AD7c-NTP Revisited
ABSTRACT & COMMENTARY
Source: de la Monte S, et al. Characterization of the AD7c-NTP cDNA expression in Alzheimer’s disease and measurement of a 41 kD protein in cerebrospinal fluid. J Clin Investig 1997;12:3093-3104.
In april 1997, Neurology Alert criticized the direct marketing of the AD7c-NTP cerebrospinal fluid test as a means to "rule out Alzheimer’s disease" without peer-reviewed studies proving its value. de la Monte and colleagues have now further characterized AD7c-NTP. Findings include the discovery of a cDNA derived from the brain that encodes a 41 kilodalton form of the AD7c-NTP protein, as well as evidence that this form of the protein is expressed by human neurons and overexpressed in Alzheimer’s disease.
The investigators examined AD7c-NTP levels in archival CSF specimens collected between 1972 and 1992. Fresh postmortem specimens were harvested from the lateral ventricles of 121 patients with histopathologically confirmed Alzheimer’s disease and 19 age-matched normal controls. Lumbar CSF samples were obtained antemortem from 89 "early Alzheimer" cases, 32 non-demented patients with Parkinson’s disease (PD), 41 multiple sclerosis (MS) patients, and 18 non-demented controls. Concentrations of AD7c-NTP in CSF were determined using a quantitative sandwich enzyme-linked immunoassay reported to be highly sensitive and reproducible. Diagnosis was gleaned from review of medical records carried out without knowledge of the CSF results. AD7c-NTP levels were examined for correlation with severity of dementia, as estimated from Blessed Dementia Scale Scores (BDSS).
The mean concentration of AD7c-NTP found in postmortem ventricular CSF of AD patients (9.2 ± 8.2 ng/mL) significantly exceeded that of the 19 controls (1.6 ± 0.9 ng/mL). In CSF obtained antemortem, a smaller but statistically significant difference was found between the mean for AD patients (4.6 ± 3.4 ng/mL) and 18 non-demented controls (1.2 ± 0.7 ng/mL). Mean levels were modestly elevated in the PD (1.8 ± 1.1 ng/mL) but not in the MS patients. de la Monte et al note that levels of AD7c-NTP above 2 ng/mL were found in 89% of clinically diagnosed AD patients but in only 11% of normal controls. When AD patients and cognitively normal controls were pooled together, a positive correlation was found between AD7c-NTP concentrations in CSF and Blessed scores.
The authors identified that human brain can express AD7c-NTP cDNA. They also analyzed the amino acid sequence of the gene product to obtain indirect evidence that it may be a membrane-spanning protein. In vitro studies in stable transfected neuronal cell lines suggested that overexpression of the gene may promote neuritic sprouting and cell death. Immunohistochemical studies in AD brain indicated co-localization of the AD7c-NTP immunoreactivity with tau positive neurofibrillary tangles and dystrophic neurites. Lower levels of immunoreactivity were observed in neurons from normal aged brains, implying that AD7C-NTP may be constitutively expressed by normal neurons and overexpressed in AD.
COMMENTARY
These well-conducted experiments illuminate much of the neurobiology of the AD7c-NTP cDNA and 41 kD protein. The published article makes no claim that AD7c-NTP CSF test possesses sufficient selective power to diagnose or exclude a diagnosis of Alzheimer’s disease. Dr. de la Monte "believes that objective reliable assays such as the AD7c-NTP test, which can be used to assist physicians and other caretakers to establish or exclude the diagnosis of early Alzheimer’s disease, are valuable."
Neurology Alert agrees that the findings are important and deserve further attention at the research level. Alert, however, remains loath to recommend for clinical diagnosis a test that has been applied to only a limited number of AD patients, detected only 62% antemortem as having AD, and has not been tested against other dementing illnesses such as vascular, Lewy body, or post-traumatic dementia. So far, the authors provide no evidence that they have determined optimal cutoff values for diagnostic purposes. A cutoff value of 3 ng/mL gave excellent discrimination of AD patients from neurological controls in postmortem CSF but detected only 62% of AD cases antemortem. The conclusion that only 11% of normals have CSF AD7c-NTP levels above 2 ng/mL was based on analysis of just 18 antemortem controls, among whom were included patients with schizophrenia and psychotic depression.
An objective and accurate antemortem test for Alzheimer’s would be extremely useful. Historically, however, the literature contains many examples of initially promising biological markers that failed to live up to their anticipated potential when tested in appropriate clinical populations. Readers may remember the tropicamide eye drop test for AD (Scinto L, et al. Science 1994;266:1051-1054; Neuro Alert 1995;13:44-45), which initially claimed to distinguish AD patients from normal controls. When applied to larger numbers of elderly patients, however, it was ultimately found inaccurate as a screening test for AD (Growdon JH, et al. Arch Neurol 1997;54:841-844.)
Alert looks forward to appropriately large, epidemiologically pre-designed studies that may validate elevated AD7c-NTP in CSF as having a high positive incidence in morphologically validated AD and a close to zero incidence in other degenerative and/or dementing neurologic disorders. nrr
The 41 kD form of the AD7c-NTP protein:
a. is found exclusively in the brain’s of Alzheimer’s disease patients.
b. is found extracellularly in the brain.
c. can be detected in cerebrospinal fluid collected antemortem.
d. is absent from ventricular CSF.
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