Cognitive decline correlates with neuropathological stage in Parkinson's disease

https://doi.org/10.1016/j.jns.2006.05.011Get rights and content

Abstract

Recently, the relationship between cognitive status and the neuropathological stages of a newly proposed staging procedure for Parkinson's disease (PD) was assessed in a cohort of 88 individuals. None of the patients had received the clinical diagnosis of dementia with Lewy bodies. The topographic distribution pattern of the cerebral Lewy body pathology was evaluated semiquantitatively in alpha-synuclein immunoreactions. MMSE scores from the last neurological examination prior to death were used to determine cognitive status and the degree of cognitive decline. Four subgroups of Mini-Mental State Examination (MMSE) scores ranging from nonsignificantly impaired to severely impaired cognition were analyzed statistically with nonparametric tests. Each of the 88 cases could be assigned to one of the PD stages 3–6, and MMSE scores correlated significantly with the aforementioned stages. Since the median MMSE scores decreased from stages 3–6, it is probable that the risk of developing dementia in PD becomes greater as the disease process in the brain progresses.

Introduction

In Parkinson's disease (PD), a few vulnerable nerve cell types in specific regions of the human peripheral, enteric, and central nervous system become progressively involved and develop aggregations of a misfolded protein, alpha-synuclein. The intraneuronal aggregations, which appear in the form of Lewy neurites and Lewy bodies [1], [2], [3], [4], are not normal concomitants of healthy aging [5].

Apart from dysfunctions of the somatomotor system, non-motor symptoms become manifested in the course of PD that cannot be attributed solely to deficiencies within the dopaminergic system [6]. Decline in cognitive status is one such major symptom, which can occur even in PD patients whose brains barely contain lesions associated with other pathologies. Cognitive decline usually appears late but can also be an early symptom and may even come to dominate the clinical picture [7], [8].

The pathological process underlying PD usually progresses slowly and requires years to reach its full extent. The neuronal damage begins prior to the appearance of initial clinical symptoms [9] and, if uninterrupted by death, leads to the full-blown manifestation of the illness. Recent findings show that the degenerative process begins in predisposed nuclei. With time, the brain pathology increases in severity and the disease process progresses beyond the initial predilection sites according to a predictable sequence. The topographic advance is so characteristic that autopsy cases can be assigned to one of six proposed neuropathological stages [10]. Within the brain, the first lesions almost always appear in the dorsal motor nucleus of the vagal nerve in the lower brain stem. From there, the disease process follows an essentially upward path through basal portions of the mid- and forebrain until it reaches the cerebral cortex [10], [11], [12]. Taken together, superordinate portions of the olfactory, limbic, visceromotor, and somatomotor systems are subjected to especially heavy damage.

James Parkinson himself and other authorities after him did not include cognitive dysfunction among the symptoms of the “shaking palsy” syndrome [13]. Presently, and possibly owing to the growing life expectancy of PD patients, this view is undergoing radical revision, and current studies estimate that nearly 70% of all patients experience significant cognitive decline [8].

Section snippets

Results

To determine whether cognitive decline in PD is related to the proposed neuropathological stages, we examined the central nervous system of 88 prospectively followed PD patients from a single clinical unit. The clinical diagnosis was confirmed at postmortem examination, and each of the cases was assigned to one of the aforementioned stages. The severity of comorbidities was relatively low. None of the cases displayed major vascular changes or lesions related to other neurodegenerative diseases.

Conclusions

Both the pathological lesions and the clinical symptoms of PD develop gradually. As such, the steadily increasing severity of the lesions may already contribute to cognitive decline before symptoms have become severe enough to warrant the diagnosis of dementia, so that a phase of mild cognitive impairment presumably precedes overt dementia. The incipient decline from intact cognition occurs in many cases during stage 3, in others possibly even earlier, i.e., before or around the time when

Acknowledgements

Funding for this publication was made possible by the German Research Council (Deutsche Forschungsgemeinschaft). We thank Ms. Inge Szasz-Jacobi for her help in preparing the illustrations.

References (29)

  • E. Perry et al.

    Acetylcholine in mind: a neurotransmitter correlate of consciousness?

    Trends Neurosci

    (1999)
  • J. Lowe

    Lewy bodies

  • L.I. Golbe

    Alpha-synuclein and Parkinson's disease

    Mov Disord

    (1999)
  • D.W. Dickson

    Alpha-synuclein and the Lewy body disorders

    Curr Opin Neurol

    (2001)
  • H. Apaydin et al.

    Parkinson disease neuropathology

    Arch Neurol

    (2002)
  • D.R. Thal et al.

    Neurodegeneration in normal brain aging and disease

    SAGE KE

    (2004)
  • B.R. Thanvi et al.

    Neuropsychiatric non-motor aspects of Parkinson's disease

    Postgrad Med J

    (2003)
  • A.D. Korczyn

    Dementia in Parkinson's disease

    J Neurol

    (2001)
  • D. Aarsland et al.

    Prevalence and characteristics of dementia in Parkinson disease. An 8-year prospective study

    Arch Neurol

    (2003)
  • K. Del Tredici et al.

    Where does Parkinson disease pathology begin in the brain?

    J Neuropathol Exp Neurol

    (2002)
  • H. Braak et al.

    Staging of brain pathology related to sporadic Parkinson's disease

    Neurobiol Aging

    (2003)
  • H. Braak et al.

    Stages in the development of Parkinson's disease-related pathology

    Cell Tissue Res

    (2004)
  • K. Del Tredici et al.

    Idiopathic Parkinson's disease: staging an α-synucleinopathy with a predictable pathoanatomy

  • J. Parkinson

    On the shaking palsy

    (1817)
  • Cited by (153)

    • The roles of connectivity and neuronal phenotype in determining the pattern of α-synuclein pathology in Parkinson's disease

      2022, Neurobiology of Disease
      Citation Excerpt :

      In later stages (4–6), LP worsens in those locations where it is seen previously and expands to include regions of the telencephalon. This broadening of LP and neurodegeneration is correlated with worsening of motor symptoms, and cognitive decline (Braak et al., 2006b; Irwin et al., 2017; Irwin et al., 2012). Braak and others followed up this initial staging with investigations of the peripheral nervous system and found that LP can be found in the gastrointestinal tract in regions innervated by the DMV through the vagal nerve (Braak et al., 2006a).

    View all citing articles on Scopus
    View full text