Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P.
Epidemiological pathology of dementia: attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study.
PLoS Med. 2009 Nov;6(11):e1000180.
PubMed.
This large population-based study has opened its shell and is coyly revealing the pearl inside. Although much dementia research in specialist centers now focuses on the preclinical stage of disease and the validation of antecedent biomarkers (e.g., ADNI), it is helpful to stand back and place dementia in the community setting. This study comes to a somewhat unexpected conclusion; namely, that in addition to AD pathology, vascular pathology explains a sizeable proportion of the dementia in the 456 individuals who donated their brains among the more than 18,000 people aged 65 years or older recruited from six sites in the UK for this study.
This is a more unexpected finding than appears at first glance, as “vascular dementia” has traditionally been considered a rare entity. Vascular pathology, or small vessel disease, in the context of the AD brain is a common finding at autopsy and consists of a variable degree of cerebral amyloid angiopathy and arteriolosclerosis. This study indicates that vascular pathology may be a more important player and may contribute to dementia in a manner that has not been fully appreciated in much smaller, center-based studies.
In multicenter studies, such comparability of protocols is essential in addition to a mechanism to ensure standardization between sites. Unfortunately, the study was started before α-synuclein immunohistochemistry became widely used in dementia centers, and so the density of lesions varies hugely from 4 percent of cases with Lewy bodies (Table 2) to 37 percent in a cohort of the original sample. Also, TDP-43 which has been reported in 20-40 percent of AD cases, is not included in this study, probably for the same reason. These data discrepancies are likely to impact on the relative contribution of vascular pathology in this study. In future analyses, in order to avoid variability between sites in staining, antibodies, and interpretation of lesion, the authors might want to give some thought to having one center perform this core function. The numbers of autopsies is not so great that this could not be done at one of the sites. There is a pearl to be seen in here, but the neuropathologic data will have to be more translucent if it is to be fully appreciated.
Comments
Washington University School of Medicine
This large population-based study has opened its shell and is coyly revealing the pearl inside. Although much dementia research in specialist centers now focuses on the preclinical stage of disease and the validation of antecedent biomarkers (e.g., ADNI), it is helpful to stand back and place dementia in the community setting. This study comes to a somewhat unexpected conclusion; namely, that in addition to AD pathology, vascular pathology explains a sizeable proportion of the dementia in the 456 individuals who donated their brains among the more than 18,000 people aged 65 years or older recruited from six sites in the UK for this study.
This is a more unexpected finding than appears at first glance, as “vascular dementia” has traditionally been considered a rare entity. Vascular pathology, or small vessel disease, in the context of the AD brain is a common finding at autopsy and consists of a variable degree of cerebral amyloid angiopathy and arteriolosclerosis. This study indicates that vascular pathology may be a more important player and may contribute to dementia in a manner that has not been fully appreciated in much smaller, center-based studies.
In multicenter studies, such comparability of protocols is essential in addition to a mechanism to ensure standardization between sites. Unfortunately, the study was started before α-synuclein immunohistochemistry became widely used in dementia centers, and so the density of lesions varies hugely from 4 percent of cases with Lewy bodies (Table 2) to 37 percent in a cohort of the original sample. Also, TDP-43 which has been reported in 20-40 percent of AD cases, is not included in this study, probably for the same reason. These data discrepancies are likely to impact on the relative contribution of vascular pathology in this study. In future analyses, in order to avoid variability between sites in staining, antibodies, and interpretation of lesion, the authors might want to give some thought to having one center perform this core function. The numbers of autopsies is not so great that this could not be done at one of the sites. There is a pearl to be seen in here, but the neuropathologic data will have to be more translucent if it is to be fully appreciated.
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