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成人男性の自閉スペクトラム症における脳形態偏倚と出生時の両親年齢

児島, 正樹 東京大学 DOI:10.15083/0002002358

2021.10.13

概要

【序文】自閉スペクトラム症(Autism Spectrum Disorder、以下ASD)は、対人的相互関係、対人的相互反応で用いられる非言語的コミュニケーション行動、および人間関係を発展・維持、および理解する能力などに関する障害である。ASDに関する過去の研究では、発症の約90%は遺伝的要因によると考えられていた。しかし、近年の研究では周産期要因および環境要因がASDの発症に関連することが注目されている。特に、近年では出生時の父親年齢(Paternal age at birth:、以下PA)と母親年齢(Maternal age at birth、以下MA)に関する研究が増加しており、各々独立してASDの発症に関わることがメタ解析で示されているが、その機序は解明されていない。
 MRI(Magnetic Resonance Imaging)を用いたASDの脳構造に関する研究は、ASDの病態解明に大きな役割を果たしてきた。しかし、これらの研究結果に不一致が多い点も指摘されており、ASD自体の生物学的異種性が関与している可能性が言及されている。ASDのリスク要因と脳形態に関する研究は、ASDの病態解明に新たな視点をもたらす可能性がある。健常者の脳形態とPA/MAに関する研究は既に行われているが、ASD当事者を対象としたPA/MAと脳形態偏倚の関連性はこれまで明らかにされていない。
 本研究はASDに関連した脳形態偏倚とASDのリスク要因であるPA/MAに関連性が認められるという仮説に基づき、脳画像解析の手法によって上述の関連性を解明することを本研究の目的とした。

【方法】知的障害を有さない成人男性のASD群39名および年齢、性別、IQ、両親の社会経済状況を一致させた定型発達の被験者群(Typical Development、以下TD)39名を対象とした。撮像されたMRI画像に対してvoxel-based morphometryに基づく脳画像の前処理を行い、ASD群とTD群の局所脳灰白質体積および局所脳白質体積を比較した。P<0.025の有意差を認めたcluster全体におけるfalse discovery rate補正後のP<0.05を有意水準とした。有意な群間差を認めた脳領域を関心領域に設定し、surface-based morphometryに基づいて同領域の脳形態指標である皮質厚および表面積を求めた。算出された各領域の皮質厚および表面積は、ASDの有無を被験者間変数、左右の側性および脳領域を被験者内因子とする反復測定共分散分析で検定し、疾患の有無に関連した有意差が認められた場合に事後検定(post hoc analysis)を行った。有意水準はP<0.05とした。有意な群間差を認めた指標のみを対象とし、ASD群またはTD群において、PA/MAの上昇と該当指標におけるPearsonの相関係数を求めた。P<0.05を有意水準とした。

【結果】脳灰白質および白質体積を対象とした2群比較では、ASD群の両側後部帯状回/楔前部の脳灰白質体積がTD群と比較して有意に低値を示した(false discovery rate補正後のP=0.014)。他の脳領域の灰白質体積および白質体積は、両群間で有意差を認めなかった。同領域における脳形態指標の比較では、右腹側後部帯状回の皮質厚はASD群において有意に菲薄化しており(F=7.50, P=0.008)、両側楔前部の表面積はASD群において有意に小さかった(左側:F=12.30, P=0.001、右側:F=4.01, P=0.049)。有意な群間差を認めた脳形態指標とPA/MAの関連性における相関解析では、ASD群において右腹側後部帯状回の皮質厚とPAに有意な弱い負の相関が認められた(r=-0.35, P=0.028)。ASD群およびTD群の双方において、上記以外に脳形態指標とPA/MAの有意な相関を認めなかった。

【考察】本研究結果より、ASDにおける右腹側後部帯状回の皮質厚の菲薄化と、出生時の父親年齢の関連性が示唆された。我々の知る限りでは、本研究はPAと脳形態偏倚、ASDの関連性を明らかにした最初の研究である。
 楔前部は特に視空間認知、エピソード記憶の再生、自己認識などの機能との関連性が注目されており、後部帯状回は内的思考を支えるdefault mode networkの中心的役割を果たしている。また、ASDの脳皮質厚と表面積は異なる発達変化を呈することが先行研究から指摘されており、ASDに特徴的な脳形態偏倚とPAの関連性を評価するうえで、皮質厚が適切な脳形態指標である可能性が示唆される。後部帯状回の皮質厚の菲薄化が脳機能に与える影響、および臨床特性との関連性については、更なる研究が必要となる。
 本研究では、ASDに特徴的な脳形態偏倚の一部がPAの上昇と有意な弱い負の相関を示し、MAの上昇と有意な相関は認められなかった。PAとASDの発症リスクとの関連性は不明な点が多いが、分子生物学的な見地から多くの研究がなされている。一方、MAの上昇は周産期合併症と関連性が高い。本研究で得られた知見と併せて、PAの上昇はMAの上昇と異なる機序でASD発症に関与しており、またPAはASDの神経病理により直接的に関与している可能性が示唆される。

【結論】本研究では、ASD群においてTD群よりも有意に後部帯状回/楔前部の脳灰白質体積が小さく、また両側楔前部の表面積が小さいことを示した。また、ASD群の右腹側後部帯状回の皮質厚はTD群よりも有意に菲薄化していた。さらに、ASD群においてPAの上昇と右腹側後部帯状回の皮質厚に有意な弱い負の相関が認められた。以上の知見はASDとPA、および脳形態偏倚の関連性にエビデンスを提供するものである。PAの上昇が発達的側面に有利な影響をもたらすという報告もあるため、今後の研究において本研究の臨床的帰結が明らかにされることが望ましい。

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