Cognitive status correlates with neuropathologic stage in Parkinson disease
Braak H, Rüb U, Jansen Steur ENH, Del Tredici K, de Vos RAI;
Commented by , 16 Jun 2005
Background
Braak and his co-workers had previously proposed a pathological staging for sporadic Parkinson disease, similar to that used for pathological staging of Alzheimer disease (ref. 1). The proposed approach consists of six stages and suggests a rostral progression of pathology starting from brainstem nuclei and ultimately affecting high-order association cortices.
Aims of the study
The objective of this study was to assess the association between cognitive status and the neuropathologic staging of sporadic PD.
Methods
The study was conducted in a cohort of 88 patients with PD from a single neurological unit. None of the patients had a clinical diagnosis of dementia with Lewy bodies (DLB). Lewy neurites and Lewy bodies immunreactive for alpha-synuclein were assessed semi-quantitavely in sections from 18 brain regions.
In addition, the authors also evaluated semi-quantitavily comorbidities potentially contributing to cognitive decline such as Alzheimer disease (AD), agyrophilic grain disease (AGD) and cerebral vascular disease using silver-stained sections and sections immunostained for tau and beta-amyloid.
With regard to cognitive status patients were divided into four subgroups using MMSE scores, ranging from marginally impaired cognition to severe dementia. The statistical analysis was performed using nonparametric tests.
Results
Each patient was assigned to one of the six pathological stages. MMSE scores significantly correlated with neuropathological stages (p<0.005) and this association showed a linear trend (p < 0.025). Median MMSE test scores for women were lower than for men. Cognitively impaired individuals displayed higher stages of AD-related neurofibriallary pathology (p < 0.05) and beta-amyloid deposition (p< 0.05) than cognitively unimpaired patients.
MMSE scores did not correlate significantly with AGD, disease duration, age at disease onset, or age at death. Hoehn and Yahr scores, however, correlated with PD stages (p< 0.0005) and MMSE scores (p< 0.0005). The authors concluded that the decrease in median MMSE scores between PD stages 3 to 6 indicates that the risk of developing dementia increases with disease progression, in some individuals, however, cognitive decline can develop in the presence of mild PD-related cortical pathology and, conversely, widespread cortical lesions do not necessarily lead to cognitive decline.
Professor Emre’s comments
Dementia associated with PD has been increasingly better recognized and characterized, prevalence in cross-sectional studies reaching 40% (ref. 2). The main risk factors are age and disease severity, a combination of old age and severe motor symptoms increases the risk of dementia by almost ten fold (ref. 3).
Dementia in PD usually occurs late in the disease process, the current study offers a plausible explanation why this may be so. Previously Braak and co-workers had proposed a staging for brain pathology related to PD (ref. 1).
They suggested a rostral progression of pathology, which commences in certain vulnerable brainstem nuclei, which then advances to higher levels, association cortices getting involved later in the process.
They now describe that pathological stages highly and linearly correlate with mental status. This explains why dementia is a late occurring phenomenon, emerging at the time of cortical involvement.
They also describe, however, not all patients with widespread cortical involvement would develop dementia and some patients with relatively mild pathology may also develop dementia.
This is in line with two previous reports that not all patients with a reasonable amount of Lewy body (LB) pathology develop dementia (ref. 4; ref. 5). In addition to the amount of pathology, individual variations in cognitive reserve as well as the site of pathology may be crucial.
Another important finding of this study is that there was also some correlation between cognitive impairment and plaque and tangle pathology, although the average additional AD-pathologic burden was low.
The pathology underlying dementia in PD has been a matter of controversy, most of the recent studies revealed that dementia best correlates with LB-type degeneration, although some amount of AD-type pathology frequently co-exists (ref. 6).
This study is another example that PD-related pathology highly correlates with cognitive impairment, but a small amount of AD-type pathology is also present. The reasons for this association between two types of pathologies are unclear, it is likely that one type of pathology may induce the other.
Thanks to this type of studies in clinically and pathologically well-defined populations, we will be better able to understand complex clinical-pathological associations.
References
1. Braak H, Del Tredici K, Rub U, de Vos RAI, jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24; 197-210
2. Emre M. Dementia associated with Parkinson’s disease. Lancet Neurology 2003; 2; 229-37
3. Levy G, Schupf N, Tang MX, Cote LJ, Louis ED, Mejia H, Stern Y, Marder K. Combined effect of age and severity on the risk of dementia in Parkinson's disease. Ann Neurol 2002; 51; 722-9
4. Colosimo C, Hughes AJ, Kilford L, Lees AJ. Lewy body cortical involvement may not always predict dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry 2003; 74:852-6 (Note: Free full text article)
5. Parkkinen L, Kauppinen T, Pirttila T, Autere JM, Alafuzoff I. Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 2005; 57; 82-91
6. Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Bouras C, Giannakopoulos P. Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson’s disease. Acta Neuropathol (Berl) 2003; 106:83-8.