplegia (HSP) in a large family with a “pure” form of the disorder. Background: The disease locus in most families with HSP is genetically linked to the SPG4 locus on chromosome 2p21-p22. Some of these families have mutations in the splice-site or coding regions of the spastin gene (SPAST). Methods: Linkage and mutational analyses were used to identify the location and the nature of the genetic defect causing the disorder in a large family. After the disease phenotype was linked to the SPG4 locus, all 17 coding regions and flanking intronic sequences of SPAST were analyzed by single-strand conformation polymorphism analysis (SSCP) and compared between affected and normal individuals. Direct sequencing and subcloning methods were used to investigate incongruous mobility shifts. Results:The genomic sequence of SPAST showed a heterozygous four–base pair deletion (delTAAT) near the 39 splice-site of exon three in all 11 affected individuals but not in 21 normal family members or in 50 unrelated controls (100 chromosomes). Conclusions: This study identifies an atypical intronic microdeletion in SPAST that causes HSP and widens the spectrum of genetic abnormalities that cause the disorder.

The Alzheimer's disease (AD) related amyloid precursor protein (APP) is stored, cleaved and released similarly from neurons and from platelets. We have reported that the proportion of 120-130 to 110 kDa carboxyl-cleaved APP present in the platelets of AD patients is significantly lower than that of platelets of age-matched controls. This reduced APP isoform ratio, not seen in several other disease groups, is further reduced as the severity of AD increases. Since the neuropathology of AD is believed to begin many years before the onset of cognitive loss, we have also compared platelet APP ratios of four pre-symptomatic young adults carrying a presenilin-1 mutation to seven siblings homozygous for the normal PS-1 gene in an effort to determine whether reduced APP ratios are present before apparent cognitive loss in familial AD. Decreased platelet APP ratios were not seen in any of these subjects at this time. We will continue to monitor these subjects as they near the mean age of AD onset in these families. As the magnitude of the APP ratio reduction is proportional to the severity of cognitive loss in sporadic AD, these cognitively normal incipient AD subjects would not be expected to present significant reductions in this AD severity index at this time. Alternatively, the absence of platelet APP ratio reductions may result from a failure of platelets from familial PS-1 AD subjects to manifest altered APPs, as has been reported for PS-2 AD subjects, unlike those of sporadic AD patients. Continued monitoring of cognitive status in our sub-set of controls with AD-like low APP ratios may yet validate the ability of this assay to detect incipient sporadic AD.

We obtained follow-up data on 22 sets of twins where at least one twin had Alzheimer’s disease (AD). The concordance rate for monozygotic twins (n = 17 pairs) was 59%, whereas that for dizygotic twins was 40%. In our series 8 monozygotic twins had hysterectomies; all had AD. The twins with hysterectomies also had a tendency to develop AD at an earlier age than their co-twin. Five twins with serious systemic infection developed AD, and they tended to have earlier onset than their corresponding twin. We found no strong evidence that head injury predisposed to AD.

We studied two candidate genes, tau (τ) and α-synuclein (SNCA), for evidence of linkage disequilibrium on a group of unrelated individuals with progressive supranuclear palsy (PSP) and a group of age-matched control subjects. The τ a1 allele and the τ a1a1 genotype were overrepresented in individuals with PSP and the τ polymorphism was in linkage disequilibrium with the PSP disease locus when a recessive inheritance model was employed. We also report a lack of evidence to support linkage disequilibrium between PSP and the SNCA candidate Parkinson's disease gene on chromosome 4q21-q23.

To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Abeta peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Abeta peptide such as Abeta1-42(43) and Abetax-42(43). This enhancing effect of PS1 mutation on Abetax-42(43) deposition was highly similar to that of a betaAPP mutation (Val717Ile) but the effects on Abetax-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Abeta in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Abetax-40 peptides in brain of subjects with PS1 mutations.

The neurodegeneration and amyloid deposition of sporadic Alzheimer disease (AD) also occur in familial AD and in all trisomy-21 Down syndrome (DS) patients, suggesting a common pathogenetic mechanism. We investigated whether defective processing of damaged DNA might be that mechanism, as postulated for the neurodegeneration in xeroderma pigmentosum, a disease with defective repair not only of UV radiation-induced, but also of some oxygen free radical-induced, DNA lesions. We irradiated AD and DS skin fibroblasts or blood lymphocytes with fluorescent light, which is known to cause free radical-induced DNA damage. The cells were then treated with either beta-cytosine arabinoside (araC) or caffeine, and chromatid breaks were quantified. At least 28 of 31 normal donors and 10 of 11 donors with nonamyloid neurodegenerations gave normal test results. All 12 DS, 11 sporadic AD, and 16 familial AD patients tested had abnormal araC and caffeine tests, as did XP-A cells. In one of our four AD families, an abnormal caffeine test was found in all 10 afflicted individuals (including 3 asymptomatic when their skin biopsies were obtained) and in 8 of 11 offspring at a 50% risk for AD. Our tests could prove useful in predicting inheritance of familial AD and in supporting, or rendering unlikely, the diagnosis of sporadic AD in patients suspected of having the disease.

Psychosocial interactions can affect physiological functions at a cellular level, resulting in increased longevity for people who have had heart attacks or who have acquired immune deficiency syndrome or cancer as well as for healthy individuals. Although social work pioneers and practitioners have always believed that social work intervention can help people feel better, recent studies show that the benefits can be measured quantitatively and qualitatively. In fact, these studies show that lack of psychosocial interaction may be a risk factor for disease progression.

The aetiology of the Shy-Drager syndrome (multiple system atrophy) is unknown. We reported previously a preliminary association between environmental-occupational risk factors and Shy-Drager syndrome. To further investigate this relationship, we evaluated olfactory function in eight patients in different stages of disease. When the eight patients' olfactory function was compared with 203 age- and sex-matched controls using a self-administered olfactory test, seven scored below the 39th percentile of this population. Five of the eight patients had total anosmia or microsmia. Additional studies will be required to elucidate the significance of this abnormal clinical observation.

This study was undertaken to evaluate smell tests as a clinical marker for identifying mutation carrier status and determining the clinical diagnosis of presenilin-1 Alzheimer's disease (AD) in family members of those afflicted with the disease. Ten years ago, we gave the self-administered, 40-question scratch and sniff University of Pennsylvania Smell Identification Test to 18 atrisk family members, individuals with dominantlyinherited Alzheimer's disease. Testing results were normal 10 years ago except in the case of one individual who had smoked three packs of cigarettes a day for more than 23 years. Four subjects tested in 1990 are now afflicted with Alzheimer's disease, including the smoker. The smell test in 1990 did not demonstrate predictive capabilities before clinical conversion to dementia. At follow-up, two subjects were too impaired to take the test. Two “converted” from normal smell function toabnormal function with a wide range in score. Study findings indicate that the smell test is too variable a measure to be used as a reliable test for predicting or verifying a diagnosis of presenilin-1 Alzheimer's disease.

This paper presents the thesis that rapidly developing areas of knowledge in neuroscience will rekindle interest in neuropsychiatry, and increase scientific and clinical interaction between psychiatrists and neurologists in teaching hospitals. A neuropsychiatric clinical research unit at the National Institute of Mental Health is described. Examples of research conducted on the unit illustrate areas of biological science that are likely to increase the interface between psychiatry and neurology. Hopefully, the explosion of knowledge in the basic neurosciences in the last decade will be followed in this decade by clinical research of increasing specificity and sophistication on central nervous system disorders.

A group of fibroblast lines from three patients with the sporadic form of Alzheimer disease (AD) showed a small but statistically significant hypersensitivity to the lethal effects of the DNA-damaging chemical N-methyl-N'-nitro-nitrosoguanidine (MNNG) when compared with lines from eight normal control subjects. A fibroblast line from a patient with a dominantly inherited form of familial AD had a hypersensitivity similar to that of the three sporadic AD lines. However, fibroblast lines from a group of five patients with spinal muscular atrophy (SMA) were not hypersensitive to the chemical, demonstrating that not every primary neuronal degeneration manifests hypersensitivity to this chemical. These findings are consistent with the possibility that a defect in DNA-repair mechanisms may be the cause of the in vitro hypersensitivity, as well as the premature death of neurons in vivo, in both the sporadic and familial forms of AD.

Fifty patients with Tourette syndrome were evaluated; data included family history, clinical characteristics, response to haloperidol, and side effects during haloperidol therapy. Sixteen patients had a family history of Tourette syndrome, and another 16 had a family history of tics. Twenty-four families had more than 2 members with Tourette syndrome or tics. There was no preponderance of families with a Jewish, Eastern European background in this sample. Thirty-four patients had obsessive-compulsive behavior. Among the 50 patients there was a high frequency of sleep disturbance, learning disability, self-destructive behavior, inappropriate sexual activity, and antisocial behavior. Family history was significantly related to the occurrence of sleep disturbance, obsessive-compulsive behavior, haloperidol response, and the frequency of side effects caused by haloperidol. The precise mode of genetic transmission in familial Tourette syndrome remains to be determined.

A Canadian family comprising 51 members affected with Alzheimer's disease was evaluated clinically, histologically, and genetically. Ancestors were traced through eight generations, and 51 members were examined at the National Institute of Mental Health, Bethesda, Md. The pedigree is consistent with autosomal dominant inheritance. The effect of interrelatedness among some parents of affected individuals is unknown. In contrast to other studies, there was not an increased incidence of Down's syndrome, hematologic malignancy, or preponderance of affected females.

Stimulant drug treatment of children with attention deficit disorder with hyperactivity (ADDH) is often dramatically successful in controlling impulsive, distractible, and even antisocial behaviors. Although this increased vigilance and decreased motor restlessness has been shown to be a nonspecific effect of stimulants (Rapoport et al., 1978), the mechanism of action of stimulants may still be of considerable importance in understanding the biological basis of restless and inattentive behavior in children. Recent reports suggest a link between alteration in central nervous system norepinephrine (NE) metabolism and the therapeutic action of stimulants in hyperactive children. Urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) is decreased with amphetamine treatment in hyperactive children (Shekim et al., 1977, 1979; Brown et al., 1979), and this decrease may correlate with clinical response to the drug.

In this 4-week, double-blind, parallel group study, eight young women with primary anorexia nervosa were evaluated on lithium carbonate, and eight patients were treated with placebo and served as a control. All patients participated in a behavior modification treatment program. The lithium-treated and placebo groups were comparable on nearly all findings measured at baseline (t tests), with no significant differences observed except for calories per day, percent fat composition of the daily calories, "interpersonal sensitivity" on the Hopkins Symptom Checklist-90 (HSCL-90), "self-care" on the Goldberg Anorectic Attitude Questionnaires, (GAAQ) and "manipulation of others" on the physician-rated Psychiatric Rating Scale (PRS). The data were analyzed using repeated measures analysis of covariance (ANCOVA) with the baseline measure as the covariate. Group differences appeared in the areas of "denial or minimization of illness" on the GAAQ, "selective appetite" on the PRS, and weight. Although the repeated measures ANCOVA for weight revealed a significant group-by-time interaction, indicating nonparallelism and invalidating the test for group differences, ANCOVAs performed for each individual time point showed greater weight gain in the lithium group at weeks 3 and 4.

• We did not find a significant association between HLA antigens and pure autonomic failure or multiple system atrophy with autonomic failure. HLA-A32, specifically, did not occur with increased frequency in either group of patients. Our results do not support an HLA contribution in these disorders of the autonomic nervous system as reported by other investigators.