Cerebral perfusion in the predementia stages of Alzheimer's disease

Objectives To investigate arterial spin-labelling (ASL) cerebral blood flow (CBF) changes in predementia stages of Alzheimer’s disease (AD). Methods Data were obtained from 177 patients with subjective complaints, mild cognitive impairment and AD from the Amsterdam Dementia Cohort. AD stages were based on diagnosis and cerebrospinal fluid biomarkers amyloid-β (Aβ) and total-tau (tau). General-linear-models were used to assess relationships between AD stages and total and regional CBF, correcting for age and sex. Results Decreasing CBF was related to more advanced AD stages in all supratentorial regions (p for trend < 0.05). Post-hoc testing revealed that CBF was lower in AD compared to controls and stage-1 predementia patients (i.e. abnormal Aβ and normal tau) in temporal and parietal regions, and compared to stage-2 predementia patients (i.e. abnormal Aβ and tau) in temporal regions. CBF values of stage-2 predementia patients were numerically in between those of stage-1 predementia patients and AD. Conclusion The continuing decrease of CBF along the continuum of AD indicates the potential of ASL-CBF as a measure for disease progression

Widespread disruption of functional brain organization in early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (AD) patients present a different clinical profile than late-onset AD patients. This can be partially explained by cortical atrophy, although brain organization might provide more insight. The aim of this study was to examine functional connectivity in early-onset and late-onset AD patients. Resting-state fMRI scans of 20 early-onset (<65 years old), 28 late-onset (≥65 years old) AD patients and 15 "young" (<65 years old) and 31 "old" (≥65 years old) age-matched controls were available. Resting-state network-masks were used to create subject-specific maps. Group differences were examined using a non-parametric permutation test, accounting for gray-matter. Performance on five cognitive domains were used in a correlation analysis with functional connectivity in AD patients. Functional connectivity was not different in any of the RSNs when comparing the two control groups (young vs. old controls), which implies that there is no general effect of aging on functional connectivity. Functional connectivity in early-onset AD was lower in all networks compared to age-matched controls, where late-onset AD showed lower functional connectivity in the default-mode network. Functional connectivity was lower in early-onset compared to late-onset AD in auditory-, sensory-motor, dorsal-visual systems and the default mode network. Across patients, an association of functional connectivity of the default mode network was found with visuoconstruction. Functional connectivity of the right dorsal visual system was associated with attention across patients. In late-onset AD patients alone, higher functional connectivity of the sensory-motor system was associated with poorer memory performance. Functional brain organization was more widely disrupted in early-onset AD when compared to late-onset AD. This could possibly explain different clinical profiles, although more research into the relationship of functional connectivity and cognitive performance is needed

MNI-coordinates (MNI 152, 2 mm) of peak voxel and total number of voxels that showed significant lower functional connectivity within the resting-state networks (RSNs) when comparing early-onset AD (EOAD) patients with age-matched young healthy controls (HC), when comparing late-onset AD (LOAD) patients with age-matched old HC and in a direct comparison between early-onset AD and late-onset AD patients.

<p>Number of voxels are reported when using the FWE corrected p<0.05 and when correcting also for the number of tests (8 RSNs×4 groups) resulting in FWE corrected p<0.0016.</p

Lowered functional connectivity in AD patients when compared to age-matched controls.

<p>Upper panel shows lower functional connectivity in early-onset AD patients when compared to ‘young’ age-matched controls. Lower panel shows decreased functional connectivity in late-onset AD patients (EOAD) when compared to ‘old’ age-matched controls. Standard maps of the Resting State Networks (RSNs) are shown in transparent blue. Upper panel: Lower functional connectivity was found in early-onset AD patients when compared to aged-matched young controls within the medial-visual system, lateral-visual system, auditory system, sensory-motor system, default mode network, the executive control network and bilateral dorsal-visual stream. Lower panel: late-onset AD patients (LOAD) show lower functional connectivity when compared to old age-matched controls within the default mode network only. Results are displayed in radiological orientation on standard MNI space (MNI152 2 mm), after correction for multiple comparisons across space (p<0.05). Gender and voxel-wise gray matter maps were used as covariates. Brighter colors represent most significant results. Abbreviations: R = right. L = left.</p

Subject characteristics for early-onset Alzheimer’s disease (AD) patients (disease onset <65 years), late-onset AD patients (disease onset ≥65 years), young (<65 years) - and old (≥65 years) healthy age-matched controls (HC).

<p>Data are presented as means ± standard deviations.</p><p>Mini Mental State Examination (MMSE) score and Normalized Gray Matter Volume (NGMV) in litre (L). Level of education using Verhage’s classification <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102995#pone.0102995-Verhage1" target="_blank">[44]</a>. Not applicable (n.a.). Alzheimer’s disease (AD). Healthy controls (HC).</p><p>*All AD patients that were on AD medication used Reminyl, with exception of 1 early-onset AD patient, who used Exelon. Both are competitive and reversible cholinesterase inhibitors.</p>♦<p>significantly different from early-onset AD.</p>¶<p>significantly different from late-onset AD.</p>†<p>significantly different from young controls.</p>‡<p>significantly different from old controls.</p

Gray matter loss.

<p>Regions of decreased gray matter volume in early-onset AD (EOAD) patients when compared to age-matched young controls (A). Regions of decreased gray matter volume in late-onset AD (LOAD) patients when compared to age-matched old controls (B). Regions of decreased gray matter volume in early-onset AD patients when compared to late-onset AD (C). Regions of decreased gray matter volume in late-onset AD patients when compared to early-onset AD (D). Results are corrected for multiple comparisons (p<0.05) and are shown in radiological orientation on standard MNI space (MNI152 2 mm). Brighter colors represent most significant results. R = Right. L = Left.</p

Functional connectivity in early-onset AD patients compared to late-onset AD patients.

<p>Standard maps of the Resting State Networks (RSNs) are shown in transparent blue. Lower functional connectivity was found in early-onset AD (EOAD) patients when compared to late-onset AD (LOAD) patients within the default mode network, the auditory system, the sensory-motor system, and bilateral dorsal visual system. Results are displayed in radiological orientation on standard MNI space (MNI152 2 mm), after correction for multiple comparisons (p<0.05). Gender and voxel-wise gray matter maps were used as covariates. Brighter colors represent most significant results. Abbreviations: R = right. L = left.</p

Significant correlations of functional connectivity with cognition in AD patients.

<p>Scatterplots of significant Spearman correlations across AD patients are shown; mean z-scores representing functional connectivity within the resting state network (RSNs) are displayed on the y-axis. Mean z-scores composing the cognitive domains are displayed on the x-axis. Functional connectivity of the right dorsal visual stream (A) was associated with attention. Functional connectivity of the default mode network (B) was associated with visuo-construction. Black squares represent early-onset (EOAD), white squares represent late-onset AD patients (LOAD). Spearman correlation coefficients (ρ) are reported, with corresponding p-value and number of subjects included in the correlation analysis.</p