軽度認知機能障害の神経病理

Neuropathology of mild cognitive impairment

　軽度認知機能障害とは，正常と痴呆の中間に位置し，適切な介入により，痴呆への進展を防ぐことが重要とされる群と定義されるが，生物学的背景に関する研究はほとんどない。筆者らは，東京都高齢者ブレインバンク内1,120名の連続剖検例より後方視的に，軽度認知障害疑い例を抽出，神経病理学的背景を検討した。170例が軽度認知機能障害疑い例と抽出された。男女比1.44，平均年齢82.0歳，平均脳重1,260gで，いずれも正常と痴呆の中間に属し，変性型では，アルツハイマー病変化，高齢者タウオパチー変化，レヴィー小体型痴呆様変化，さらに血管障害型においては多発性脳梗塞，Binswanger型白質脳症型変化とも，痴呆例と正常例との中間の病理を示すことが明らかとなった。方法論的限界はあるが，この結果は，軽度認知機能障害の概念および，その群への早期介入への妥当性を支持する所見と考えられる。

　Mild cognitive impairment（MCI）is defined as the intermediate state between normal cognition and dementia. MCI has been highlighted as the main target for preventive scheme against cognitive decline in the elderly. However, there are very few studies about neuropathological background of this state. Moreover, many of these studies only reported MCI as substrate of early Alzheimer disease（AD）.

　We screened clinical records of 1,120 serial autopsy cases from Tokyo Metropolitan Brain Bank for Aging Research in these five years. These cases represent serial autopsy cases from a general geriatric hospital for community care and reasonably represent a cohort of the elderly in Tokyo metropolitan urban district. The cases equivalent to MCI were retrospectively selected by two professional neurologists, on the following criteria：1）the description of memory impairment incurring problems for medical care, 2）no definite description of dementia, and 3）CDR 0.5. One hundred and seventy cases were pulled out. A male to female ratio was 1.44, the average age, 82.0 years and the average brain weight, 1,260g respectively. These values were just between those of the cases with normal cognition and with dementia. The frequency of apoEε4 allele is also between cognitively normal cases and cases with dementia.

　The background pathology of these MCI cases were evaluated on our standard pathology protocol. The areas examined followed the recommendations of the Consortium to Establish a Registry for Alzheimer's Disease（CERAD）and the consensus guidelines for the diagnosis of dementia with Lewy bodies. Six-μm-thick sections were routinely stained with hematoxylin and eosin（H＆E）and the Klüver-Barrera（KB）method. Selected sections were stained with the modified methenamine silver and Gallyas-Braak silver method for senile changes, with Congo red for amyloid deposition, and with elastica Masson trichrome for vascular changes. Immunohistochemically employed were the antibodies raised against amyloidβ, phosphorylated tau（AT8）, phosphorylatedα-synuclein, ubiquitin, phosphorylated neurofilament, glial fibrillary acidic protein and HLA-DR. The description of the location, size and nature（thrombotic, embolic or lacunar）of all vascular lesions and the semi-quantitative assessment of each abnormally accumulated proteins（tau, amyloid beta protein, alpha-synuclein and ubiquitin）were applied to all the cases examined.

　Among the 170 cases, 25 cases mainly presented with Alzheimer-type pathology including neurofibrillary tangles and senile plaques. 10 cases presented with Lewy-related neuronal degeneration without parkinsonism. 11 cases each show dementia with grain-or neuforibrillary tangle predominant form of dementia-type changes and one case showed the combination of these two changes. All of these changes were generally milder than the cases with dementia.

　In addition to cases with mainly degenerative changes, 72 cases presented with mainly vascular lesions. Among them, 27 cases experienced stroke events, among whom 2 cases exhibited with Binswanger-type white matter changes. These vascular changes were generally milder than those of cases with vascular dementia. Moreover, 35 cases carried asymptomtic cerebral infarcts as only morphological substrates of cognitive decline.

　Our data indicate that MCI comprised heterogeneous background pathology of probable pre-symptomatic phase. Similar data have been now accumulating in the literature. Thus, the prospective studies of MCI is quite important to develop the tools for the prevention of the progression to dementia from MCI stage.