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EDITORIALS: Adrian Williams Defining neurodegenerative diseases BMJ 2002; 324: 1465-1466 [Full text]

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Beware the simplification in defining neurodegenerative diseases.

Alexei R. Koudinov, Natalia V. Koudinova   (24 June 2002)

Is neurodegeneration a unique multifarious human brain disease?

Alexei R. Koudinov, Natalia V. Koudinova   (25 June 2002)

Beware the simplification in defining neurodegenerative diseases. 24 June 2002
Alexei R. Koudinov, neuroscientist Berezov Academic Lab, Russian Academy of Medical Scences, P.O.Box 1665, Rehovot 76100, Israel, Natalia V. Koudinova Send response to journal: Re: Beware the simplification in defining neurodegenerative diseases.	Inform a Colleague In our view defining neurodegenerative diseases is much more complicated as defining the continent of Europe (BMJ 2002;324:1465-1466). May be a planet. But likely a universe and not "after responsible rogue proteins". Why? Because we have significant overlap of the involvement of different proteins in different neurodegenerative disorders [ 1 ]. The reason could be simple. While making us humans planet brain operates the standard set of basic tools such as neurotransmission, synaptic function, neural plasticity, etc (largely missed in the discussion of the BMJ theme issue editorials). The proteins named under the "evolving terminology" statement of the editorial by Williams (including amyloid beta [ 2 ], tau [ 3 ], and superoxide dismutase 1 (SOD1) [ 1, 2 ]) represent essential (normal and not pathological) elements of the brain/neuron self maintanance and function. Infact, in 1999 we knew about more than one hundred such elements [ 4 ]). When the function fail the above proteins (and surely many others) react in an organized compensatory way to fix the function, although the proportion of the involevement and the particular compensatory reaction target (see Ref. 2 for further discussion) could be different for different proteins and for different brain neurotransmitter systems involved.   Thus, one should be cautious to simplify the definition of neurodegenerative diseases. Not convinced? Learn about the sad prime example of the simplification that just become the history [ Ref. 5 ]. Competing interests: none References:  1. Koudinov AR, Koudinova NV, Beisiegel U. Cholesterol disbalance at neuromuscular junctions and CNS synapses: a unifying cause of degeneration. Neurology. Published online 26 February 2002 [ Full Text ]; Dunnett AB, Bjorklund A. Prospects for new restorative and neuroprotective treatments in Parkinson disease.  Nature. Neurological disorders. 399 (Supplement), A32-A39 (1999).  Please make a note of the Box 2 entitled: "Is PD a distinct clinical entity or part of a spectrum of neurodegenerative disorders?" [ PubMed ]. 2. Koudinov AR, Koudinova NV. Brain Cholesterol Pathology is the Cause of Alzheimer's Disease. Clin Med Health Res. published online November 27, 2001, clinmed/2001100005  [ Full Text ] [ Authors Preface ]. 3. Koudinov AR, Koudinova NV. Alzheimer's pathogenesis: tau and amyloid - a consensus or a challenge for a third party quest? BMJ. Published online 4 September, 2001 [ Full Text ]. 4. Sanes JR, Lichtman JW. Can molecules explain long-term potention? Nature Neurosci. 2, 597-604 [ PubMed ].   Must-See References: 5. Koudinov AR, Smith MA, Perry G, Koudinova NV. Alzheimer’s amyloid dogma. A time for change. BMJ. Published online 21 June, 2002 [ Full Text ]; Koudinov AR, Koudinova NV. What biomedical scientists and clinical audience have to know is not what top journals offer to read. BMJ. Published online 23 June, 2002 [ Full Text ] [ list of BMJ eLetters by Koudinov et al ] [ Other related eLetters ]      [Inform a Colleague] [Send us an email] [Authors Internet Office] Search PubMed for:  [ AR Koudinov | NV Koudinova ]
Is neurodegeneration a unique multifarious human brain disease? 25 June 2002
Alexei R. Koudinov, neuroscientist, editor Berezov Acad Lab, RAMS; Neurobiology of Lipids, P.O.Box 1665, Rehovot 76100 Israel, Natalia V. Koudinova Send response to journal: Re: Is neurodegeneration a unique multifarious human brain disease?	Inform a Colleague We realized that it will be difficult for readers to find the article by Dunnett and Bjorklund (in Nature Neurological disorders supplement issue [ 1 ]) that we refer to in one [ 2 ] of the related letters to BMJ [ 2, 3; please see these letters first ]. There is the box 2 (in the above article [ 1 ]) entitled "Is PD a distinct clinical entity or part of a spectrum of neurodegenerative disorders?". We cite this box message below, and believe that it will provide additional arguments against the simplification in defining neurodegenerative disorders. The box 2 of the article by Dunnett and Bjorklund [ 2 ] states:   "PD and Alzheimer's disease (AD) are generally considered to be separate and distinct clinical entities, with PD involving predominantly motor symptoms associated with loss of dopamine neurons and Lewy-body pathology in the substantia nigra, and AD characterized by manifest cognitive symptoms associated with neurofibrillary tangles (tau) and senile plaques (amyloid-b protein), and primarily affecting cortical areas of the forebrain (see review by Selkoe, this supplement). Nevertheless, there has been increasing recognition that the two diseases overlap4. Thus, a substantial proportion of PD patients show cognitive impairments, particularly on tasks of executive function, similar to those seen after frontal-lobe damage99. The incidence of dementia in PD patients is 6-12 times higher than in age-matched controls, and most of these (about 75%) have cortical pathology cheracteristic of AD. Concersely, about two-thirds of diagnosed AD patients develop extrapyramidal symptoms, such as bradykinesia and rigidity, and many have neurodegenerative changes in the substantia nigra consistent with the diagnosis of PD. The extent of overlap between the two diseases is thus much greater than would be expected to occur by chance4.  Consequently, we need to consider whether the two diseases may not be distinct entities, as generally considered, but rather be extremes of a spectrum of disease. Perl and colleagues4 propose that PD and AD should be viewed as part of continuum of neurodegenerative disorders with considerable overlap (see inset). Patients with similar pathology, involving both Lewy bodies in the substantia nigra and senile plaques and neurofibrillary tangles in the neocortex, are as likely to be diagnosed as 'AD with parkinsonism' as 'PD with dementia'. Alternatively, if both classes of symptom are apparent at first appearance, the diagnosis may be 'diffuse Lewy-body disease' or 'Lewy-body dementia'4. This emerging concept suggests that multiple aetiologies can lead to similar clinical phenotypes, and that there may exist unifying neurodegenerative mechanism(s), triggered by different aetiological factors, that are expressed differently in different disease entities. Thus, in future research on pathogenesis and treatment, it may be important to consider not only overlaps between the major neurodegenerativee diseases, but also heterogeneous aetiologies within each disease entity"  The above box has inset at the bottom. Our description of the inset follows:   There are several text labels at the bottom of the inset scheme. This text line lists (from left to the right): Parkinson's disease, Parkinson's disease with dementia, Diffuse Lewy body disease, Lewy body dementia, Alzheimer's disease with parkinsonism, and finally Alzheimer's disease. Just above this line with the diseases list there is a simple line drawing that has a text labeling at the margins. The labels are 'Lewy body pathology' and 'Neurofibrillary pathology' on the left and right, respectively.  Simple line drawing shows: i) the increase of the Neurofibrillary pathology in the diseases ordered above, from zero in Parkinson's disease to maximal in AD, and ii)  the increase of the Lewy body pathology in the diseases back ordered above, from zero in Alzheimer's disease to maximal in PD. To add to the cited above excellent writing by Dunnett and Bjorklund [ 1 ] we would like to highlight the overlap in the hallmarks of two other pairs of the neurodegenerative diseases. These pairs are Alzheimer's/inclusion-body myositis and Alzheimer's/ALS, jointly characterized by amyloid and tau abnormalities, respectively (see also Ref. 5 ]. It is important to note that reactions of oxidative cascade are also impaired in the above mentioned pathologies, as well as in Parkinson's disease. We also would like to invite readers to review the online record for one of live discussions conducted by AlzForum. This discussion pointed to an inability of 'amyloid deposits as the key diagnostic Alzheimer's feature' to meet today knowledge and current fields' needs.   "One should be cautious to simplify the definition of neurodegenerative diseases.  Not convinced? Learn about the sad prime example of the simplification that just become the history" Koudinov & Koudinova BMJ online, 24 June 2002 Competing interests: none References: 1. Dunnett AB, Bjorklund A. Prospects for new restorative and neuroprotective treatments in Parkinson disease.  Nature. Neurological disorders. (suppl). 399, A32-A39 (1999) [ PubMed ]. 2. Koudinov AR, Smith MA, Perry G, Koudinova NV. Alzheimer’s amyloid dogma. A time for change. BMJ. Published online 21 June, 2002 [ Full Text ]; Koudinov AR, Koudinova NV. What biomedical scientists and clinical audience have to know is not what top journals offer to read. BMJ. Published online 23 June, 2002 [ Full Text ] [ list of BMJ eLetters by Koudinov et al ] [ Other related eLetters ] 3. Koudinov AR, Koudinova NV. Beware the simplification in defining neurodegenerative diseases. BMJ. Published online 24 June, 2002 [ Full Text ]   Below are two references from the grey-box citation (see above and Ref.1) 4. Perl DP, Olanow CW, Calne DB. Alzheimer's disease and Parkinson's disease; distinct entities or extremes of a spectrum of neurodegeneration? Ann Neurol. (suppl). 44, S19-S31 (1998) [ PubMed ]; 99. Owen AM, Sahakian BJ, Robbins TW. in Memory in Neurodegenerative Disease: Biological, Cognitive and Clinical Perspectives (ed.Trosyter AI) 157-171 (Cambridge Univ. Press, Cambridge, 1998). 5. Koudinov AR, Koudinova NV, Beisiegel U. Cholesterol disbalance at neuromuscular junctions and CNS synapses: a unifying cause of degeneration. Neurology. Published online 26 February 2002 [ Full Text ]; Koudinov AR, Koudinova NV. Alzheimer's pathogenesis: tau and amyloid - a consensus or a challenge for a third party quest? BMJ. Published online 4 September, 2001 [ Full Text ].      [Inform a Colleague] [Send us an email] [Authors Internet Office] Search PubMed for:  [ AR Koudinov | NV Koudinova ]