White matter integrity and vulnerability to Alzheimer’s disease: preliminary findings and future directions

“This is because the neuropathology of AD in GM brain regions is well established: Amyloid plaques and intracellular neurofibrillary tangles initially target medial temporal lobe (MTL) GM, resulting in prominent neurodegeneration of the hippocampus and entorhinal cortex (ERC) [6, 7].”

“The TBSS method has several advantages compared to other whole-brain analysis techniques including improved registration of WM tracts across subjects [41] and the lack of a need to apply an arbitrary smoothing kernel, which can produce different results based on kernel size [42].”

“DTI is an extended form of diffusion-weighted tensor trace imaging that is sensitized to the motion of water molecules as they interact within tissues, thus reflecting characteristics of their immediate structural surroundings [24, 25].”

“In the brain, APOE is mainly produced by glial cells and is thought to be involved in neuronal growth and regeneration [15].”

“of axonal orientation compared to the direction orthogonal to the main fiber direction [26, 27].”

“Axial diffusivity (DA) reflects the diffusion coefficient along the direction of maximal 'apparent' diffusion (λ1), whereas radial diffusivity (DR) reflects the average diffusion coefficients along the two perpendicular directions ((λ2 + λ3)/2) [30].”

“DTI is an extended form of diffusion-weighted tensor trace imaging that is sensitized to the motion of water molecules as they interact within tissues, thus reflecting characteristics of their immediate structural surroundings [24, 25].”

“2 million by 2050 [1].”

“Apolipoprotein E—Apolipoprotein E (APOE) confers the greatest genetic risk for lateonset AD among at least six other genes recently discovered or confirmed [14].”

“The IFOF contains connections between occipital visual regions and ventrolateral prefrontal cortex, a region with an established role in memory encoding [53].”

“of axonal orientation compared to the direction orthogonal to the main fiber direction [26, 27].”

“There is now strong evidence that significant Alzheimer's neuropathology is present years before the appearance of clinical symptoms associated with amnestic mild cognitive impairment (aMCI) or AD [2, 3].”

“However, ever since the work of Brun and Englund [8], it has been known that microscopic WM changes are also present in AD.”

“The signaling scheme between axons and investing glia, particularly oligodendroglia in the CNS, is not yet well defined [67].”

“This pattern of DTI-based findings is consistent with data demonstrating that myelin and its components such as cholesterol and myelin proteins are reduced early in the AD process [64, 65] and with a recently proposed theory suggesting that disruption of myelin integrity is an early event in the course of AD [66].”

“The TBSS method has several advantages compared to other whole-brain analysis techniques including improved registration of WM tracts across subjects [41] and the lack of a need to apply an arbitrary smoothing kernel, which can produce different results based on kernel size [42].”

“This pattern of DTI-based findings is consistent with data demonstrating that myelin and its components such as cholesterol and myelin proteins are reduced early in the AD process [64, 65] and with a recently proposed theory suggesting that disruption of myelin integrity is an early event in the course of AD [66].”

“association bundles [51].”

“However, the most prominent decreases have been reported in tracts with direct or secondary connections to MTL structures, including tracts showing decreases in AD-risk studies (parahippocampal WM, the cingulum, the IFOF / UNC, and the corpus callosum) [44–50].”

“In contrast, a decrease in DA has been reported in both rodents and humans with axonal damage associated with axonal swelling, fragmentation and organelle accumulations [32, 33].”

“Neuropathology affects the hippocampus and entorhinal cortex (ERC) early in the course of AD [6, 7], and atrophy of these MTL structures is evident with MR imaging early in the AD disease process [59–61].”

“The DA increases reported were widespread, prominently affecting not simply medial temporal lobe tracts such as the fornix and cingulum, but also tracts of temporo-parietal regions such as the superior longitudinal fasciculus [55, 57, 58].”

“Individuals with a first-degree relative affected with AD have been found to have between a 4 to 10 fold increase in AD-risk [19, 20, 21].”

“In each of these studies except one [56] symptomatic AD was associated with increases in DA (in addition to DR).”

“Within WM, water diffusion is highest in tracts that contain the largest numbers of fibers running in parallel, such as the corpus callosum [29].”

“In contrast, a decrease in DA has been reported in both rodents and humans with axonal damage associated with axonal swelling, fragmentation and organelle accumulations [32, 33].”

“This pattern of DTI-based findings is consistent with data demonstrating that myelin and its components such as cholesterol and myelin proteins are reduced early in the AD process [64, 65] and with a recently proposed theory suggesting that disruption of myelin integrity is an early event in the course of AD [66].”

“The DA increases reported were widespread, prominently affecting not simply medial temporal lobe tracts such as the fornix and cingulum, but also tracts of temporo-parietal regions such as the superior longitudinal fasciculus [55, 57, 58].”

“Specifically, the caudal portion of the cingulum contains fibers that connect the posterior cingulate cortex with the entorhinal cortex and hippocampus [52].”

“Recent reviews have summarized evidence that WM microstructural integrity is decreased in AD and aMCI [12, 13].”

“DTI-based declines have been shown to contribute to age-related cognitive declines [9–11], suggesting they are functionally significant to the study of healthy and pathological forms of aging.”

“Study Technique N WM Tract Nierenberg et al., 2005 ROI 29 PHW Persson et al., 2006 ROI, SPM-VBM 60 CC, CING/IFOF, HC Honea et al., 2009 FSL-TBSS 53 PHW Gold et al., 2010 FSL-TBSS 57 CING, FORNIX, CC, ILF, IFOF/UNC Smith et al., 2010 FSL-TBSS 65 PHW, CING, CC, ILF/IFOF Bendlin et al., 2010 SPM-VBM…”

“One theory is that APOE-4 may result in decreased plasticity of neuronal synapses, and decreased ability to repair damaged neurons compared to other allelic variants [18].”

“Neuropathology affects the hippocampus and entorhinal cortex (ERC) early in the course of AD [6, 7], and atrophy of these MTL structures is evident with MR imaging early in the AD disease process [59–61].”

“However, the most prominent decreases have been reported in tracts with direct or secondary connections to MTL structures, including tracts showing decreases in AD-risk studies (parahippocampal WM, the cingulum, the IFOF / UNC, and the corpus callosum) [44–50].”

“Recent reviews have summarized evidence that WM microstructural integrity is decreased in AD and aMCI [12, 13].”

“However, the most prominent decreases have been reported in tracts with direct or secondary connections to MTL structures, including tracts showing decreases in AD-risk studies (parahippocampal WM, the cingulum, the IFOF / UNC, and the corpus callosum) [44–50].”

“DTI-based declines have been shown to contribute to age-related cognitive declines [9–11], suggesting they are functionally significant to the study of healthy and pathological forms of aging.”

“However, the most prominent decreases have been reported in tracts with direct or secondary connections to MTL structures, including tracts showing decreases in AD-risk studies (parahippocampal WM, the cingulum, the IFOF / UNC, and the corpus callosum) [44–50].”

“There is an emerging consensus that the focus of AD research should move toward identification of presymptomatic biomarkers [4, 5].”

“Study Technique N WM Tract Nierenberg et al., 2005 ROI 29 PHW Persson et al., 2006 ROI, SPM-VBM 60 CC, CING/IFOF, HC Honea et al., 2009 FSL-TBSS 53 PHW Gold et al., 2010 FSL-TBSS 57 CING, FORNIX, CC, ILF, IFOF/UNC Smith et al., 2010 FSL-TBSS 65 PHW, CING, CC, ILF/IFOF Bendlin et al., 2010 SPM-VBM 136 HC, CING, IFOF/UN…”

“However, the most prominent decreases have been reported in tracts with direct or secondary connections to MTL structures, including tracts showing decreases in AD-risk studies (parahippocampal WM, the cingulum, the IFOF / UNC, and the corpus callosum) [44–50].”

“Individuals with a first-degree relative affected with AD have been found to have between a 4 to 10 fold increase in AD-risk [19, 20, 21].”

“In addition, recent results suggest that smaller MTL volumes can be detected several years prior to aMCI diagnosis [62, 63].”

“Study Technique N WM Tract Nierenberg et al., 2005 ROI 29 PHW Persson et al., 2006 ROI, SPM-VBM 60 CC, CING/IFOF, HC Honea et al., 2009 FSL-TBSS 53 PHW Gold et al., 2010 FSL-TBSS 57 CING, FORNIX, CC, ILF, IFOF/UNC Smith et al., 2010 FSL-TBSS 65 PHW, CING, CC, ILF/IFOF Bendlin et al., 2010 SPM-VBM 136 HC, CING, IFOF/UN…”

“There is an emerging consensus that the focus of AD research should move toward identification of presymptomatic biomarkers [4, 5].”

“…et al., 2009 FSL-TBSS 53 PHW Gold et al., 2010 FSL-TBSS 57 CING, FORNIX, CC, ILF, IFOF/UNC Smith et al., 2010 FSL-TBSS 65 PHW, CING, CC, ILF/IFOF Bendlin et al., 2010 SPM-VBM 136 HC, CING, IFOF/UNC, CC Heise et al., in press FSL-TBSS 39 CING, CC, SLF Notes: ROI, region of interest; SPM-VBM,…”

“Of the AD-risk studies conducted to date, four have explored component diffusivities in addition to FA and MD [34, 38, 39, 40].”

“Adapted from Smith et al. (2010) with permission.”

“Tracts showing declines in individuals at high AD-risk involve a subset of tracts showing decline in symptomatic AD, including WM of the parahippocampal region, the cingulum, IFOF, and splenium of the corpus callosum.”

“However, the most prominent decreases have been reported in tracts with direct or secondary connections to MTL structures, including tracts showing decreases in AD-risk studies (parahippocampal WM, the cingulum, the IFOF / UNC, and the corpus callosum) [44–50].”

“In addition, recent results suggest that smaller MTL volumes can be detected several years prior to aMCI diagnosis [62, 63].”

“However, the most prominent decreases have been reported in tracts with direct or secondary connections to MTL structures, including tracts showing decreases in AD-risk studies (parahippocampal WM, the cingulum, the IFOF / UNC, and the corpus callosum) [44–50].”

“Individuals with a first-degree relative affected with AD have been found to have between a 4 to 10 fold increase in AD-risk [19, 20, 21].”

“It is tempting to speculate that the progression of other neuro-psychiatric disorders, including Alzheimer’s disease [3,61] and schizophrenia [62], could be likewise influenced by glycolytic oligodendrocytes and white matter abnormalities.”

“…the past decade, numerous DTI studies have re- ported spatial and temporal changes in white matter that arise over the course of Alzheimer’s disease, the results of which are summarized in a number of extensive reviews (Chua et al., 2008; Sexton et al., 2011; Gold et al., 2012; Mak et al., 2017).”