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Deep White Matter Lesions Are Associated with Early Recognition of Dementia in Alzheimer's Disease.

笠原, 浩生 カサハラ, ヒロオ Ksahara, Hiroo 群馬大学

2020.03.24

概要

【目的】
アルツハイマー病(Alzheimer's disease: AD)では脳内にアミロイドβ蛋白 (amyloid-β: Aβ)が蓄積する．11C-labeled Pittsburgh Compound B(PiB)を用いたPET検査(PiB PET)を行うことで，脳内のAβ蓄積を画像化できる．脳血管障害の危険因子 (vascular risk factors: VRF)はAD発症の危険因子でもあることが判明しており，頭部 MRIでの大脳白質病変(white matter lesions: WML)および血管周囲腔拡大(enlarged perivascular spaces: EPVS)は，脳微小血管障害(cerebral small vessel disease: SVD)を反映するとされる．WMLおよびEPVSは血管性認知症と関連しているが，ADの病態における意義は明らかでない．そこでPiB PETおよび頭部MRIを用いて，脳Aβ蓄積とSVDとの関連を調査した．

【方法】
臨床的にADが疑われPiB PETを施行した78例を対象とし，後ろ向きに調査を行った．対象者は全員頭部MRIを施行し，WMLおよびEPVSについて視診で重症度評価を行った．WMLは脳室周囲高信号病変(periventricular hyperintensity: PVH)と深部白質高信号病変(deep white matter hyperintensity: DWMH)を区別し，Fazekas分類にて重症度評価を行った．EPVSは2004年にMacLullichらが提唱した分類に準じて重症度評価を行った．PiB PETの結果については，陽性・陰性を視診にて判定した．PiB PET陽性例の一部では，mcSUVR(mean cortical standardized uptake value ratio)値を算出することで定量的評価を行った．mcSUVR値の算出にあたっては，まず複数の領域の大脳皮質に関心領域を設定し，小脳皮質を参照領域として，各皮質関心領域におけるPiBの集積についてSUVR値を測定した．さらに複数の皮質関心領域を集合したArea A～Dを設定し，各 Areaに含まれる全ての関心領域のSUVR値を平均することでmcSUVR値を算出した．Area Aは前頭葉・頭頂葉・側頭葉・後頭葉・前部帯状回・後部帯状回，Area Bは前頭葉・頭頂葉・前部帯状回・後部帯状回，Area Cは前頭葉・前部帯状回，Area Dは頭頂葉・後部帯状回から構成されるように設定した．一部の対象例ではAPOE(apolipoprotein E)遺伝子型についても解析を行った．

【結果】
PiB PET結果は視診で，67例(86%)が陽性，11例(14%)が陰性であった．APOE遺伝子型については， ADの遺伝的危険因子となるAPOEε4アリル保有者がPiB PET陽性群で陰性群より有意に高かった．次に，MRI所見の重症度について，PiB PET陽性群と陰性群で比較した． APOEε4アリルはAD発症と関連するため，APOEε3アリルのホモ接合例に限って検討を行ったところ，PiB PET陽性群は陰性群に比べてMRI所見の重症度が高い傾向があった．次に視診でPiB PET陽性と診断され臨床的にもADと診断された30例においてmcSUVR値を算出し，MRI所見の重症度との関連性についてSpearmanの順位相関係数を用いて評価を行った．DWMHではArea A～Dの全てにおいて，PVHではArea B，Cにおいて，mcSUVR値とMRI所見の重症度との間に有意な負の相関を認めたが，EPVSではいずれのAreaにおいても有意な相関を認めなかった．またmcSUVR値を従属変数，MRI所見の重症度・VRF・年齢を独立変数として重回帰分析を行った．重回帰分析の結果，DWMHおよびPVHではArea A～Dの全てにおいてmcSUVR値とMRI所見の重症度の間に有意な関連があったが，EPVSではArea Dのみで有意な関連があった．

【考察】
APOE遺伝子型はPiB PET陽性群で陰性群に比べAPOEε4アリル保有者が多く， APOEε4アリルがAD発症に関与していることを示している．APOEε3アリルのホモ接合例では，PiB PET陽性群は陰性群に比べ，高度のWMLおよびEPVSを有する頻度が高く，WMLおよびEPVSがAβ蓄積と関連していると考えられた．WMLおよびEPVSはSVDの画像マーカーとされているが，病理学的には背景が異なると考えられている．EPVSは血管透過性の増大により生じるとされている．WMLは脳虚血性変化の結果生じるとされているが， DWMHとPVHで成因は異なると考えられている．DWMHは脳虚血性変化との関連が強いが， PVHは脳虚血性変化以外にも血液脳関門の機能不全や脳室周囲の上衣細胞の障害とも関連すると報告されている．本研究ではMRI所見が重度であるほどmcSUVR値が低値である傾向を示したが，WMLではMRI所見の重症度とmcSUVR値の間に有意な負の相関を認めた一方で，EPVSではいずれのAreaにおいても有意な相関を認めなかった．さらに同じAreaで比較した場合，PVHの重症度と比較して，DWMHの重症度はmcSUVR値と強い負の相関を示した．病理学的に脳虚血性変化と関連の強いDWMHにおいて，MRI所見とmcSUVR値との間に強い負の相関を認めた点から，SVDと脳Aβ蓄積に関連があることが示唆された．多くの既報告では，ADおよび健常者においてMRI上のWMLの程度と脳Aβ蓄積との間には有意な関連はないとされている．本研究では，複数のAreaにおけるmcSUVR値を検討し，さらにWMLについてもPVHとDWMHに分けて検討することにより，脳虚血性変化の程度と脳Aβ蓄積の程度に負の相関があることを明らかにした．この理由として，AD患者では脳Aβ蓄積が比較的軽度であっても，脳虚血性変化が重度であれば，臨床的に認知機能低下を来す可能性が示唆された．SVDはAD患者における認知機能低下を加速し，認知症の早期認識を促進する可能性があると考えられた．

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