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Lerner and Bagic1 have to be congratulated for their hypothesis on PD pathogenesis. They suggest that the sequence of the brain changes in PD follows specific and repeatable patterns in all cases, as well as that a prion-like process underlies neurodegeneration. These ideas could explain several features of PD, such as the high prevalence of olfactory, autonomic, or sleep abnormalities. However, any pathogenic hypothesis should also explain:

  • 1
    The variable rate of progression.
  • 2
    The heterogeneous presentation.
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    The persistent asymmetry of motor symptoms and signs.
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    The progressive worsening and somatotopic spreading of the same symptom, meaning that neurons displaying similar gene expression profile, intracellular enzymatic machinery, and signaling pathways are differentially affected by the process.
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    The case of young-onset cases: whereas they must have severe disease to present so early, disability progresses slowly.

None of them are covered in the article.1 Certainly, PD is a multisystem disorder. The view of PD resulting from the sequential pathological involvement of brain nuclei is based on the work by Braak,2 which has received strong criticisms.3 It relies on the presence of α-synuclein inclusions, Lewy bodies, and Lewy neurites in the brain of subjects' dead of different causes. However, clinical information was extremely limited, some of the subjects included did not develop neither motor nor cognitive symptoms during life, staging was independent of disease duration, and neuronal loss was not recorded. Despite these limitations, Braak's findings have been interpreted as an open door to presymptomatic diagnosis according to the presence of abnormalities resultant from this pattern of involvement (i.e., hyposmia, REM behavior disorder, constipation,…). Compelling evidence suggests that α-synuclein inclusions not closely correspond to the severity of neuronal loss, neuronal dysfunction, or clinical expression. There is a gap between pathology and clinical picture. Thus, even admitting that pathology could follow a predefined order, the view of PD as a disease that starts with hyposmia, sleep disturbances, and constipation, follows with motor symptoms and ends with dementia, is not always true. Thus, the predictive value of premotor symptoms is relative. The prevalence of α-synuclein inclusions in the brain of old individuals dead without any neurological dysfunction is around 30%, whereas the prevalence of PD in this group of age is 2%.

Further arguments come from the development of nondopaminergic symptoms. A recent study showed that age and severity of PD but not duration of illness, act as independent risk factors for developing dementia.4 Furthermore, the brain of the majority of parkinsonian patients displaying dementia presents abundant changes characteristic of Alzheimer's disease. The relationship between dementia, aging, PD, and associated pathologies needs clarification. Additionally, rate of progression is more determinant of PD outcome than its multisystemic nature. It is likely linked to compensatory mechanisms and, thus, to the age at onset of the disease, as well as to the aging process. In fact, the older the age of onset, the worst the prognosis. These arguments do not rule out the proposed hypothesis.1 However, they challenge its applicability in the clinical setting without considering the contribution of just mentioned factors which, indeed, fill the gap between pathology and clinical features.

PD do not fulfill key criteria to be diagnosed as a prionopathy. Nonetheless, abnormal forms of α-synuclein seem to propagate in the brain of PD patients affecting different nuclei in different phases of the disease process. The finding of Lewy bodies and α-synuclein deposits in nigral fetal neurons transplanted over a decade earlier into the striatum5 could support the existence of a prion-like pathogen as the cause of PD.6 However, alternative possibilities, such as the presence of a pathogenic circulating factor that promotes α-synuclein phosphorylation and aggregation, should be considered.

In a few years, we will define genetic susceptibility profiles and pathological changes in the brain but neither who is going to develop clinical symptoms of PD nor its outcome. Further insight into the role of compensatory mechanisms, aging, and associated pathologies in PD is needed to elucidate these issues. These factors account for the heterogeneity of PD. Unfortunately, none of them are mentioned in recent reviews,7 which contribute to spread the false image of PD as a homogeneous and monolithic entity.

References

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  • 1
    Lerner A,Bagic A. Olfactory pathogenesis of idiopathic Parkinson disease revisited. Mov Disord 2008; 23: 10761084.
  • 2
    Braak H,Del Tredici K,Rub U,de Vos RA,Jansen EN,Braak E. Staging of brain pathology related to sporadic PD. Neurobiol Aging 2003; 24: 197211.
  • 3
    Linazasoro G. Parkinson complex vs clinically significant Parkinson's disease. Eur J Neurol 2007; 14: 721728.
  • 4
    Aarsland D,Kvaløy JT,Andersen K, et al. The effect of age ofonset of PD on risk of dementia. J Neurol 2007; 254: 3845.
  • 5
    Kordower JH,Chu Y,Hauser RA,Freeman TB,C WOlanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med, doi:10.1038/nm1747.
  • 6
    Braak H,Del Tredici K. Assessing fetal nerve cell grafts in Parkinson's disease. Nat Med, doi:10.1038/nm1748.
  • 7
    Marras C,Lang AE. Neurology 2008; 70: 19962003.