White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease

Caballero, Miguel Ángel Araque; Suárez‐Calvet, Marc; Duering, Marco; Franzmeier, Nicolai; Benzinger, Tammie L.S.; Fagan, Anne M.; Bateman, Randall J.; Jack, Clifford R.; Xiong, Chengjie; Dichgans, Martin; Jucker, Mathias; Karch, Celeste M.; Masters, Colin L.; Morris, John C.; Weiner, Michael W.; Rossor, Martin N.; Fox, Nick C.; Lee, Jae Hong; Salloway, Stephen; Danek, Adrian; Goate, Alison; Yakushev, Igor; Hassenstab, Jason; Schofield, Peter R.; Haass, Christian; Ewers, Michael

doi:10.1093/brain/awy229

Cited by 131 publications

(143 citation statements)

References 110 publications

(158 reference statements)

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“…13 In autosomal dominant AD, we previously reported higher MD within the forceps major 10 years before symptom onset, with other major long-projecting fibers tracts such as the inferior frontooccipital fasciculus, superior longitudinal fasciculus, and forceps minor affected subsequently. 13 Similarly, in the current study, we observed significant amyloid-related MD increase that was located primarily in temporal and posterior brain regions. It should be noted that the white matter alterations extended to frontal fiber tracts such as the anterior thalamic radiation.…”

Section: Discussionmentioning

confidence: 84%

Age‐dependent amyloid deposition is associated with white matter alterations in cognitively normal adults during the adult life span

Caballero

Song

Rubinski

et al. 2020

Alzheimer's & Dementia

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Introduction Both beta‐amyloid (Ab) deposition and decline in white matter integrity, are brain alterations observed in Alzheimer's disease (AD) and start to occur by the fourth and fifth decades. However, the association between both brain alterations in asymptomatic subjects is unclear. Methods Amyloid positron emission tomography (PET) and diffusion tensor imaging (DTI) were obtained in 282 cognitively normal subjects (age 30‐89 years). We assessed the interaction of age by abnormal amyloid PET status (Florbetapir F‐18 PET >1.2 standard uptake value ratio [SUVR]) on regional mean diffusivity (MD) and global white matter hyperintensity (WMH) volume, controlled for sex, education, and hypertension. Results Subjects with abnormal amyloid PET (n = 87) showed stronger age‐related increase in global WMH and regional MD, particularly within the posterior parietal regions of the white matter. Discussion Sporadic Aβ deposition is associated with white matter alterations in AD predilection areas in an age‐dependent manner in cognitively normal individuals.

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Section: Discussionmentioning

confidence: 84%

Age‐dependent amyloid deposition is associated with white matter alterations in cognitively normal adults during the adult life span

Caballero

Song

Rubinski

et al. 2020

Alzheimer's & Dementia

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“…Such improved specificity may be due to neuroaxonal degradation occurring secondary to neuronal death during the onset and progression of AD‐related cortical atrophy. Furthermore, emerging evidence leveraging CSF Aβ42 and hyperphosphorylated tau have linked these core AD pathologies to white matter microstructural damage among aging adults [5] even in familial AD [27,28]. These findings suggest damage to the cerebral white matter (and underlying axons) may be more directly involved in the AD pathological cascade than previously recognized.…”

Section: Discussionmentioning

confidence: 94%

Cerebrospinal fluid and plasma neurofilament light relate to abnormal cognition

Osborn

Khan

Kresge

et al. 2019

Alz & Dem Diag Ass & Dis Mo

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Introduction Neuroaxonal damage may contribute to cognitive changes preceding clinical dementia. Accessible biomarkers are critical for detecting such damage. Methods Plasma and cerebrospinal fluid (CSF) neurofilament light (NFL) were related to neuropsychological performance among Vanderbilt Memory & Aging Project participants (plasma n = 333, 73 ± 7 years; CSF n = 149, 72 ± 6 years) ranging from normal cognition (NC) to mild cognitive impairment (MCI). Models adjusted for age, sex, race/ethnicity, education, apolipoprotein E ε4 carriership, and Framingham Stroke Risk Profile. Results Plasma NFL was related to all domains (P values ≤ .008) except processing speed (P values ≥ .09). CSF NFL was related to memory and language (P values ≤ .04). Interactions with cognitive diagnosis revealed widespread plasma associations, particularly in MCI participants, which were further supported in head‐to‐head comparison models. Discussion Plasma and CSF NFL (reflecting neuroaxonal injury) relate to cognition among non‐demented older adults albeit with small to medium effects. Plasma NFL shows particular promise as an accessible biomarker with relevance to cognition in MCI.

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“…3A,B). Thus suggesting that a marked degree of hypoperfusion-ischemia that may remain however below the T2-weighted MRI detectability and does not lead to strokes, may trigger APP misfolding and may explain the link between brain microstructural changes detected on diffusion tensor imaging (DTI) and likely hypoxic-ischemic hyperintensities in white matter, detected decades before the onset of symptomps and autosomal dominant AD cases 66,67 as well as common late-onset sporadic cases and elderly people 68 .…”

Section: Discussionmentioning

confidence: 99%

Investigating APOE, APP-Aβ metabolism genes and Alzheimer’s disease GWAS hits in brain small vessel ischemic disease

Blumenau

Foddis

Müller

et al. 2020

Sci Rep

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Alzheimer's disease and small vessel ischemic disease frequently co-exist in the aging brain. However, pathogenic links between these 2 disorders are yet to be identified. Therefore we used Taqman genotyping, exome and RnA sequencing to investigate Alzheimer's disease known pathogenic variants and pathways: APOE ε4 allele, APP-Aβ metabolism and late-onset Alzheimer's disease main genomewide association loci (APOE, BIN1, CD33, MS4A6A, CD2AP, PICALM, CLU, CR1, EPHA1, ABCA7) in 96 early-onset small vessel ischemic disease Caucasian patients and 368 elderly neuropathologically proven controls (HeX database) and in a mouse model of cerebral hypoperfusion. only a minority of patients (29%) carried APOE ε4 allele. We did not detect any pathogenic mutation in APP, PSEN1 and PSEN2 and report a burden of truncating mutations in App-Aß degradation genes. the single-variant association test identified 3 common variants with a likely protective effect on small vessel ischemic disease (0.54>oR > 0.32, adj. p-value <0.05) (EPHA1 p.M900V and p.V160A and CD33 p.A14V). Moreover, 5/17 APP-Aß catabolism genes were significantly upregulated (LogFC > 1, adj. p-val<0.05) together with Apoe, Ms4a cluster and Cd33 during brain hypoperfusion and their overexpression correlated with the ischemic lesion size. finally, the detection of Aβ oligomers in the hypoperfused hippocampus supported the link between brain ischemia and Alzheimer's disease pathology.Late-onset sporadic Alzheimer's disease (LOAD) and small vessel ischemic disease (SVID) frequently influence each other and co-exist in the aging brain depicting a clinical, neuroradiological and neuropathological spectrum defined as 'mixed dementia' . Although mixed dementia represents the second common form of dementia in the elderly, as over 45% of LOAD patients neuropathologically diagnosed displayed significant cerebrovascular pathology 1 , the nature and the pathogenic ground at the basis of AD-SVID interaction is poorly understood 2 . APOE ε4 allele is the strongest risk factor for sporadic LOAD 3-5 , however its role in SVID has not been extensively investigated. Common hallmark in small vessel disease is cerebral amyloid angiopathy (CAA), which is caused by excessive deposition of Aβ 40 and 42 on the walls of small vessels 6,7 , responsible both for its ischemic and hemorragic manifestations (SVID and intracerebral hemorrhage [ICH]) 8 . Both rare familial and common sporadic small vessel disease cases pointed to the potential role of APP-Aß dysmetabolism as key pathogenic mechanism underlying CAA small vessel disease subtype. First, autosomal dominant fully penetrant mutations in the secretase domain of APP, APP duplication, CST3 and TTR rare mutations cause familial CAA 9-11 . Second, common variants in IDE and LRP1 have been associated with increased risk of diabetes type 2 and migraine, respectively, that frequently are co-morbidities in SVID patients 12,13 . Third, perivascular and parenchymal Aß deposits have been reported in genetically diagnosed CADASIL patients and vascular ...

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White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease

Cited by 131 publications

References 110 publications

Age‐dependent amyloid deposition is associated with white matter alterations in cognitively normal adults during the adult life span

Age‐dependent amyloid deposition is associated with white matter alterations in cognitively normal adults during the adult life span

Cerebrospinal fluid and plasma neurofilament light relate to abnormal cognition

Investigating APOE, APP-Aβ metabolism genes and Alzheimer’s disease GWAS hits in brain small vessel ischemic disease

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