Abstract：
BACKGROUND: Alzheimer\'s disease (AD) is a heterogeneous proteinopathy. Co-pathology with Lewy bodies (LB) is frequent and known to contribute to a differential pattern of executive cognitive impairment compared to typical AD. While primary age-related tauopathy (PART) presents with neurofibrillary tangles, mainly restricted to the temporal lobe and in the absence of amyloid-beta plaques, LB co-pathology is also present. However, it is still unknown how the combination of these proteinopathies affects patterns of brain atrophy, which might help clarify the clinical importance and pathophysiology of combined pathology within these groups. Here we investigated the influence of LB on patterns of brain atrophy in AD and PART.
METHODS: We selected 214 patients with AD neuropathological change (ADNC) with no LB (n = 102), ADNC with LB (ADNC+LB) (n = 77), PART with no LB (n = 22) and PART with LB (PART+LB) (n = 13) with ante-mortem volumetric MRI from the National Alzheimer\'s Coordinating Center, after exclusion of other neurodegenerative pathologies. Dementia severity was compared using Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Cortical and subcortical MRI volume residuals were compared between groups after correction for age. Statistical significance was considered at p-value < 0.05 after false discovery rate correction for multiple comparisons.
RESULTS: We found that ADNC, ADNC+LB and PART+LB presented similar levels of dementia severity, whereas PART with no LB was the least affected group. MRI revealed higher atrophy of the right frontal operculum and amygdala in ADNC+LB compared to ADNC. ADNC and ADNC+LB showed increased atrophy in regions across all cortical lobes, hippocampus, amygdala and putamen compared to PART, but did not reveal significant differences compared to PART+LB. Interestingly, PART+LB showed higher atrophy of the frontal poles bilaterally, right superior frontal gyrus, left frontal operculum and right putamen compared to PART.
CONCLUSIONS: Altogether, these results suggest that LB co-pathology contributes to frontal lobe regional atrophy in ADNC and likely drives it in PART. Particularly in PART+LB, it suggests that cognitive impairment might derive from alpha-synuclein pathology rather than tauopathy. These findings indicate that LB pathology determines disease severity within the PART- and AD-continuums.
METHODS: We selected 214 patients with AD neuropathological change (ADNC) with no LB (n = 102), ADNC with LB (ADNC+LB) (n = 77), PART with no LB (n = 22) and PART with LB (PART+LB) (n = 13) with ante-mortem volumetric MRI from the National Alzheimer\'s Coordinating Center, after exclusion of other neurodegenerative pathologies. Dementia severity was compared using Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Cortical and subcortical MRI volume residuals were compared between groups after correction for age. Statistical significance was considered at p-value < 0.05 after false discovery rate correction for multiple comparisons.
RESULTS: We found that ADNC, ADNC+LB and PART+LB presented similar levels of dementia severity, whereas PART with no LB was the least affected group. MRI revealed higher atrophy of the right frontal operculum and amygdala in ADNC+LB compared to ADNC. ADNC and ADNC+LB showed increased atrophy in regions across all cortical lobes, hippocampus, amygdala and putamen compared to PART, but did not reveal significant differences compared to PART+LB. Interestingly, PART+LB showed higher atrophy of the frontal poles bilaterally, right superior frontal gyrus, left frontal operculum and right putamen compared to PART.
CONCLUSIONS: Altogether, these results suggest that LB co-pathology contributes to frontal lobe regional atrophy in ADNC and likely drives it in PART. Particularly in PART+LB, it suggests that cognitive impairment might derive from alpha-synuclein pathology rather than tauopathy. These findings indicate that LB pathology determines disease severity within the PART- and AD-continuums.
摘要：
背景：阿尔茨海默病（AD）是一种异质性蛋白质病。与典型的AD相比，与路易体（LB）的共病是常见的，并且已知会导致执行认知障碍的不同模式。虽然原发性年龄相关性tau蛋白病（部分）表现为神经原纤维缠结，主要限于颞叶，在没有β淀粉样蛋白斑块的情况下，LB共病理学也存在。然而,目前尚不清楚这些蛋白质病的组合如何影响脑萎缩的模式，这可能有助于阐明这些组中联合病理学的临床重要性和病理生理学。在这里，我们研究了LB对AD和PART脑萎缩模式的影响。
方法：我们选择了214例无LB的AD神经病理变化（ADNC）患者（n=102），ADNC与LB（ADNC+LB）（n=77），没有LB的部分（n=22）和LB部分（PART+LB）（n=13）与来自国家阿尔茨海默氏症协调中心的死前体积MRI，排除其他神经退行性病变后。使用临床痴呆评定量表框总和(CDR-SB)比较痴呆严重程度。校正年龄后，比较各组之间的皮质和皮质下MRI体积残留。在多个比较的错误发现率校正后,在p值<0.05时考虑统计学显著性。
结果：我们发现ADNC，ADNC+LB和PART+LB表现出相似的痴呆严重程度，而没有LB的PART是受影响最小的组。MRI显示，与ADNC相比，ADNCLB中右额叶和杏仁核的萎缩程度更高。ADNC和ADNC+LB显示所有皮质叶区域的萎缩增加，海马体,杏仁核和壳核与部分相比，但与PART+LB相比没有显着差异。有趣的是,PART+LB显示双侧额叶高度萎缩，右额上回,与PART相比，左额脑膜和右壳核。
结论：总而言之，这些结果表明，LB共同病理有助于ADNC的额叶区域萎缩，并可能在PART引起。特别是在Part+LB中，这提示认知障碍可能源自α-突触核蛋白病理而非tau蛋白病.这些发现表明LB病理学决定了PART-和AD-连续体中的疾病严重程度。
方法：我们选择了214例无LB的AD神经病理变化（ADNC）患者（n=102），ADNC与LB（ADNC+LB）（n=77），没有LB的部分（n=22）和LB部分（PART+LB）（n=13）与来自国家阿尔茨海默氏症协调中心的死前体积MRI，排除其他神经退行性病变后。使用临床痴呆评定量表框总和(CDR-SB)比较痴呆严重程度。校正年龄后，比较各组之间的皮质和皮质下MRI体积残留。在多个比较的错误发现率校正后,在p值<0.05时考虑统计学显著性。
结果：我们发现ADNC，ADNC+LB和PART+LB表现出相似的痴呆严重程度，而没有LB的PART是受影响最小的组。MRI显示，与ADNC相比，ADNCLB中右额叶和杏仁核的萎缩程度更高。ADNC和ADNC+LB显示所有皮质叶区域的萎缩增加，海马体,杏仁核和壳核与部分相比，但与PART+LB相比没有显着差异。有趣的是,PART+LB显示双侧额叶高度萎缩，右额上回,与PART相比，左额脑膜和右壳核。
结论：总而言之，这些结果表明，LB共同病理有助于ADNC的额叶区域萎缩，并可能在PART引起。特别是在Part+LB中，这提示认知障碍可能源自α-突触核蛋白病理而非tau蛋白病.这些发现表明LB病理学决定了PART-和AD-连续体中的疾病严重程度。
