Alzheimer\'s disease: Aß or ApoE amyloidosis?

In our risk-adjusted comparisons the tertiary neonatal units did better in 1988-90, with lower hospital mortality3 and no increase in late deaths or disability rate (April 22 paper). Although designed to predict death, CRIB scores up to 12 h after birth also stratified the risk of disability after 18 months more accurately than did birthweight or gestation (figure). CRIB similarly stratified the risk of major cerebral impairment before discharge in a separate cohort of survivors.3 Did early severity of illness predispose to brain damage, or vice versa? While prenatal brain damage may sometimes cause or share the same cause as respiratory illness, acidosis, and higher CRIB scores, it seems more likely that these conditions lead to subsequent impairment. Either way, by stratifying soon after birth the risks of death, cerebral impairment, and disability, CRIB will allow more reliable comparisons of the added value of neonatal care in reducing subsequent adverse outcomes, especially if prenatal brain damage is identified. Risk-adjusted studies of impairments and associated disabilities could improve performance in several ways-by suggesting possible causes and new methods for prevention; by stimulating better implementation of effective therapies, more critical appraisal of local practice, and more discussion with parents about possible outcomes; and by assessing whether greater intensity of skilled cotside care is associated with increased intact survival. It is a tragedy for these vulnerable children that the need to coordinate standardised follow-up receives so little priority. Health-policy makers should support the recommendation that all survivors of neonatal intensive care be assessed at about 2 years of age. 4,S *William Tarnow-Mordi, Lesley Mutch, Gareth Parry, Forrester Cockburn, Neil McIntosh, for Scottish Neonatal Consultants Collaborative Study Group and International Neonatal Network *Centre for Research into Human Development, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK

1 Roth SC, Baudin J, McCormick DC, et al. Relation between ultrasound appearance of the brain of very preterm infants and neurodevelopmental impairment at eight years. Dev Med Child Neurol 1993; 35: 755-68. 2 Fujimoto S, Togari H, Yamaguchi N, Mizutani F, Suzuki S, Sobajima H. Hypocarbia and cystic periventricular leukomalacia in premature infants. Arch Dis Child 1994; 71: F107-10. 3 International Neonatal Network. The CRIB (clinical risk index for babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. Lancet 1993; 342: 193-98. 4 National Perinatal Epidemiology Unit and Oxford Regional Health Authority. Disability and perinatal care; measurement of health status at two years. Oxford: National Perinatal Epidemiology Unit, 1994. 5 Johnson A. Disability and perinatal care. Pediatrics 1995; 95: 272-74.

Alzheimer’s disease:

Aß

SiR-Wisniewski and others co-purification from senile

or

ApoE amyloidosis?

(April 15, p 956) describe the plaques of a carboxyterminal of E fragment apolipoprotein (ApoE) with amyloid [3 (A(3) from an Alzheimer’s disease (AD) patient with an ApoE3/E4 isotype. They suggest that AD is an ApoE amyloidosis. We too have demonstrated the co-purification of ApoE with Ap peptide aggregated within amyloid deposits,’ and report here on the relation between ApoE genotype and the presence of this molecule within amyloid deposits. Brains of 23 AD patients (76-5 [SD10-1] years old) were obtained at necropsy. Neuropathological examination indicated that all had amyloidosis. ApoE allele frequencies were e2 6-5%, e3 63%, and e4 30-5%. We used a dot-blot immunoassay’ to look for Ap and ApoE in the superior frontal cortex. ApoE does not always co-purify with A[3; five (26%) of the AD cases showing amyloid deposits and strong

Ap immunoreactivity by dot-blot immunoassay did not have any ApoE signal and three of the 13 AD patients with at least one E4 allele and A(3 immunoreactivity did not exhibit ApoE immunoreactivity. However, the only case genotyped e4/e4 was an AD patient showing the highest ApoE immunoreactivity despite only moderate amounts of A(3. Our findings suggest that ApoE is a risk factor in only a subgroup of AD patients. In late-onset AD, Roses and colleagues2 have estimated that the ApoE gene accounts for about 50% of the total genetic effect, suggesting that additional genes are important. Thus AD is still an Ap, not an ApoE, amyloidosis. Buée, Bruno Permanne, Jordi Pérez-Tur, Marie-Christine Chartier-Harlin, André Delacourte *Luc

INSERM U422 (Vieillissement Cérébral et place de Verdun, 59045 Lille, France

1

2

Dégénérescence du Neurone),

B, Buée L, David JPh, Di Menza C, Delacourte A. Quantitation of Alzheimer’s amyloid peptide and identification of related amyloid proteins by dot-blot immunoassay. Brain Res (in press). Roses AD, Saunders AM, Corder EH, et al. Influence of the susceptibility genes apolipoprotein E-e4 and apolipoprotein E-e2 on the rate of the disease expressivity of late-onset Alzheimer’s disease. ArzneimittelForschung/Drug Res 1995; 45: 413-17. Permanne

Bone-marrow

transplantation

SiR-Although strong on rhetoric Gale and colleagues’ (May 13, p 1235) to my commentary (March 11) provides no convincing data to refute my sense that veryhigh-dose therapy with bone-marrow transplantation (BMT) is unlikely to be the wave of the future. Consider the abstract they cite in support of their unequivocal statement that leukaemia-free survival (not, apparently, overall survival) in acute myeloid leukaemia in first remission is better with BMT than with chemotherapy.’ It begins by stating that response

"The best treatment for adults with AML in first remission who have an HLA-identical sibling is controversial". It goes on to describe a comparison of the outcome of a matched cohort of patients from the International Bone Marrow Transplant Registry with a single German AML Cooperative Group study (AML86). I suspect that these data will be persuasive only to those already convinced. This debate has been going on for years-a sure sign that neither approach is unequivocally better. Gale et al allege that I "wrongly lump together different types of leukaemia." I could equally argue that the very lack of disease-specific preparative regimens is one of the limitations of BMT. One could see BMT as a means of permitting donor immune cells to react against tumour cells unhindered by the host immune response in which case the approach would indeed be similar for all leukaemias. In the specific context of chronic myeloid leukaemia, for which BMT is available to only a fraction of patients (more than half are over 60 at diagnosis), my point (apparently missed) was simply that the cytogenetic remissions produced by a-interferon hold the promise that cheaper and less toxic therapies than BMT will eventually be found. Gale et al deny that the report of the US General Accounting Office on BMT3 was directed towards attempting to determine whether Americans have "better access to advanced medical technologies" but this was an almost verbatim quotation of the wording used in the statement of the purpose of the report.3 The report was one element of a two-part response to a request to "examine differences in the availability of health services and outcomes across developed countries". I still question the priority given to BMT in attempting to fulfil this purpose, even I am very glad that Gale et al "generally value criticism" but this statement suggests that they missed

partly. Moreover,

59