Brain Fables

Brain Fables
Authors: Alberto Espay and Benjamin Stecher

Overview

This book, the outcome of a constructive collaboration of a neurologist and an expert patient, is a determined onslaught against the prevailing assumptions and hypotheses that have driven, and continue to drive, research into neurodegenerative diseases. In a systematic approach, the authors reveal the contradictions and inconsistencies, and the conjectures and suppositions, that have been advanced to support these notions. After explaining how mainstream neuroscience, without firm supportive evidence, has flagrantly maintained these theories, the authors go on to outline in forensic detail the research findings that have established the falsity of what they refer to as myths and fables. The book’s core arguments focus on Parkinson’s and Alzheimer’s diseases, but the authors make it clear that their conclusions apply to all neurodegenerative diseases which they contend only exist as ‘labels neurologists created before we had the insight and tools needed to accurately define them’. The authors are particularly concerned that the erroneous understanding of these diseases is hampering the search for their cures. With very disturbing facts and statistics that are a sad indictment of neuroscience, the book makes a strident call for the specialty ‘to put an end to these fables’ and to develop new and more reliable paradigms (pages ix-x).

Brain Inflammation from Alzheimer’s Disease. NIH Image Gallery on Flickr. https://www.flickr.com/photos/nihgov/38730047881

Synopsis

The authors provided a most enlightening historical perspective of how the current framework of the neurodegenerative diseases emerged, and they illustrated this with the example of Parkinson’s disease. In this narrative, the authors attributed the first clinical recognition of the disorder to James Parkinson; its refinement as a syndrome to Jean-Martin Charcot; and its association with dopamine deficiency to Arvid Carlsson, Oleh Hornykiewicz, and George Cotzias. More significantly, they chronicled the emergence of MPTP toxicity as the dominant research model of Parkinson’s disease – a concept which the authors said ‘might have done more to slow than accelerate the development of disease modifying therapies’ because all the treatments that have been developed using it have uniformly failed. The book also discussed the dominant alpha-synuclein hypothesis, an idea that followed the discovery of a gene mutation in a large Contursi family. The authors blamed this hypothesis for creating the false representation of Parkinson’s disease as a homogenous disorder, and for giving the wrong impression that misfolded protein aggregates cause the disease; this postulate, they affirmed, casted ‘a long shadow‘ over ‘almost every research endeavor for decades to come’ (pages 1-2, 11-15 and 49).

Alpha synuclein ring-like oligomer interacting with the amyloid-beta peptide. Argonne National Laboratory on Flickr. https://www.flickr.com/photos/argonne/3974223045

The most radical argument that the authors make is against what they said is the  ‘fundamental tenet‘ of neuroscience – that neurodegenerative diseases result from the accumulation of abnormal protein aggregates. Citing studies which have shown either no correlation, or an inverse relationship, between the protein aggregates and clinical disease, the authors argue that aggregates such as amyloid and tau are not detrimental; on the contrary, they maintained that the proteins serve a brain protective function against other hazards such as cerebrovascular disease. They particularly noted the seminal study by Robert Burke which showed that alpha synuclein is actually ‘the major protein expressed during regeneration by the substantia nigra‘, and that this increased protein expression is ‘a compensatory response in neurons destined to survive’. Alluding to the observation that the brains of people with chronic traumatic encephalopathy are riddled with tau proteins, just as the brains of woodpeckers are, the book metaphorically conceived of protein aggregation as ‘the helmet that protects‘. Pointing out that ‘the accumulation of abnormal proteins has never been demonstrated to accelerate the aging of neurons‘, the authors argued against the portrayal of these proteins as ‘arsonists‘ or ‘the ashes of a former fire’; rather, the book rendered a contrary portrait of the proteins as ‘the last standing soldiers fighting against the fire’ (pages 36-41, 48 and 60-65).

Abnormal tau. NIH Image Gallery on Flickr. https://www.flickr.com/photos/nihgov/38629689756

An equally revolutionary concept the book advances is the far-reaching argument that all the neurodegenerative diseases are not discrete disorders but ‘clinical descriptive entities‘ which lie within the same spectrum. To illustrate the lack of distinctiveness of the neurodegenerative disorders, the authors referred to the observation that most people with Parkinson’s disease ‘have enough plaques and tangles to qualify as having Alzheimer’s disease’, adding that ‘the extent of overlap…is far greater than one would anticipate by chance alone’. The book also noted the significant pathological co-morbid association of Parkinson’s and Alzheimer’s diseases; it noted, for example, that about 80% of people with Parkinson’s disease have Alzheimer’s disease pathology, and about 50% the other way round. The authors therefore contended that these figures support their assertion that ‘co-pathology has been the rule rather than the exception since the beginning’. Using similar statistics, the authors likewise dismissed what they regard as the false distinction between dementia with Lewy bodies and Alzheimer’s disease, pointing out that the majority of subjects with Lewy body pathology ‘have enough plaques and tangles’ to qualify for diagnosis with Alzheimer’s disease’ (pages 2, 133, 64 and 42-43).

Electron micrograph of tau clusters. NIH Image Gallery on Flickr. https://www.flickr.com/photos/nihgov/46603522841

A glaring paradox the book attempted to resolve was why so many neurodegenerative disease researchers continue to work within the parameters of what are clearly ineffectual theories. The answers the authors put forward were rather disquieting and made for discomfiting reading for neuroscience as a whole. For example, they asserted that the errors in these theories ‘have been overlooked by so many for so long’ because neurologists tend to be ‘originalists‘ – physicians who are ‘keen to honor the legacy of our forbears’, and who therefore find it difficult to engage in ‘shifting the paradigm‘. The authors explained that it is this ‘reverence for their mentors’ that makes neurologists unable ‘to maintain the skeptical nature that should be the hallmark of their field’. The other reasons the authors gave for the persistence of these theories were similarly unsettling, and these included the career-protecting self-interests of the scientists; the ‘rigid funding models‘ which disproportionately favour ‘esteemed researchers‘; and the enthusiasm of high-ranking journals to publish ‘any evidence of something having even the slightest effect on protein buildups‘. The consequence of all these factors, the authors concluded, is that brain scientists have become ‘trapped into this wheel that creates science for scientists rather than science for society’ (pages 53-54, 71, ix, 111, and 103).

CC BY-SA 3.0, Link

In setting out its alternative approach to the study of neurodegenerative diseases, the book placed the search for diagnostic biomarkers right at the centre. Regretting that ‘the field of neurodegenerative disorders is among the last in medicine where diagnoses are made using clinical criteria‘, the authors argued that the current ‘reductionist‘ approach which leads to the diagnosis of a single disorder should be replaced by a biomarker-driven strategy in which there are different models for the different expressions of each neurodegenerative disease. The advantage of such a strategy, the authors suggest, is that treatment will be diversified to cover the many ‘biological disruptions‘ that underlie each of these disorders. The authors go on to recommend the use of ‘hypothesis-free‘ trials which they said have ‘the best chance of finding biomarkers for these diseases’ because these hypotheses dispense with misleading clinical labels. In their management recommendations, the authors similarly advocated the development of ‘targeted therapeutic strategies‘ using biological rather than clinical subtypes. They specifically urged researchers to abandon the strategy of targeting protein aggregates with monoclonal antibodies because this has not only been uniformly unsuccessful, it is also potentially detrimental (pages 26-28, 78, 83, 38, 66, 69, 50-51, and 96-101).

CC BY-SA 4.0, Link

Opinion

This unique co-authoring approach worked surprisingly well, blending as it does a central scientific narrative with a patient’s intuitive perspective. With an assertive but non-condemnatory prose, the authors support their arguments with evidence that practically speaks for itself. The book’s central theme is unimpeachable – that the current neurodegeneration hypotheses have failed, and new paradigms are desperately required. It also advanced an alternative paradigm based on a biological rather than a phenotypic approach, one that will however need refinement to address the clinical and etymological challenges of the countless biological subtypes that will emerge to replace the currently limited number of recognised neurodegenerative diseases. A counterbalance to the very academic contents of the book are the patient advocate commentaries which gave a refreshing and eye-opening view of the lived experience of patients who seem to subsist in a world almost completely divorced from the one in which the clinicians who treat them thrive.

Overall assessment

This is a revealing book which makes an urgent clarion call for a reconsideration of what appears to be a clog in the wheel of progress in the neurodegenerative sphere. It argues particularly for jettisoning the old syndromic approach to neurodegenerative diseases, and to replace this with a more precise biologically based system. Whilst this poses practical challenges, the evidence marshalled in the book shows that an alternative to the prevailing paradigm is inevitable if the goal of curing neurodegenerative diseases is to be achieved. The book’s fundamental arguments are valid not just in neuroscience because they can legitimately be extended to any medical specialty where poorly characterised syndromes dominate clinical practice and hinder the development of appropriate treatments. The book’s well-articulated arguments therefore have major implications not just for neurology but for healthcare and society as a whole, and I strongly recommend it to all doctors.

Book details

Publisher, Place, Year:  Cambridge University Press, Cambridge, 2020
Number of chapters: 15
Number of pages: 162
ISBN: 978-1-108-74462-1
Star rating: 5
Price: £9.99

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