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Vascular risks and dementia
- Albert J Kirshen (16 June 2001)
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Alzheimer's disease: the primary role of both insulin and cerebral insulin-receptors responce.
- Sergio Stagnaro (16 June 2001)
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two sides of the same coin
- Pablo Millares-Martin (18 June 2001)
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Raised systolic blood pressure or serum cholesterol may not increase the risk of Alzheimers Disease
- Mark Yates (19 June 2001)
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Differential Diagnosis of Dementia Uncertain
- Gerson T Lesser (6 July 2001)
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Cholesterol, synaptic function and Alzheimer’s disease
- Alexei R Koudinov, Natalia V Koudinova (17 October 2001)
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Albert J Kirshen, Assistant Professor - Geriatric Medicine, Faculty of Medicine University of Toronto, Toronto Canada
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I read this article with interest and hope but regret that I cannot adequately assess the methodology and therefore the validity of this paper, for which I take the editors and reviewers significantly to task. There is a grossly inadequate description in the published paper, nor is the extra figure on the website adequate. Would the authors please specify a) Inter and intra-rater reliability of the MMSE on this occasion, and the general psychometric properties of the version they used and its validity statistics when given in Finnish compared with the original development in English. b) The neuropsychological tests used in Phases 2 and 3, and provide references to their validity when administered in Finnish. c) The details of the general and neurological examinations to which subjects were subjected. d) Details of the process for determining the diagnosis, and the process for settling disputes among authors. Further, could the authors specify whether they tested regression assumptions prior to performing multiple logistic regression analyses, and could they publish the validity statistics of the analyses. Having started out with this sample, could the authors please provide us with information about power of the post-hoc analyses, and what corrections they used for multiple comparisons. Finally, it would have been helpful had the authors commented on the perceived difference in rates of dementia among northern Europeans and Japanese individuals developing dementia that, if memory serves me correctly, has reportedly been more related to vascular events than Alzheimer's disease when compared to a North American population. While the information presented is interesting academically, I regret that the flaws in the study as published prevent me from taking away any information. I look forward to the authors' reply. |
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Sergio Stagnaro, Specialist in Blood, Metabolic and Gastrointestinal Disease Riva Trigoso (Genoa) Italy
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Miia Kivipelto et al. (1) examined the relation of midlife raised blood pressure and serum cholesterol concentration to Alzheimer’s disease in later life, and concluded that raised blood pressure and high serum cholesterol concentration, and particularly the combination of these risks, increase the risk of the disease in later life. In a early biophysical-semeiotic research (2, 3), briefly referred in the site: http://utenti.tripod.it/la_piazzetta/professione/professione.htm.; title: “Diagnosi Semeiotico-biofisica Precoce della Malattia di Alzheimer”, I gathered interesting data, which agree with those referred in the excellent paper, due to the fact that there is notoriously an association between high serum cholesterol, raised blood pressure and, finally, hyperinsulinism. Briefly, in healthy, from the microcirculatory point of view, during stress test both vasomotility (chaotic-deterministic oscillations of arterioles) and vasomotility (chaotic-deterministic fluctuations of nutritional capillaries and post-capillary venules) particularly in hippocampus, pre-frontal and parietal cerebral regions are maximally activated. (2, 3, 4, 5). On the contrary, in individuals with a family history positive for Alzheimer’s disease and, of course, in patients in the first stages, under identical conditions appears a particular form of microcirculatory activation, characterized by increased vasomotility and decreased vasomotion (i.e. dissociated type). In a few words, the flow- and flux-motion in the cerebral microcirculatory bed appears to be clearly decreased, due to the dangerous phenomenon of the so -called “microcirculatory blood-flow centralization”. Unfortunately, it is generally admitted that diagnosing Alzheimer’s disease, particularly in initial stages, is very difficult. In my 44-year-long clinical experience the test of acute pick of insuline secretion (2, 3) proved to be reliable in bed-side recognizing this (and other numerous) disorder, even in its first stage. Although insulin isn’t necessary in the glucose utilizations of cerebral neurons, surely in both cerebral cortex and hippocampus there is a largely amounts of insulin receptors (6). In initial stages of the disease has been demonstrated a scarse glucose metabolism in cerebral tissue: venous glucose level appears to be slightly decreased (6). The authors, in addition, demonstrated that O2 consumption is unchanged, due to the fact that the neurons utilize other “endocellular” substances rather than glucose, probably causing neurons death (7). Although insulin isn’t necessary in glucose utilizations of cerebral neurons, however in both cerebral cortex and hippocampus there is surely a largely amounts of insulin receptors (6). In addition, in the initial sages of the disease has been demonstrated a scarse glucose metabolism in cerebral tissue: venous glucose level appears to be slightly decreased (6). These authors, moreover, demonstrated that O2 consumption is unchanged, due to the fact that the neurons utilize other “endocellular” substances rather than glucose, probably causing neurons death. In summary, in the complex and non completely understood pathophysiology of Alzheimer’s disease does exist a fault response of cerebral insulin receptors, while the hormon acts likily as a growth factor. From these work hypothesis, in a previous clinical research I observed that acute pick of insulin secretion (2, 3, 4) in healthy activates the microcirculation in all biological systems, while in patients at “real” risk of Alzheimer’s diesease and, naturally, in patients involved by the disease, even in early stage, microcirculatory activation is totally absent. Importantly, in no other cerebral disorders, including cerebral arteriosclerosis, I did observe the absence of insulin-receptors responce, i.e. the absense of microcirculatory activation, type I, associated. Yours. Stagnaro Sergio MD., Member NYAS and AAAS 1) Mia Kivipelto et al.Midlife vascular risk factors of Alzheimer's disease in later life: longitudinal population based study. BMJ. 323: 1447 -1451, 2001. 2) Stagnaro S., Valutazione percusso-ascoltatoria della microcircolazione cerebrale globale e regionale. Atti, XII Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. 13-15 Ottobre, Salerno, e Acta Med.Medit. 145, 163 1986 3) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: la manovra di Ferrero- Marigo nella diagnosi clinica della iperinsulinemia-insulinoresistenza. Acta Med. Medit. 13, 125 1997 4 Stagnaro S., Stagnaro-Neri M., Valutazione percusso- ascoltatoria degli attacchi ischemici transitori e della insufficienza cerebrovascolare cronica in pazienti trattati con mesoglicano. Atti, IX Congr. Naz. It. Patologia Vascolare. Copanello, 6-9 Gennaio 1987. A cura di R. Del Guercio, G. Leonardo e G. Zanini. Pg. 765, Monduzzi Ed. Bologna 1987 5) Stagnaro S., Stagnaro-Neri M., Il Test dell’Apnea nella Valutazione della Microcircolazione cerebrale in Cefalalgici. Atti, Congr. Naz. Soc. Ita. Microangiologia e Microcircolazione. A cura di C. Allegra. Pg. 457, Roma 10-13 Settembre 1987. Monduzzi Ed. Bologna 1987 6) Hoyer S. Models of Alzheimer’s disease: cellular and molecular aspects. Journal of Neurotrasmission.(Suppl.) 49, 11, 1997. 7) Baringai M. Is Apoptosis Key in Alzheimer’s Disease? Science. 281, 1301, 28 August 1998 |
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Pablo Millares-Martin, GP Leeds
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The article by Kivipelto et al [1] not only demonstrates how raised blood pressure and high serum cholesterol are important risk factors in the pathogenesis of Alzheimer's disease but to some extent confirms that multi infarct dementia and Alzheimer's disease, the two major players in dementia, share the same origin. In consequence one has to argue that the response of the brain to these factors is what determines ultimately the clinical picture to be seen. We have been told how to differentiate these two entities clinically by tests like the Hachinski Ischaemic Score [2] and perhaps we have always been wrong considering Alzheimer's a neurodegenerative disease and not a vascular disease. Perhaps we should consider them in the same way that we consider the effects of hypertension, hypercholesterolemia and other factors on the heart, resulting in heart failure and myocardial infarction, perhaps we should consider them two sides of the same coin. The study also implies that other risk factors for ischaemic heart disease should be studied in this context and that the medical profession needs to be even more aggressive in the management of the primary conditions to prevent secondary end organ damage in brain and heart and its huge burden in our society. Bibliography: 1. Kivipelto M et al "Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study" BMJ (2001) 322:1447-51. 2. Moroney JT et al "Meta-analysis of the Hachinski Ischaemic Score in pathologically verified dementias". Neurol (1997) 49:1096-1105. |
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Mark Yates, GP Registrar East Bridgeford Medical Center, East Bridgeford, Nottingham NG13 8NY
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Editor: Kivipelto et al 1 report that raised systolic blood pressure or high serum cholesterol concentrations in midlife increases the risk of Alzheimers Disease in later life. This is based on an odds ratio of 2.3(95% confidence interval 1.0-5.5) for raised blood pressure and an odds ratio of 2.1 (95% confidence interval 1.0-4.4)for raised serum cholesterol as stated in the abstract. This claim is based on data which is not statistically significant and therefore may be due to chance alone.In addition, this abstract data does not correlate with any of the data presented in the results. Only patients with both risk factors have a significant association with Alzheimers Disease with an odds ratio of 3.5 (95% confidence interval 1.6- 7.9). However the multiple analysis may have increased the chance of finding significant results and has not been corrected for. Their conclusion that raised systolic blood pressure or high serum cholesterol concentrations in midlife increases the risk of Alzheimers disease is therefore not a correct interpretation of their data. 1 Kivipelto, Helkala, Laakso, Hanninen, Hallikainen, Alhainen, Soininen, Tuomilehto and Nissien. Midlife vascular risk factors and Alzheimer's disease in later life:longitudinal, population based study.BMJ 2001;322:1447-1451, |
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Gerson T Lesser, Assistant Professor, Dept of Geriatrics & Adult Development, Mt Sinai School of Medicine The Jewish Home and Hospital, NY NY
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To the Editor: Kivipelto and co-workers’ (1) longitudinal data add important information on risk factors for dementia. These findings are of particular interest, since we have observed that very old patients with autopsy- documented Alzheimer’s Disease (AD) had had significantly greater serum total and LDL cholesterol than had patients with non-AD dementias (2). However, the conclusions are clouded, since neither the diagnosis of AD nor its clinical distinction from other dementias is currently possible without pathological confirmation. The authors cite an earlier clinico- pathological study at their primary institution indicating high pathological correlation with clinical AD diagnosis (3). However, in that study, and in many other clinico-pathological studies of dementia, including our own (2,4,5): (a) the large majority of those with clinical dementia show some degree of AD changes at autopsy; and (b) an important minority show coexistence of AD changes and wtih other abnormalities, especially vascular changes or excessive Lewy bodies. One should then anticipate their findings: that clinically diagnosed dementia cases of the greatest frequency (AD) would also prove to have pathological AD changes; and that some degree of AD pathologic change would also be found in most (here 80%) of clinically diagnosed vascular dementia (VaD) cases. In a related vein, several reviewers have further noted that the relationships of AD and VaD are not well defined, and of the need to reassess the role of vascular factors in AD, as well as inVaD (5). In view of the above, I would hope that Kivipelto, et al., will not rely on clinical distinction of dementias, and also analyze their longitudinal data for the relationships of blood pressure and cholesterol with all their dementia cases. Since autopsy rates in Finland are historically high, one also looks forward with great interest to confirming the present findings with future pathological studies. References: 1. Kivipelto M, Helkala E-L, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ 2001;322:1447- 1451. 2. Lesser G, Kandiah K, Libow LS, Likourezos A, Breuer B, Marin D, et al. Elevated serum total and LDL cholesterol in very old patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2001;12:138-145. 3. Kosunen O, Soininen H, Paljarvi L, Heinonen O, Talasniemi S, Riekkinen Sr PJ. Diagnostic accuracy of Alzheimer’s disease: a neuropathological study. Acta Neuropathol 1996;91:185-193. 4. Lim A, Tsuang D, Kukull W, Nochlin D, Levernz J, McCormick W, et al. Clinico-neuropathological correlation of Alzheimer’s disease in a community-based case series. J Am Geriatr Soc 1999;47:564-569. 5. Nyenhuis DL, Gorelick PB. Vascular dementia: a contemporary review of epidemiology, diagnosis, prevention,and treatment. J Am Geriatr Soc 1998;46:1437-1448. Sincerely, Gerson T. Lesser, MD
and
DISCLAIMER: I am sole author and have no professional, financial or other conflicts of interest concerning these matters. |
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Alexei R Koudinov, neuroscientist Berezov Academic Lab, Rus Acad Med Sci, and Weizmann Inst., Biological Regul, Rehovot 76100, Israel, Natalia V Koudinova
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To update readers on the hot subject of cholesterol and Alzheimer's pathogenesis ( BMJ 2001; 322: 1447-51 and BMJ 2001; 323: 771 ) we would like to notice that today the role of cholesterol in AD is mainly discussed in the context of the reduction of amyloid burden by lowering cholesterol (for reviews see Ref. 1). This viewpoint is based on more then dozen reports implicating cholesterol in amyloid precursor protein processing and amyloid b protein (Ab) generation in cell cultures and in laboratory animals. The paper by Yamazaki et al. [ 2 ] and very recent contribution by Puglielli et al. [ 3 ] further reported that cellular generation of Ab is modulated by cholesterol compartmentation and intracellular cholesteryl-ester levels. We would like to add important missing discussion venue. The biochemical relation of cholesterol and Ab is bidirectional. Furthermore, modulation of neuronal cholesterol dynamics by soluble form of Ab, a normal human protein, likely to have important consequences for neuronal and synaptic function. We and others reported previously that near physiological concentrations of Ab inhibit cholesterol esterification [ 4, 5 ]. Ab also increases lipid synthesis (specifically that of cholesterol and phospholipids) in PC12 and rat primary neuronal cell cultures, fetal brain, and in ex vivo hippocampal slices; cellular cholesterol uptake (see Ref. 6 for detailed bibliography); and lipid efflux [ 7 ]; and modulates membrane physical properties [ 8, 9 ]. Taken together, the data by Puglielli et al. and our data indicate feedback functional relation between Acyl-coenzyme A:cholesterol acyltransferase-catalyzed cholesterol esterification, cholesterol esterase-catalyzed cholesteryl-ester hydrolysis [ 10 ], and Ab. In this light additional facilitation of neuronal cholesterol synthesis, cholesterol cellular uptake and cholesterol efflux by Ab [ 6, 7 ] may contribute to the efficiency with which neurons coordinate the influx, efflux, synthesis, and esterification of free cholesterol, and the release of cholesterol from the ester storage pool [ 10 ]. However, the failure in the dynamic equilibrium of the complex processes of tight regulation of intracellular cholesterol is important not only for the excessive Ab generation [ 3 ], but also for synaptic functional failure and excessive tau phosphorylation, another Alzheimer’s hallmarks. Thus, neuronal cholesterol homeostasis decay (experimentally achieved by cholesterol synthesis inhibition or increased cholesterol efflux) causes paired helical filaments (PHF)-tau phosphorylation and is sufficient to induce neurotransmission and synaptic plasticity impairment in rat hippocampus [ 6, 11 ]. As it was proposed [ 12 ] and discussed [ 6 ], the change in both Ab and tau protein neurochemistry may independently help to recover synaptic function and plasticity, the neurodegeneration aim, that in AD may well be caused by neuronal cholesterol turnover misregulation [ 6, 13 ], a welcome question indeed. There are many more open questions in this ever interesting functional relations. The answers should facilitate Alzheimer’s cure and basic knowledge on how and what for neuronal cells handle cholesterol. References 1. Simons, M., Keller, P., Dichgans, J. & Schulz, J.B. Cholesterol and Alzheimer’s disease: Is there a link? Neurology57, 1089-1093 (2001) [ PubMed Citation ] [ Full Text at Neurology ]; Golde, T.E. & Eckman, C.B. Cholesterol modulation as an emerging strategy for the treatment of Alzheimer's disease. Drug Discovery Today 6, 1049-1055 (2001) [ PubMed Citation ] [ Full Text at BioMedNet ]; Wolozin, B. A fluid connection: Cholesterol and Ab.Proc. Natl. Acad. Sci. USA 98, 5371-3 (2001) [ Full Text at PNAS ]. 2. Yamazaki, T., Chang, T.Y., Haass, C. & Ihara, Y. Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann-pick type C cells. J. Biol. Chem. 276, 4454-4460 (2001) [ PubMed citation ] [ Abstract and Full Text at J Biol Chem ]. 3. Puglielli L, Konopka G, Pack-Chung E, et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nature Cell. Biol. 10, 905-912 [ PubMed Citation ] [ Abstract and Full text at Nat Cell Biol ]. 4. Koudinov, A.R., Koudinova, N.V. & Berezov, T.T. Alzheimer's peptides Ab1-40 and Ab1-28 inhibit the plasma cholesterol esterification rate. Biochem. Mol. Biol. Inter. 38, 747-752 (1996) [ PubMed Citation ] [ Reprint Order ]. 5. Liu, Y., Peterson, D.A. & Schubert, D. Amyloid beta peptide alters intracellular vesicle trafficking and cholesterol homeostasis. Proc. Natl. Acad. Sci. USA 95, 13266-13271 (1998). [ PubMed Citation ] [ Abstract and Full text at PNAS ] 6. Koudinov, A.R & Koudinova, N.V. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 15, 1858-1860 (2001), published online June 27, 2001, 10.1096/fj.00-0815fje. [ PubMed Citation ] [ Abstract and Full text at FASEB J ] [ Reprint Order ]. 7. Michikawa, M., Gong, J.S., Fan, Q.W., Sawamura, N. & Yanagisawa, K. A novel action of Alzheimer's amyloid beta-protein (Abeta): oligomeric Abeta promotes lipid release. J. Neurosci. 21, 7226-7235 (2001). [ PubMed Citation ] [ Abstract and Full Text at J Neurosci ] 8. Chochina, S.V., Avdulov, N.A., Igbavboa, U., Cleary, J.P., O'Hare, E.O. and Wood, W.G. Amyloid beta-peptide(1-40) increases neuronal membrane fluidity. Role of cholesterol and brain region. J Lipid Res.42, 1292-1297 (2001) [ PubMed Citation ] [ Full text at J Lip Res ]. 9. Muller, W.E., Kirsch, C. and Eckert, G.P. Membrane-disordering effects of beta-amyloid peptides Biochem Soc Trans. 29, 617-623 (2001) [ PubMed Citation ]. 10. Simons, K. & Ikonen, E. How cells handle cholesterol. Science 290, 1721-1726 [ PubMed citation ] [ Full Text at Science ]. 11. Fan, Q.W., Yu, W., Senda, T., Yanagisawa, K. & Michikawa, M. Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J. Neurochem. 76, 391-400 (2001). [ PubMed citation ] [ Abstract and Full Text at J Neurochem ]. 12. Mesulam. M.M. (1999) Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron. 24, 521-529 (1999). [ PubMed citation ] [ Full Text at Neuron ]. 13. Matthies, H., Schulz, S., Hollt, V. & Krug, M. Inhibition by compactin demonstrates a requirement of isoprenoid metabolism for long-term potentiation in rat hippocampal slices. Neurosci.79, 341-346 (1997). [ PubMed citation ] [ Abstract and Full Text at Neuroscience ]. 14. The earlier version of this letter was submitted to Nature Cell Biology on October 8, 2001 to comment on the paper by Puglielli, L. et al. [ 2 ]. 15. Authors [ Internet Office ] |
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