How much Alzheimer is really CJD?
How good are neurologists at diagnosis anyway?
Alzheimer's very first case
Question: is there any review article on the whole issue of CJD misdiagnosed as Alzheimer or might you have a rough estimate or personal best guess as to what fraction this might be? The issue is that if it is even 1 per 100, that would put the methodology of the recent CDC study of CJD incidence in the US (and the stability of this incidence) into serious question.
Response: (contributed by Jim Lowe, Queen¼s Medical Centre, Nottingham ... Web site Tel: +44 (0)115 9709269 Fax: +44 (0)115 9709759
This question comes down to the specificity of clinical features to discriminate AD/vascular disease/Lewy disease etc from prion disease. I doubt if many patients with clinical features of classicial CJD get missed. There have always been very small numbers of elderly patients with "subacute" CJD who only come to light if the patient has an autopsy. The question of precisely how many patients with clinical AD have CJD is somewhat uncertain. In "expert" centres it is probably very small as published autopsy-validated series can demonstrate. A problem is arising now with trying to work out the clinical limits for CJD since the emergence of the new variant form (nvCJD).
In the UK, any elderly patient who has ataxia, depression, or dementia in the absence of clinical features of classical CJD is very unlikely to have an autopsy and to have the brain looked at by a neuropathologist with an interest in the diagnosis of neurodegenerative disease (using any techniques). An extremely small proportion of the at-risk population is being assessed by neuropathology. (Benbow and Benbow 1994; Benbow, Benbow et al. 1994) with each neuroscience centre performing an average of 8.8 autopsies on old age psychiatry patients each year (Benbow, Reid et al. 1995). The overall age-standardized (65 yrs) prevalence rates in the UK population for organic disorder is 4.7%, depressive illness 10.0% and neuroses 2.5% (Saunders, Copeland et al. 1993). With a neuroscience centre serving about 2.8 million population of all ages you can work out how small a proportion of the aged with a neurological disease have an autopsy. Autopsy rates are going down for a variety of reasons (Start et al 1993).
If there was to be an increase in the incidence of nvCJD in the elderly then, based on established autopsy rates for patients with these types of clinical features, it is highly unlikely that it would be detected until it competed with the incidence of vascular disease, Alzheimer's disease or Lewy body disease. As CJD is such a rare disease you could have a large relative increase in its incidence, for example if there was to be BSE transmission, and still not detect it with established rates for neuropathological autopsies in this section of the population. I suspect that this is also the case in most other countries, however this is only a hunch as I have not looked for similar published evidence from the US or other countries.
The Medical Research Council and the Department of Health are at present implementing increased surveillance for the elderly population in the UK. It is a difficult thing to plan without very large resources for surveillance given the range of clinical features for nvCJD and their overlap with the establshed degenerative diseases of old age.
6.1.97 webmaster commentary"Alzheimers" is now said to be the fourth leading casue of death in the US. After making adjustments for aging populations, better diagnosis, and so on, it seems fair to say that there is a lot more of it around than there used to be. In fact, it seems to be increasing fairly dramatically in all industrialized countries.
The genetic component of Alzheimers amounts to 10% or so, with 90% sporadic, centered around presenilin and apolipoprotein E. I find it improbable that much of the observed increase in Alzheimers could be attributed to an increase in familial Alzheimer or an increase of the allele epsilon 4.
So now the argument is that CJD, as buried in Alzheimers, might also have been undergoing a marked rate increase for the last decade or two, and account for some (small?) proportion of the Alzheimer incidence increase. This could be testable if sufficient representative material was set aside over the years -- CJD might be more or less a constant percentage of Alzheimers and so grow as it grows.
My point is not that there might be 40,000 cases of CJD a year like they said on ABC News (instead of the 400 that CDC would like to have), but, worse, that the number of cases per year is growing.
Perry RT; Go RC; Harrell LE; Acton RT Am J Med Genet 60: 12-8 (1995)"Alzheimer's disease (AD) is a progressive, degenerative neurological disorder of the central nervous system. AD is the fourth leading cause of death in elderly persons 65 years or older in Western industrialized societies. The etiology of AD is unknown, but clinical, pathological, epidemiological, and molecular investigations suggest it is etiologically heterogeneous...."
National Center for Health Statistics (NCHS) February 29, 1996Alzheimer's disease accounted for 16,754 deaths in 1993, 98 percent of which were to Americans 65 years of age and over. The number of people who died from Alzheimer's disease in 1993 was nearly 20 times the number reported in 1979 (857) when the disease was first identified separately as a cause of death. However, the increase likely reflects improvements in reporting and diagnosis of the disease rather than increases in prevalence.
The overall age-adjusted death rate from Alzheimer's disease increased to 2.3 deaths per 100,000 in 1993. Rates increased rapidly from 1979 to 1988 before leveling off between 1988 and 1992. Death rates from Alzheimer's disease increase with age. For Americans aged 65-74 years the death rate was nearly 10 deaths per 100,000 population. For persons aged 75-84 years the rate increased to 64 per 100,000 population and for those age 85 years and over it was almost 228 per 100,000 population....
Neurology 48: 119-125 (1997) Litvan I, Agid Y, Goetz C, Jankovic J, Wenning GK, Brandel JP, Lai EC, Verny M, Ray-Chaudhuri K, McKee A, Jellinger K, Pearce RK, Bartko JJ Neuroepidemiology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-9130, USA.The accuracy of the clinical diagnosis of corticobasal degeneration (CBD) is unknown. To determine its diagnostic accuracy, we presented 105 cases with known neuropathologic diagnoses, including CBD (n = 10), progressive supranuclear palsy (PSP, n = 24), Parkinson's disease (n = 15), diffuse Lewy body disease (n = 14), multiple system atrophy (n = 16), postencephalitic parkinsonism (n = 7), Pick's disease (n = 7), Creutzfeldt-Jakob disease (n = 4), Alzheimer's disease (n = 4), vascular parkinsonism (n = 3), and Whipple's disease (n = 1), as clinical vignettes to six neurologists unaware of the autopsy findings. Reliability was measured with the kappa statistics. The neurologists' clinical diagnoses were compared with clinicopathologic diagnoses for sensitivity, specificity, and positive predictive values at first and last clinic visits. The group reliability for the diagnosis of CBD significantly improved from moderate for the first visit (mean = 34 months after onset) to substantial for the last (68 months after onset).
For the first visit, mean sensitivity for CBD was low (35%), but specificity was near-perfect (99.6%). For the last visit, mean sensitivity minimally increased (48.3%), and specificity remained stable. False-negative misdiagnoses mainly occurred with PSP. False-positive diagnoses were rare.
The extremely low sensitivity of the clinical diagnosis of CBD suggests that this disorder is markedly underdiagnosed. Although the validity of the clinical diagnosis might have been improved if neurologists could have examined these patients, more important is that this disorder was misdiagnosed by the primary neurologists. In our data set, the best predictors for the diagnosis of CBD included limb dystonia, ideomotor apraxia, myoclonus, and asymmetric akinetic-rigid syndrome with late onset of gait or balance disturbances.
23 May 1997 notes by webmasterThere is a wonderfully detailed account of Alzheimer and his first case, Auguste D, encountered 25 Nov 1901, in this week's Lancet. They just found the original case file after all these years, in Frankfurt, Germany.
"Kraepelin introduced [in 1910] the eponym Alzheimer's disease, but why did he use Alzheimer's name, and not Perusini's, Bonfiglio's, or Fischer's? Since Alzheimer described the two cases, and since Perusini republished the Auguste D case (with photographs and drawings of the histo-pathological findings), we are convinced that the eponym was based on Alzheimer's 1907 report of Auguste D's case. Moreover, she only showed neuritic plaques and neurofibrillary tangles typical of the disease."
"Several hypotheses to account for the haste with which Kraepelin created the new eponym have been put forward.10,11 Beach11 says that Kraepelin did so for scientific reasons, because he believed that Alzheimer had discovered a new disease. Another reason might have been the existing rivalry between his department and that of Pick in Prague (where Fischer also worked) and the desire for prestige for his Munich laboratory. Also plausible is Kraepelin's wish to show the superiority of his school over psychoanalytical theories and to show (vis-a-vis Freud) that some mental disorders were organically based. The most likely explanation, however, is the close collaboration between Kraepelin and Alzheimer, and Kraepelin's awareness of Alzheimer's clinical and scientific work on presenile cases."
"There are doubts about the diagnosis of Auguste D's illness, and other diagnoses have been put forward, especially arteriosclerosis of the brain. Both descriptions of Auguste D's dementia by Alzheimer and Perusini confirm that Auguste D had a degenerative and not a vascular form of dementia. Alzheimer mentioned the miliary foci (later called senile plaques), which represented the sites of deposition of a peculiar substance in the cerebral cortex. This substance has since turned out to be þ-amyloid protein. Alzheimer showed clumps and condensations of intracellular fibrils and called them "neurofibrillary degeneration".
1 Alzheimer A. Ðber einen eigenartigen schweren Erkrankungsprozeþ der Hirnrinde. Neurologisches Centralblatt 1906; 23: 1129-36.