CSF-tau, CSF-Abeta1-42, ApoE-genotype and clinical parameters in the diagnosis of Alzheimer's disease: combination of CSF-tau and MMSE yields highest sensitivity and specificity.

This study evaluated the sensitivity and specificity of the cerebrospinal fluid (CSF) levels of tau-protein, amyloid-beta-peptide 1-42 (Abeta1-42), ApoE-genotype and the degree of cognitive decline as diagnostic markers for Alzheimer's disease (AD). Data was obtained from 105 AD patients and 68 controls. Median CSF-tau levels were increased (512 pg/ml vs. 145 pg/ml, p<0.001) and Abeta1-42-levels were decreased (238.5 pg/ml vs. 310 pg/ml, p<0.001) in AD patients compared to controls. A weak correlation was found between CSF-Abeta1-42 and MMSE score (r=.245). Within all subjects, a correlation of CSF-Abeta1-42 (r=-.337) and CSF-tau (r=.384) with age was found. The combination of CSF-tau levels and MMSE revealed the highest sensitivity (92%) and specificity (87%). In summary, CSF-tau was a useful biological marker to discriminate AD from normal aging, neurological and psychiatric disorders. CSF-Abeta1-42 showed no additional benefit in discriminating patients from controls but might be useful for tracking the severity of the disease.

Association of late-onset Alzheimer disease with a genotype of PLAU, the gene encoding urokinase-type plasminogen activator on chromosome 10q22.2.

Urokinase-type plasminogen activator (uPA) converts plasminogen to plasmin. Plasmin is involved in processing of amyloid precursor protein and degrades secreted and aggregated amyloid-beta, a hallmark of Alzheimer disease (AD). PLAU, the gene encoding uPA, maps to chromosome 10q22.2 between two regions showing linkage to late-onset AD (LOAD). We genotyped a frequent C/T single nucleotide polymorphism in codon 141 of PLAU (P141L) in 347 patients with LOAD and 291 control subjects. LOAD was associated with homozygous C/C PLAU genotype in the whole sample (chi2=15.7, P=0.00039, df 2), as well as in all sub-samples stratified by gender or APOE epsilon4 carrier status (chi2> or = 6.84, P< or =0.033, df 2). Odds ratio for LOAD due to homozygosity C/C was 1.89 (95% confidence interval 1.37-2.61). PLAU is a promising new candidate gene for LOAD, with allele C (P141) being a recessive risk allele or allele T (L141) conferring protection.

[The role of depression in rehabilitation of geriatric patients with hip fracture]. / Depression bei geriatrischen Patienten mit hüftgelenksnahen Frakturen und deren Auswirkung auf den Rehabilitationsverlauf.

The effect of depression on the rehabilitation course of 64 geriatric inpatients with hip fracture was examined. At the beginning of treatment 38.5% had a depressive disorder according to GDS-15. After 3 weeks it was still 32%, although in 7 patients the GDS-score had decreased. Additionally, 18% had a cognitive disorder (MMSE<24). There was a correlation between depression and Barthel-Index at the start of treatment (58.4; SD 14.7 vs 48.3; SD 21.8; ANOVA; p<0.01), Barthel-Index at discharge (86.1; SD 13.1 vs 75.0; SD 25.11; ANOVA; p<0.01), mobility measured by timed "Up and Go" (Chi(2); p<0.01) and the number of prescribed drugs, as equivalent for severity of somatic diseases. Treatment of depression was inadequate in the beginning and at follow-up. Treated patients had a better outcome than untreated.

Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer's disease.

Because increased oxidation is an important feature of Alzheimer's disease (AD) and low concentrations of antioxidant vitamins C and E have been observed in cerebrospinal fluid (CSF) of AD patients, supplementation with these antioxidants might delay the development of AD. Major targets for oxidation in brain are lipids and lipoproteins. We studied whether supplementation with antioxidative vitamins E and C can increase their concentrations not only in plasma but also in CSF, and as a consequence decrease the susceptibility of lipoproteins to in vitro oxidation. Two groups, each consisting of 10 patients with AD, were for 1 month supplemented daily with either a combination of 400 IU vitamin E and 1000 mg vitamin C, or 400 IU vitamin E alone. We found that supplementation with vitamin E and C significantly increased the concentrations of both vitamins in plasma and CSF. Importantly, the abnormally low concentrations of vitamin C were returned to normal level following treatment. As a consequence, susceptibility of CSF and plasma lipoproteins to in vitro oxidation was significantly decreased. In contrast, the supplementation with vitamin E alone significantly increased its CSF and plasma concentrations, but was unable to decrease the lipoprotein oxidizability. These findings document a superiority of a combined vitamin E + C supplementation over a vitamin E supplementation alone in AD and provide a biochemical basis for its use.

Non-replication of association between cathepsin D genotype and late onset Alzheimer disease.

In two recent studies from Germany, a strong association was found between the allelic variant T of the amino acid substitution encoding polymorphism 224 C/T (A38V) in exon 2 of the cathepsin D gene (CTSD) and late onset Alzheimer disease (AD). Other studies from Europe and the USA revealed ambiguous results. Therefore, we performed an independent association study on CTSD and AD in a sample of 324 Caucasian patients from Germany, Switzerland, and Italy with late onset AD, and 302 non-demented controls. We could not confirm an association between CTSD genotype and AD, although there was a slight but not significant increase in frequency of the T allele and T carrier status in AD. Post hoc data analyses suggested that there might be a stronger effect of CTSD genotype on AD risk in males, and an interaction between CTSD and APOE genotypes in males but not females.

[Lipid peroxidation as a common pathomechanism in coronary heart disease and Alzheimer disease]. / Lipoproteinoxidation als gemeinsamer Pathomechanismus der koronaren Herzerkrankung und der Alzheimer Krankheit.

Oxidative processes are involved in aging as well as the pathogenesis of different degenerative diseases. In the last few years the role of low density lipoprotein oxidation in the development of artherosclerosis and coronary heart disease has become evident. Lipoprotein oxidation in plasma is used as a marker for disease progression. We were interested in the role of lipoprotein oxidation in Alzheimer's disease. For this purpose we developed methods to determine the in vitro oxidizability of cerebrospinal fluid and plasma lipoproteins of Alzheimer patients. In addition we measured the lipophilic and hydrophillic antioxidants, alpha-tocopherol (vitamin E) and ascorbate (vitamin C). Cerebrospinal fluid and plasma lipoprotein oxidation was found to be increased in Alzheimer's patients compared to controls and a corresponding decrease of antioxidant vitamins was found. In a pilot study, in vitro lipoprotein oxidation in cerebrospinal fluid of Alzheimer patients could be delayed by vitamin E and C supplementation. In conclusion these data show that increased lipoprotein oxidation could play an important role in Alzheimer's disease and possibly provide a rationale for the treatment of this disease with antioxidant drugs. The clinical effect of this therapeutical approach remains to be proved in long-term studies.

Genetic association of a cystatin C gene polymorphism with late-onset Alzheimer disease.

OBJECTIVE: To determine whether the cystatin C gene (CST3) is genetically associated with late-onset Alzheimer disease (AD). DESIGN: A case-control study with 2 independent study populations of patients with AD and age-matched, cognitively normal control subjects. SETTING: The Alzheimer's Disease Research Unit at the University Hospital Hamburg-Eppendorf, Hamburg, Germany, for the initial study (n = 260). For the independent multicenter study (n = 647), an international consortium that included the Massachusetts Alzheimer's Disease Research Center at the Massachusetts General Hospital, Boston; the Scientific Institute for Research and Patient Care, Brescia, Italy; and Alzheimer's research units at the Universities of Basel and Zurich, Switzerland, and Bonn, Goettingen, and Hamburg, Germany. PARTICIPANTS: Five hundred seventeen patients with AD and 390 control subjects. MEASURES: Molecular testing of the KspI polymorphisms in the 5' flanking region and exon 1 of CST3 and the apolipoprotein E (APOE) genotype. Mini-Mental State Examination scores for both patients with AD and control subjects. RESULTS: Homozygosity for haplotype B of CST3 was significantly associated with late-onset AD in both study populations, with an odds ratio of 3.8 (95% confidence interval, 1.56-9.25) in the combined data set; heterozygosity was not associated with an increased risk. The odds ratios for CST3 B/B increased from 2.6 in those younger than 75 years to 8.8 for those aged 75 years and older. The association of CST3 B/B with AD was independent of APOE epsilon4; both genotypes independently reduced disease-free survival. CONCLUSIONS: CST3 is a susceptibility gene for late-onset AD, especially in patients aged 75 years and older. To our knowledge, CST3 B is the first autosomal recessive risk allele in late-onset AD.

Subnormal serum vitamin B12 and behavioural and psychological symptoms in Alzheimer's disease.

The objective of this study was to examine whether patients with Alzheimer's disease (AD) with subnormal vitamin B12 levels show more frequent behavioural and psychological symptoms of dementia (BPSD) than AD patients with normal vitamin B12 levels. The design was a prospective case-control study. The study took place at a memory-clinic of a department of geriatric medicine in a teaching hospital. There were seventy-three consecutive outpatients with probable AD, including 61 patients with normal and 12 patients with subnormal (<200 pg/ml) vitamin B12. BPSD were measured using the subscales disturbed behaviour and mood of the Nurses' Observation Scale for Geriatric Patients (NOSGER), the Cornell Scale for Depression and the four criteria for personality change in dementia from the International Classification of Diseases (ICD-10). Controlling for dementia duration and degree of severity of the cognitive deficits, there were significant inverse associations between vitamin B12 status and ICD-10 irritability (p=0.045) and NOSGER subscale disturbed behaviour (p=0.015). Low vitamin B12 serum levels are associated with BPSD in AD. Vitamin B12 could play a role in the pathogenesis of behavioural changes in AD.

Increased lipoprotein oxidation in Alzheimer's disease.

Oxidation has been proposed to be an important factor in the pathogenesis of Alzheimer's disease (AD) and amyloid beta is considered to induce oxidation. In biological fluids, including cerebrospinal fluid (CSF), amyloid beta is found complexed to lipoproteins. On the basis of these observations, we investigated the potential role of lipoprotein oxidation in the pathology of AD. Lipoprotein oxidizability was measured in vitro in CSF and plasma from 29 AD patients and found to be significantly increased in comparison to 29 nondemented controls. The levels of the hydrophilic antioxidant ascorbate were significantly lower in CSF and plasma from AD patients. In plasma, alpha-carotene was significantly lower in AD patients compared to controls while alpha-tocopherol levels were indistinguishable between patients and controls. In CSF, a nonsignificant trend to lower alpha-tocopherol levels among AD patients was found. Polyunsaturated fatty acids, the lipid substrate for oxidation, were significantly lower in the CSF of AD patients. Our findings suggest that (i) lipoprotein oxidation may be important in the development of AD and (ii) the in vitro measurement of lipid peroxidation in CSF might become a useful additional marker for diagnosis of AD.

High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.

Clinical differential diagnosis of early-onset dementia (EOD) includes familial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for unambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease. To investigate the proportion of EOD attributable to known genes, we prospectively (i.e., antemortem) screened these four genes for mutations by sequencing genomic PCR products from patients with EOD before age 60 years. Family history for dementia was positive (PFH) in 16 patients, negative (NFH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we found five novel mutations (in PS1, F105L; in PS2, T122P and M239I; and in PrP, Q160X and T188K) and five previously reported mutations (in APP, in three patients who were most likely unrelated, V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found two mutations (APP V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patients with NFH. We conclude that because of the lack of specific antemortem diagnostic markers for FAD and hereditary prion disease, all four genes should be included in a molecular diagnostic program in patients with EOD who had PFH.

High frequency of mutations in four different disease genes in early-onset dementia.

Heterozygous mutations in the genes for amyloid precursor protein (APP), the presenilins (PS1, PS2), prion protein (PrP), neuroserpin, and tau are associated with early-onset dementia (EOD) with or without neurological signs in the early disease stage. To investigate the proportion of EOD without early neurological signs attributable to known genes we prospectively (i.e., ante mortem) screened these six genes for mutations in 36 patients with EOD before age 60. Family history for dementia was positive (PFH) in 16, negative (NFH) in 17, and unknown (UFH) in 3 patients. In 12 patients, we found 5 novel mutations (PS1: F105L; PS2: T122P, M239I; PrP: Q160X, T188K) and 5 previously reported mutations (APP: in three most likely unrelated patients V717I; PS1: A79V, M139V; PrP: P102L, T183A) that all are considered disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found 2 mutations (APP V717I) in 2 of the 3 the UFH-patients, and only 1 mutation (PrP T188K) in 1 of the 17 patients with NFH. No mutation was found in tau and neuroserpin genes. To date, three patients died and FAD, predicted by PS mutations in two patients, and prion disease, predicted by a PrP mutation in the third one, were histopathologically confirmed at autopsy. Up to now, mutation findings may be the most specific biomarkers for an ante mortem diagnosis of FAD or hereditary prion disease.

[Psychiatric disorders in the elderly and psychosocial background. A study of geriatric inpatients]. / Psychiatrische Störungen im Alter und deren psychosoziale Hintergründe. Eine Untersuchung an stationären geriatrischen Patienten.

OBJECTIVE: In the past, little attention was paid to psychiatric problems of geriatric inpatients. One reason for this may be that little is known about the necessity and the dimension of psychiatric help in this population. METHODS: Psychiatric morbidity was studied in a sample of geriatric inpatients aged 65 years and older. RESULTS: Dementia was found in 26%, depressive disorders in 22%, alcohol abuse in 11% and benzodiazepine abuse in 2%. 38% had no psychiatric disorder. Dementing disorders were more frequent in older patients, other disorders showed no association to age. Men had a better education level and higher professional positions but more frequent psychiatric disorders than women. Neither social network nor financial situation was related to psychiatric disorders. But chronic somatic diseases were associated with depressive disorders. CONCLUSIONS: Psychiatric disorders are frequent and affect geriatric treatment. A collaboration between psychiatrists and geriatrics should therefore be a necessity and not an exception.

Suicide among schizophrenic adolescents in the long-term course of illness.

The significance of the suicide problem for patients showing first symptoms of schizophrenic disorders between 14 and 18 years of age is presented in a long-term follow-up study including two follow-up periods after a minimum of 5 and 11 years. The suicide rate of 13.1% is significantly higher than in other studies with patients who developed a schizophrenic psychosis in a later period of life. In addition, there is a significant sex difference in the rate of suicide--21.5% of the men and 6% of the women--although the latter made more attempts at suicide.

Schizophrenia with onset in adolescence: an 11-year followup.

This study examined the course of illness and factors affecting it in schizophrenias with onset between the ages of 14 and 18. Noteworthy in comparison to findings from other followup studies is the higher proportion of chronic courses of illness, about 50 percent. In addition, the type of course of illness corresponds in general with the treatment status. A possible explanation for this observation is the early age of onset, at which point the patient has not yet developed a sufficient degree of social and emotional independence and maturity before developing a schizophrenic psychosis. The age of onset is also shown to be an important predictor for the overall course of illness, as in other studies.