Research Article: Amyloid-independent atrophy patterns predict time to progression to dementia in mild cognitive impairment

Date Published: September 12, 2017

Publisher: BioMed Central

Author(s): Mara ten Kate, Frederik Barkhof, Pieter Jelle Visser, Charlotte E. Teunissen, Philip Scheltens, Wiesje M. van der Flier, Betty M. Tijms.


Amyloid pathology in subjects with mild cognitive impairment (MCI) is an important risk factor for progression to dementia due to Alzheimer’s disease. Predicting the onset of dementia is challenging even in the presence of amyloid, as time to progression varies considerably among patients and depends on the onset of neurodegeneration. Survival analysis can account for variability in time to event, but has not often been applied to MRI measurements beyond singular predefined brain regions such as the hippocampus. Here we used a voxel-wise survival analysis to identify in an unbiased fashion brain regions where decreased gray matter volume is associated with time to dementia, and assessed the effects of amyloid on these associations.

We included 276 subjects with MCI (mean age 67 ± 8, 41% female, mean Mini-Mental State Examination 26.6 ± 2.4), baseline 3D T1-weighted structural MRI, baseline cerebrospinal fluid (CSF) biomarkers, and prospective clinical follow-up. We fitted for each voxel a proportional Cox hazards regression model to study whether decreased gray matter volume predicted progression to dementia in the total sample, and stratified for baseline amyloid status.

Dementia at follow-up occurred in 122 (44%) subjects over an average follow-up period of 2.5 ± 1.5 years. Baseline amyloid positivity was associated with progression to dementia (hazard ratio 2.4, p < 0.001). Within amyloid-positive subjects, decreased gray matter volume in the hippocampal, temporal, parietal, and frontal regions was associated with more rapid progression to dementia (median (interquartile range) hazard ratio across significant voxels 1.35 (1.32–1.40)). Repeating the analysis in amyloid-negative subjects revealed similar patterns (median (interquartile range) hazard ratio 1.76 (1.66–1.91)). In subjects with MCI, both abnormal amyloid CSF and decreased gray matter volume were associated with future progression to dementia. The spatial pattern of decreased gray matter volume associated with progression to dementia was consistent for amyloid-positive and amyloid-negative subjects. The online version of this article (doi:10.1186/s13195-017-0299-x) contains supplementary material, which is available to authorized users.

Partial Text

Subjects with mild cognitive impairment (MCI) are at increased risk of dementia with annual conversion rates of 10–15% [1, 2]. According to the NIA–AA research criteria [3], a diagnosis of MCI due to AD requires the presence of amyloid pathology as measured in cerebrospinal fluid (CSF) or on amyloid PET. Since amyloid reaches a plateau relatively early in the disease course [4–6], it has limited prognostic value for the time to onset of dementia. Neuronal injury markers, such as brain atrophy measured with structural MRI, are more closely related to cognitive impairment and could thus be useful for estimating time to clinical progression [7–10]. Previous studies found that hippocampal atrophy can be used to predict time to dementia in MCI patients with positive amyloid markers [11, 12]. However, other brain regions may also be valuable for the prediction of progression, as indicated by voxel-based morphometry studies [13–15]. Two previous studies have used hypothesis-free voxel-level survival analyses to show that decreased gray matter in the medial temporal lobe and posterior cingulate cortex can predict time to conversion to AD-type dementia in nondemented subjects [16, 17]. However, it is still unclear whether such predictive atrophy patterns are specific for amyloid pathology.

Of the 276 subjects with MCI, 122 (44%) progressed to dementia. Among those who progressed to dementia, 104 (85%) subjects progressed to AD-type dementia and 18 (15%) subjects to another type of dementia (four fronto-temporal dementia, eight vascular dementia, one mixed vascular and AD, three Lewy body dementia, and two dementia unspecified). Clinical characteristics of subjects are summarized in Table 1. Subjects who progressed were on average older, had lower baseline scores on the Mini-Mental State Examination (MMSE), and had lower baseline CSF Aβ1–42 than subjects who remained stable. The groups had similar follow-up times. Subjects who were amyloid positive had a higher risk of progressing to dementia compared to amyloid-negative subjects (HR 2.4, p < 0.001). When stratifying for amyloid status, 160 subjects were amyloid positive and 99 (62%) of them showed clinical progression. Of those amyloid-positive subjects who progressed, most subjects progressed to AD-type dementia (n = 94, 95%). A total of 116 subjects were amyloid negative, of whom 23 (20%) subjects progressed. Amyloid-negative subjects more often progressed to non-AD dementias (57%) than AD-type dementia (43%). Within the amyloid-positive group, continuous CSF Aβ1–42 levels were unrelated to progression to dementia (HR 1.0, p = 0.8). Within the amyloid-negative group, continuous CSF Aβ1–42 levels were associated with an increased risk of progression to dementia (HR 2.2, p = 0.01).Table 1Subject characteristics according to progression and amyloid statusCharacteristicAll subjects (n = 276)Amyloid negative (n = 116)Amyloid positive (n = 160)StableProgressionStableProgressionStableProgressionNumber of subjects154 (56)122 (44)93 (80)23 (20)61 (38)99 (62)Age (years)65.5 ± 7.768.3 ± 8.1*63.8 ± 7.968.2 ± 8.7†68.2 ± 6.568.3 ± 8.0Male gender97 (63)67 (56)64 (69)16 (70)33 (54)51 (51)Education5.0 ± 1.54.9 ± 1.74.8 ± 1.75.0 ± 1.65.3 ± 1.24.9 ± 1.7MMSE27.0 ± 2.226.1 ± 2.6*27.0 ± 2.226.6 ± 2.527.0 ± 2.226.0 ± 2.6†CSF Aβ1–42794 ± 307534 ± 194*999 ± 207848 ± 172*481 ± 104462 ± 107WMH (Fazekas)0.99 ± 0.921.03 ± 0.800.88 ± 0.931.30 ± 1.021.15 ± 0.890.97 ± 0.73NGMV0.41 ± 0.040.39 ± 0.05*0.42 ± 0.040.39 ± 0.06*0.41 ± 0.040.39 ± 0.04†Follow-up (years)2.5 ± 1.52.6 ± 1.72.3 ± 1.42.8 ± 2.02.7 ± 1.72.6 ± 1.3Follow-up diagnosis AD–104 (85)–10 (43)–94 (95) DLB–3 (2)–2 (9)–1 (1) FTD–4 (3)–3 (13)–1 (1) VaD and mixed–9 (7)–6 (26)–3 (3) Other–2 (2)–2 (9)–0 (0)Data presented as mean ± SD or count (%)AD Alzheimer’s disease, CSF cerebrospinal fluid, DLB Lewy body dementia, FTD fronto-temporal dementia, MMSE Mini-Mental state examination, NGMV normalized gray matter volume, VaD vascular dementia, WMH white matter hyperintensities measured with 4-point Fazekas scale*p < 0.01 different from stable subjects†p < 0.05 different from stable subjects The main finding of this article is that a widespread pattern of decreased gray matter volume, beyond the hippocampal region, is predictive of time to progression to dementia in subjects with MCI. The presence of amyloid pathology was also a predictor of time to progression to dementia. The pattern of decreased gray matter volume that was predictive of progression was mostly similar in amyloid-positive and amyloid-negative subjects. Widespread decreases in gray matter volume are useful for the prediction of clinical progression and time to dementia in subjects with MCI. Findings were largely similar in subjects with and without evidence of amyloid pathology. This leads us to consider that although brain atrophy does not seem specific for the underlying pathology, it is a useful marker that reflects incipient dementia and thereby is valuable for predicting clinical progression.   Source:


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