Malene Jensen

Cerebrospinal fluid Aβ42 is increased early in sporadic Alzheimer's disease and declines with disease progression

All mutations known to cause familial Alzheimers disease (AD) act by increasing the levels of soluble β‐amyloid peptide (Aβ), especially the longer form, Aβ42. However, in vivo elevation of soluble Aβ in sporadic AD has so far not been shown. In the present study, we used enzyme‐linked immunosorbent assays specific for Aβ42 and Aβ40 to investigate cerebrospinal fluid from sporadic AD at different stages of disease severity, to clarify the roles of Aβ42 and Aβ40 during disease progression. We also evaluated three other groups—one group of patients with mild cognitive impairment who were at risk of developing dementia, a cognitively intact, nondemented reference group diagnosed with depression, and a perfectly healthy control group. We found that Aβ42 is strongly elevated in early and mid stages of AD, and thereafter it declines with disease progression. On the contrary, Aβ40 levels were decreased in early and mid stages of AD. The group of cognitively impaired patients and the depression reference group had significantly higher levels of Aβ42 than the healthy control group, implying that Aβ42 is increased not only in AD, but in other central nervous system conditions as well. Our data also point out the importance of having thoroughly examined control material. The initial increase and subsequent decrease of Aβ42 adds a new biochemical tool to follow the progression of AD and might be important in the monitoring of therapeutics. Ann Neurol 1999;45:504–511

Increased cerebrospinal fluid tau in patients with Alzheimer's disease.

One of the pathological features in Alzheimers disease (AD) is neurofibrillary tangles in the brain. The main constituent of tangles is the microtubuli-associated protein tau in a hyperphosphorylated state. Tau is also released into cerebrospinal fluid (CSF), and in this study we have used an enzyme linked immunosorbent assay to measure tau in CSF from AD and control cases. Our findings show that tau levels in AD cases are significantly elevated compared to healthy control individuals. We suggest that tau may serve as a biochemical marker of Alzheimers disease.

Increasing cerebrospinal fluid tau levels in a subgroup of Alzheimer patients with apolipoprotein E allele ϵ4 during 14 months follow-up

The concentration of tau protein is elevated in the cerebrospinal fluid (CSF) in Alzheimers disease (AD), suggesting that CSF tau may be a useful biochemical diagnostic marker for this disorder. We investigated CSF tau concentrations on two occasions in AD (n = 18), mild cognitive impairment (MCI, n = 9) and other dementing disease (OD, n = 9) by ELISA (Innotest hTau Antigen, Innogenetics, Belgium). Tau levels were statistically significant higher in the AD group than in MCI and OD groups on both occasions. Twelve of the AD patients showed increasing values of tau at follow-up and six demonstrated diminished values. All AD patients with increasing tau were carriers of one or two epsilon 4 alleles of the apolipoprotein E (APOE, gene. Of those AD cases with decreasing tau levels only three individuals had the epsilon 4 allele, a difference that was statistically significant (P < 0.05). These findings suggest that there may be apolipoprotein E (apoE) isoform-specific differences of tau regulation in AD.

Reduced cerebrospinal fluid estradiol levels are associated with increased β-amyloid levels in female patients with Alzheimer's disease

Recent in-vitro studies indicate that estrogens such as 17beta-estradiol (E2) may decrease the production of beta-amyloid 1-42 (Abeta42), a peptide central for the formation of senile plaques in Alzheimers disease (AD). To test this hypothesis in a clinical study, cerebrospinal fluid levels of E2 were compared between 30 female AD patients and 11 female patients with non-dementing diseases such as major depression and investigated with respect to beta-amyloid 1-40 and Abeta42 levels. E2 levels were significantly (P<0.05) lower in the AD group than in controls; within the AD group E2 levels were inversely correlated with Abeta42 concentrations (r=-0.36, P=0.05). This is the first clinical study providing evidence for an influence of E2 on Abeta42 metabolism in vivo. This observation corresponds to the putative beneficial effects of estrogen replacement therapy on the development and course of AD.

Cerebrospinal fluid apolipoprotein E (apoE) levels in Alzheimer's disease patients are increased at follow up and show a correlation with levels of tau protein.

Apolipoprotein E (apoE) levels were compared in cerebrospinal fluid (CSF) taken on two occasions, with an average 15 months follow up, from groups of patients with Alzheimers disease (AD: n = 18), mild cognitive impairment (MCI; n = 9) and other dementia disorders (ODD; n = 9). In these groups, CSF apoE levels were between 2-3-fold higher than values for a group of 27 healthy age-matched controls. CSF apoE levels in the AD group were significantly increased at follow up, compared to levels obtained on the first sampling occasion. For the same cases it had been shown previously that CSF tau protein levels were increased at follow up [Blomberg, M., Jensen, M., Basun, H., Lannfelt, L. and Wahlund, L-O., Neurosci. Lett., 214 (1996) 163-166]. The AD, but not MCI, ODD or control groups, also showed statistically significant correlations between CSF apoE and tau protein levels at both the first (r = 0.585, P < 0.01) and follow up (r = 0.695, P > 0.001 ) samplings. It is concluded that CSF measures of both apoE and tau may reflect an intimate relationship between these two proteins in AD and could prove useful in monitoring the progression of this condition.

EEG slowing and cerebrospinal fluid tau levels in patients with cognitive decline.

WE explored the relationship between cerebrospinal fluid (CSF) tau levels as indirect markers of tau-related pathology in Alzheimers disease (AD) and EEG slowing, a typical neurophysiological finding in the disease. A positive correlation between CSF tau levels and ratio of alpha/delta global field power was found in 14 AD patients (r = 0.65, p = 0.01). This relationship was better approximated by polynomial fit of 2nd degree (p = 0.002). A subgroup of AD patients (n = 7) with higher tau levels and shorter duration of illness showed a strong relationship between CSF tau levels and alpha/theta (r = 0.83, p = 0.02), and alpha/delta (r = 0.87, p = 0.01) ratios of the global field power. There were no significant correlations between EEG slowing and CSF tau levels in 12 patients with mild cognitive dysfunction or in 14 healthy control subjects. That a strong inverse linear correlation exists in AD patients with higher levels of tau and shorter duration of illness may imply that with longer illness duration CSF tau levels decrease due to neuronal death.

Cerebrospinal Fluid Tau Levels Increase with Age in Healthy Individuals

Cerebrospinal fluid (CSF) tau is a promising biochemical ante-mortem marker for Alzheimer’s disease (AD). Levels are increased in AD compared to other dementias, neurological diseases and healthy controls. An age-related decrease in both soluble tau and tau bound to paired helical filaments has been shown in brains from non-demented subjects. To study tau levels in normal ageing, we investigated CSF in 29 healthy individuals aged 45–80 years. A statistically significant increase in CSF tau with increasing age was found which might be caused by neuronal loss during normal ageing and redistribution of soluble tau from the brain into CSF. We could not demonstrate any influence by the APOE genotype, though larger populations have to be investigated to confirm this result. In conclusion, we found an age-dependent increase in CSF tau in healthy individuals. We emphasise the importance of establishing an age-dependent interval of CSF tau in non-demented subjects.

Clinical findings in nondemented mutation carriers predisposed to Alzheimer's disease: a model of mild cognitive impairment

Individuals carrying a mutation associated with Alzheimers disease (AD) may serve as a model of mild cognitive impairment (MCI). Nondemented individuals from these families can be subdivided into asymptomatic and symptomatic groups. Four families were studied. Two families are associated with APP mutations (KN670/671ML, E693G) and two with PS1 mutation (M146V, H163Y). Clinical symptoms, level of global cognitive functioning as evaluated by Mini‐Mental State Examination, neuropsychological test results, neuroradiological examinations (magnetic resonance imaging (MRI) and single‐photon emission tomography (SPECT)), as well as cerebrospinal fluid (CSF) measurements of tau and β‐amyloid are reported. Nondemented mutation carriers did not report any symptoms indicating cognitive decline. In addition, no clinical signs of dementia or marked cognitive impairment in neuropsychological tests were found. A reduction of temporal blood flow with SPECT was indicated in 5/13 nondemented mutation carriers. Two of these 13 individuals had moderate hyperintensities in deep white matter as observed on MRI. CSF measurements of Aβ42/43 were inconclusive because of large biological variation. A nonsignificant elevation of tau was detected in mutation carriers. In conclusion, clinical examinations of relatively young individuals carrying an AD mutation did not reveal any marked abnormalities before the clinical onset of dementia.

Amyloid Aβ40 Csf concentrations correlate to frontal lobe atrophy in frontotemporal dementia

We wanted to further study amyloid Abeta protein alterations in non-AD neurodegenerative diseases. Cerebrospinal fluid concentrations of the amyloid Abeta protein with 40 (Abeta40) and 42 (Abeta42) amino acid residues were measured in eleven patients with frontotemporal dementia (FTD). Abeta40 and Abeta42 concentrations were related to the degree of frontal lobe atrophy as assessed with MRI volumetry. Abeta40 concentrations showed a statistically significant linear correlation with degree of frontal lobe atrophy (r = -0.77, p<0.02). Similar results have not been found in previous studies of CSF Abeta40 concentrations and atrophy in patients with AD which suggest that the role of Abeta40 differs between the pathological processes of FTD and AD.

Inhibition of prolylendopeptidase does not affect γ-secretase processing of amyloid precursor protein in a human neuroblastoma cell line

Abeta peptides are major components of the amyloid plaques that characterize Alzheimers disease. The enzyme activities (beta- and gamma-secretases) involved in generating Abeta from amyloid precursor protein (APP) are unidentified. It has been suggested that prolylendopeptidase (PEP), an oligopeptidase that normally cleaves after proline residues, could also cleave after the alanine at position 42 of Abeta to generate Abeta42. We investigated whether inhibition of PEP activity in human neuroblastoma cells affected Abeta levels in cell culture media. An SH-SY5Y cell line expressing SPA4CT, encoding the C-terminal 100 residues of APP and the signal sequence, was used. Only gamma-secretase activity is required for Abeta production in this cell line. The PEP inhibitor Fmoc-AlaPro-CN (10 microM) reduced PEP activity in these cells by approximately 95% in the absence of significant toxicity, but had no effect on Abeta40 or Abeta42 levels in cell culture media. We conclude that PEP is unlikely to be involved in gamma-secretase processing of APP.