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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.

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.

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.

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.

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.