Brain︱常染色体显性阿尔兹海默症中，白质改变先于痴呆症状出现的机制阐明（英文阅读）
Human brain right dissected lateral view description. Credit: Wikipedia. (https://en.wikipedia.org/wiki/White_matter)
According to recent advanced findings, white matter alterations, resulting from cerebrovascular disease, may contribute to amyloid deposition on neurodegeneration and cognition in ageing and AD [4-6].
However, there remains a major question: when and where in the brain white matter alterations occur during the course of AD.
A difficulty in the interpretation of these previous findings is the uncertain future development of dementia symptoms at the presumed preclinical stage of AD. In contrast, in autosomal-dominant AD mutation carriers will all develop dementia and the future onset of dementia symptoms can be more precisely estimated [7].
Furthermore, because of the younger age at onset of autosomal-dominant AD, there is less likelihood of confounding vascular disease. Thus these s which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease [8].
However, these studies either lacked sufficient statistical power considering the relatively low sample sizes (n = 8 to 18 of asymptomatic carriers) to detect subtle pre-symptomatic phase or did not estimate years from symptom onset (EYO) [9-10].
More interestingly, Miguel Ángel Araque Caballero, et al. showed that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary AD pathology and microglia activity in the brain [11].
And their paper titled White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease was published on Brain ( 2018 IF=11.199), 25 September 2018.
In this work, M. A. Araque Caballero et al. dealt with as flowing:
(i). Assessing mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers (table 1).
(ii). Mapping the interaction of mutation status by estimated years from symptom onset on mean diffusivity.
(iii). Testing the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable.
(iv). Determining the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity.
As expected, results showed a significant interaction of mutations status within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres between 5 to 10 years before estimated symptom onset (Fig. 1).
Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts’ projection zones (Fig. 2-3). Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2 (Fig. 5).
All together, this findings by Miguel Ángel Araque Caballero, et al. suggested that white matter alterations start in circumscribed regions predominantly in posterior parietal and medial prefrontal white matter, preceding the onset of dementia symptoms by more than a decade. These fibre tract changes are an integral part of the AD pathological cascade.
Also, the current findings encourage future studies to assess the effect of white matter alteration on the cascading breakdown of functional brain networks in AD.
Supplementary Readings
[1] Alzheimer’s & Dementia综述︱阿尔兹海默病(AD)中焦虑症状的生物标志物
[2] LTNS Brief︱Imaging Strengthens Knowledge of Alzheimer disease
[3] Alzheimer`s & Dementia: 前沿! 理论完善: 低水平补体C3是阿尔兹海默症(AD)的一个高风险因子
[4] Nature：重磅！清除衰老的神经胶质细胞，可以阻止tau蛋白沉积和认知能力下降（长文解析）
[5] Neuron：前沿！Tau蛋白会破坏阿尔茨海默氏病(AD)的核质转运（新机制）
Key References
[1] Brun A, Englund E. A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 1986; 19: 253–62.
[2] Englund E. Neuropathology of white matter changes in Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn Disord 1998; 9 (Suppl 1): 6–12.
[3] Agosta F, et al. White matter damage in Alzheimer disease and its relationship to gray matter atrophy. Radiology 2011; 258: 853–63.
[4] Bos I, et al. Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline. Alzheimers Res Ther 2017; 9: 101
[5] Taylor AN, et al. Tract-specific white matter hyperintensities disrupt neural network function in Alzheimer’s disease. Alzheimers Dement 2017; 13: 225–35.
[6] Vemuri P, et al. Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain 2015; 138 (Pt 3): 761–71.
[7] Ryman DC, et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 2014; 83: 253–60.
[8] Iturria-Medina Y, et al. Alzheimer’s disease neuroimaging I. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun. 2016; 7: 11934.
[9] Ringman JM, et al. Diffusion tensor imaging in preclinical and pre-symptomatic carriers of familial Alzheimer’s disease mutations. Brain 2007; 130 (Pt 7): 1767–76.
[10] Parra MA, et al. Memory binding and white matter integrity in familial Alzheimer’s disease. Brain 2015; 138 (Pt 5): 1355–69.
[11] Miguel Ángel Araque Caballero,et al. White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease. Brain 2018; 141: 3065–3080.
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