[ZucchiniFlower]

Parkinsonism & Related Disorders
Volume 10, Issue 8 , December 2004, Pages 461-463



Current opinion

Is the neuropathological ‘gold standard’ diagnosis dead? Implications of clinicopathological findings in an autosomal dominant neurodegenerative disorder

Ryan J. Uittia, Corresponding Author Contact Information, E-mail The Corresponding Author, Donald B. Calneb, Dennis W. Dicksona and Zbigniew K. Wszoleka

aDepartment of Neurology and the Section of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
bPacific Parkinson's Research Centre, University of British Columbia Vancouver, Canada

Accepted 12 October 2004. Available online 2 November 2004.


Abstract

Genetically-derived neurodegenerative disorders offer a rare opportunity to test validity of neuropathological criteria for diagnosis. Implications regarding an autosomal dominant neurodegenerative disorder (PARK 8) in which four different neuropathological diagnoses were found at autopsy are discussed. We suggest that just as there is currently no clinical ‘gold standard’ for Parkinson's disease, there is no pathological ‘gold standard.’ We conclude that in certain circumstances genetic studies may provide definitive arbitration of validity of clinical and pathological diagnostic criteria.



1. Introduction

Neuropathological diagnoses relating to neurodegenerative disease presently define many disorders as synucleinopathies or tauopathies, etc. implying that these designations relate to central pathophysiology and therefore, define the diagnostic ‘gold standard.’ There are few opportunities for testing the validity of such diagnostic standards. However, familial genetic disorders with a consistent clinical phenotype offer one such opportunity to investigate the consistency of neuropathological findings and the wisdom of accepting current definitions of diagnostic ‘gold standards.’
2. Summary

Parkinson's disease is defined as a clinical disorder confirmed by neuropathological findings including nigral neuronal cell loss, gliosis, and Lewy bodies/synucleinopathy. Similar clinical phenotypes with varying neuropathology are generally thought to represent common clinical presentations stemming from different causes or pathogeneses. However, this reasoning may be questioned when considering an autosomal dominant disorder with variable pathology. The authors present findings relating to a family, recently found to represent a PARK8 kindred, in which there were different neuropathological diagnoses in each of the four brains studied. Interestingly, each of the four patients demonstrated a consistent, ‘typical Parkinson's disease’ phenotype during life, despite their dissimilar neuropathological findings. The authors suggest that the current neuropathological diagnostic ‘gold standards’ relating to parkinsonism need to be reevaluated critically.
3. Commentary

Clinicians have grown accustomed to awaiting a pathologist's proclamation regarding the ‘final diagnosis.’ This is particularly true for patients with neurodegenerative disorders of unknown pathogenesis and scant definitive biomarkers of disease. The clinical diagnosis is ‘incorrect,’ with a different neuropathological diagnosis, in approximately one in five patients thought to have Parkinson's disease by an experienced clinician [1].

Just as the clinical diagnosis of Parkinson's disease and atypical parkinsonian syndromes revolves around a constellation of clinical findings, the neuropathological basis of Parkinson's disease and its common differential diagnostic considerations hinge upon the presence of a constellation of pathological findings.

These pathological findings have included specific regions of neuronal cell loss and gliosis coupled with other features, such as inclusions and extracellular accumulations. Historically, Lewy bodies and neurofibrillary tangles, and now more specifically, synuclein and tau-positive deposits, represent major neuropathological diagnosis determinants. However, the basis for synuclein and tau aggregates is not understood. Categorization of diseases as a ‘synucleinopathy’ or ‘tauopathy’ further strengthens the perception that these accumulations represent findings central to the pathogenesis and understanding of these disorders. This perception may or may not be true.

We have studied members of Family D from Western Nebraska for more than a decade [2]. Affected individuals have shown signs of levodopa-responsive, asymmetric parkinsonism, typically presenting in older individuals. Essentially, such patients would routinely be diagnosed as having Parkinson's disease were it not for their strong family histories. Additionally, members of this kindred have demonstrated various other features such as supranuclear gaze palsy and postural tremor. Seen in isolation these patients may have been diagnosed as having an atypical parkinsonian syndrome, such as progressive supranuclear palsy.

We have also recently reported neuropathological findings from the four autopsied members of this kindred. All have been examined by the same, experienced neuropathologists who were blinded to previous neuropathological diagnoses. Following appropriate pathological examination, four different neuropathological diagnoses were made in the four brains. If the four cases were presented individually and without knowledge of their hereditary links, they would be considered in the following manner: case #1 as straightforward Lewy body Parkinson's disease, case #2 as straightforward diffuse Lewy body disease, case #3 as possible parkinsonism secondary to strategically located tauopathy, and case #4 as possible parkinsonism secondary to nigral degeneration without distinctive pathology. The singular pathological hallmark of these autopsies is neuronal loss and gliosis in the substantia nigra. This finding is variably accompanied by Lewy bodies and neurofibrillary tangles [3].

Considered as four isolated cases, one might posit that parkinsonism was the final common clinical result in these patients who may have had different environmental exposures and genetic makeup. However, in the setting of known hereditary influences, a very different interpretation presents itself. What if a single common gene abnormality is found in all four cases? This, in fact, is precisely the scenario that has unfolded.

We have recently accumulated genetic evidence strengthening the assessment that affected family members derive their neurological disorder from an autosomal dominant genetic abnormality with linkage to PARK 8 on Chromosome 12 [4]. We hypothesize that the presence of Lewy bodies and neurofibrillary tangles, and their distribution in the context of PARK8 in Family D members, may have a number of potential explanations, including those given below.

The variable pathology may reflect the following.

(1) The differing neuropathological findings may be explained on the basis of completely independent, sporadic diseases, that happened to have occurred within a single family with no unifying cause; the odds of four family members exhibiting identical phenocopies without any similar pathogenesis would seem remote.

(2) There may be pathological heterogeneity, just as there is clinical heterogeneity; for example, Lewy bodies frequently being seen in the context of viral encephalopathies;

(3) Synuclein and/or tau may be indirectly, inconsistently, or unpredictably related to the pathological process, ‘bystander pathology;’

(4) There may be different states along a single neuropathological process or continuum; such as variable pathology seen in tuberculosis or syphilitic infectious processes (eventually culminating in tuberculoma or gumma);

(5) The same genetic process may give rise to tau or synuclein accumulation susceptibility/pathology;

(6) An individual's response to other genetic or environmental factors may influence the pathological process, as in Creutzfeldt–Jakob disease or inherited prion disease;

(7) The findings may represent a preclinical aspect of additional stages of disease; some of the pathology may have no clinical correlate, as seen in incidental Lewy body disease; or incidental Lewy body disease may be a pathological precursor for Lewy body Parkinson's disease or diffuse Lewy body disease;

(8) The observations may result from multiple factors, for example, genetics and age at onset of symptoms; onset time may result from predisposition of certain cellular populations to greater or lesser sensitivity to synuclein/tau-related pathological processes culminating in clinical variability; dissimilar clinical presentations/pathology may be seen in a single genetic disease, for example in SCA-3 (Machado–Joseph disease) where childhood presentations often demonstrate dystonia, rare initial elderly presentations demonstrate peripheral neuropathy, while all ages may manifest ataxia.

An additional limitation in determining the true nature of neuropathological findings is the scope of neuropathological information available. Scant numbers of patients with neurodegenerative disease ever come to autopsy. Additionally, despite the striking asymmetry in clinical symptoms and signs that frequently are seen during life, for example in Parkinson's disease and cortical basal ganglionic degeneration, there are no neuropathological studies that directly compare ipsilateral and contralateral brain pathology (as most autopsy research protocols call for ‘half frozen, half formalin’ fixation). Consequently, even in instances where one is fortunate to have brain tissue, it is not completely certain whether neuropathological findings are necessarily homogeneous across hemispheres.

Whereas the distribution and presence of Lewy bodies and neurofibrillary tangles has formed the bases of various neuropathological diagnoses, our clinicopathological studies suggest that these findings may not be ‘diagnostic.’ Consequently, the acceptance of a neuropathological diagnosis as a ‘gold standard’ is no longer universally reasonable.

What does it all mean? Are the current neuropathological diagnostic criteria meaningless? We suggest that both clinical and neuropathological findings are meaningful but not in the traditional way.

Three factors have emerged in the investigation of this family's neurological disorder: (1) shared genetic abnormality, (2) shared but somewhat variable clinical presentation, and (3) shared but highly variable neuropathological presentation.

While a summation analogous to Koch's postulate for germ theory is not possible, we can conclude that the clinical hallmark of PARK 8 is parkinsonism with or without other variable clinical features. Similarly, the pathological hallmark of PARK 8 is nigral neuronal loss and gliosis with or without other variable pathological features.

By analogy, the same types of observations may be made in other neurogenetic disorders. For example, mutations in the tau gene (Chr. 17) are associated with neurodegenerative disorders characterized by variability in clinical features including age at symptomatic onset, symptomatic duration, type of presentation (parkinsonism, dementia, personality change, eye movement abnormalities, epilepsy, myoclonus, amyotrophy, etc.), and variable pathology (location of tau deposit, type of cellular involvement, electronmicroscopy findings, etc.) both being influenced by the specific type of tau gene mutation [5].

Equally importantly, the same concepts being considered in our PARK 8 family may apply to other kindreds, to sporadic Parkinson's disease, and to atypical parkinsonian syndromes. We consider that those affected in our kindred suffer from a single disease dictated by genetic means. The variability in clinical and neuropathological findings may stem from variability in environmental exposures and interactions with a specific genotype. Formulation of truly adequate diagnostic gold standards will be predicated upon advancements in our understanding of the pathogenesis of PARK 8 and other neurodegenerative syndromes.

We sum up with an analogy. Just as there is no clinical ‘gold standard’ for Parkinson's disease, we conclude there is no pathological ‘gold standard.’ Diagnosis must be based upon patterns of findings, and the task facing both clinicians and pathologist is the assignment of ‘weighting’ to the individual clinical (e.g. resting tremor) and pathological (e.g. Lewy body) features. Recognition of these determinants may help us to move toward better understanding the nature of neurodegenerative disorders.

Our observations and arguments also place under scrutiny the practice of defining diseases by clinical or pathological criteria. Instead, we suggest that etiology should be the determining factor in distinguishing separate disease entities. Where we do not know etiology, we can only speak of syndromes.

[chasmo]

developed in Australia, that promises to give us an early diagnosis of PD. I will find out more when my Aussie friends wake up.

Charlie

[chasmo]

and her test is a blood test that will discern depletion of melatonin/ iron levels unique to pd.
This makes an early diagnosis possible.

http://www.unsw.edu.au/news/pad/arti...s_disease.html
thanks to Cate for supplying this info

Charlie