Lower cerebral blood flow is associated with faster cognitive decline in Alzheimer's disease.

OBJECTIVE: To determine whether lower cerebral blood flow (CBF) is associated with faster cognitive decline in patients with Alzheimer's disease (AD). METHODS: We included 88 patients with dementia due to AD from the Amsterdam Dementia Cohort. Mean follow-up was 2 ± 1 years. Linear mixed models were used to determine associations of lower whole brain and regional pseudo-continuous arterial spin labelling measured CBF with rate of cognitive decline as measured with repeated mini-mental state examination (MMSE). Model 1 was adjusted for age, sex, and education. Model 2 was additionally adjusted for normalized gray matter volume, medial temporal lobe atrophy, white matter hyperintensities, microbleeds, and lacunes. Analyses were repeated after partial volume correction (PVC) of CBF. Statistical significance was set at p ≤ 0.05. RESULTS: Patients were 65 ± 7 years old, 44 (50 %) were women, and mean baseline MMSE was 22 ± 4. Annual decline (ß[SE]) on the MMSE was estimated at -2.11 (0.25) points per year. Lower whole brain (ß[SE]-0.50[0.25]; p ≤ 0.05) and parietal (ß[SE]-0.59[0.25]; p < 0.05) CBF were associated with faster cognitive decline. PVC cortical CBF was not associated with cognitive decline. CONCLUSIONS: Lower CBF, in particular in the posterior brain regions, may have value as a prognostic marker for rate of cognitive decline in AD. KEY POINTS: • In AD, lower CBF is associated with more rapid cognitive decline. • Decreasing CBF does not reach a plateau early in AD. • PcASL-CFB has additive value to conventional structural MRI measures in AD.

Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer's disease.

INTRODUCTION: We examined the association between decreased cerebral blood flow (CBF) and cognitive impairment in Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD). METHODS: We included 161 AD, 95 MCI, and 143 SCD patients from the Amsterdam Dementia Cohort. We used 3-T pseudo-continuous arterial spin labeling to estimate whole-brain and regional partial volume-corrected CBF. Neuropsychological tests covered global cognition and five cognitive domains. Associations were investigated using linear regression analyses. RESULTS: In the whole sample, reduced overall and regional CBF was associated with impairment in all cognitive domains. We found significant interactions between diagnosis and CBF for language and between diagnosis and parietal CBF for global cognition and executive functioning. Stratification showed that decreased CBF was associated with worse performance in AD patients but not in MCI or SCD. DISCUSSION: Our results suggest that CBF may have potential as a functional marker of disease severity.

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-ß (Aß) 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 Aß and normal tau) in temporal and parietal regions, and compared to stage-2 predementia patients (i.e. abnormal Aß 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. KEY POINTS: • Decreasing CBF relates to more advanced AD stages in all supratentorial regions. • The reduction of CBF does not reach a bottom level. • ASL-CBF has potential as a measure for disease progression in AD.

Cerebral perfusion and glucose metabolism in Alzheimer's disease and frontotemporal dementia: two sides of the same coin?

OBJECTIVES: Alzheimer's disease (AD) and frontotemporal (FTD) dementia can be differentiated using [(18)F]-2-deoxy-2-fluoro-D-glucose (FDG)-PET. Since cerebral blood flow (CBF) is related to glucose metabolism, our aim was to investigate the extent of overlap of abnormalities between AD and FTD. METHODS: Normalized FDG-PET and arterial spin labelling (ASL-MRI)-derived CBF was measured in 18 AD patients (age, 64 ± 8), 12 FTD patients (age, 61 ± 8), and 10 controls (age, 56 ± 10). Voxel-wise comparisons, region-of-interest (ROI), correlation, and ROC curve analyses were performed. RESULTS: Voxel-wise comparisons showed decreased CBF and FDG uptake in AD compared with controls and FTD in both precuneus and inferior parietal lobule (IPL). Compared with controls and AD, FTD patients showed both hypometabolism and hypoperfusion in medial prefrontal cortex (mPFC). ASL and FDG were related in precuneus (r = 0.62, p < 0.001), IPL (r = 0.61, p < 0.001), and mPFC across groups (r = 0.74, p < 001). ROC analyses indicated comparable performance of perfusion and metabolism in the precuneus (AUC, 0.72 and 0.74), IPL (0.85 and 0.94) for AD relative to FTD, and in the mPFC in FTD relative to AD (both 0.68). CONCLUSIONS: Similar patterns of hypoperfusion and hypometabolism were observed in regions typically associated with AD and FTD, suggesting that ASL-MRI provides information comparable to FDG-PET. KEY POINTS: • Similar patterns of hypoperfusion and hypometabolism were observed in patients with dementia. • For both imaging modalities, parietal abnormalities were found in Alzheimer's disease. • For both imaging modalities, prefrontal abnormalities were found in frontotemporal dementia.

Brain network alterations in Alzheimer's disease measured by eigenvector centrality in fMRI are related to cognition and CSF biomarkers.

Recent imaging studies have demonstrated functional brain network changes in patients with Alzheimer's disease (AD). Eigenvector centrality (EC) is a graph analytical measure that identifies prominent regions in the brain network hierarchy and detects localized differences between patient populations. This study used voxel-wise EC mapping (ECM) to analyze individual whole-brain resting-state functional magnetic resonance imaging (MRI) scans in 39 AD patients (age 67 ± 8) and 43 healthy controls (age 69 ± 7). Between-group differences were assessed by a permutation-based method. Associations of EC with biomarkers for AD pathology in cerebrospinal fluid (CSF) and Mini Mental State Examination (MMSE) scores were assessed using Spearman correlation analysis. Decreased EC was found bilaterally in the occipital cortex in AD patients compared to controls. Regions of increased EC were identified in the anterior cingulate and paracingulate gyrus. Across groups, frontal and occipital EC changes were associated with pathological concentrations of CSF biomarkers and with cognition. In controls, decreased EC values in the occipital regions were related to lower MMSE scores. Our main finding is that ECM, a hypothesis-free and computationally efficient analysis method of functional MRI (fMRI) data, identifies changes in brain network organization in AD patients that are related to cognition and underlying AD pathology. The relation between AD-like EC changes and cognitive performance suggests that resting-state fMRI measured EC is a potential marker of disease severity for AD.

Amyloid and its association with default network integrity in Alzheimer's disease.

The purpose of this study was to investigate the association between functional connectivity and ß-amyloid depositions in the default mode network (DMN) in Alzheimer's disease (AD), patients with mild cognitive impairment (MCI), and healthy elderly. Twenty-five patients with AD, 12 patients with MCI, and 18 healthy controls were included in the study. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in the DMN. In parallel, amyloid burden was measured in the same subjects using positron emission tomography with carbon-11-labeled Pittsburgh Compound-B as amyloid tracer. Functional connectivity of the DMN and amyloid deposition within the DMN were not associated across all subjects or within diagnostic groups. Longitudinal studies are needed to examine if amyloid depositions precede aberrant functional connectivity in the DMN.

Distinct perfusion patterns in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies.

OBJECTIVES: To compare pseudo-continuous arterial spin-labelled (PCASL) magnetic resonance imaging (MRI) measured quantitative cerebral blood flow (CBF) of patients with frontotemporal dementia (FTD), dementia with Lewy Bodies (DLB), Alzheimer's disease (AD) and controls, in a region of interest (ROI) and voxel-wise fashion. METHODS: We analysed whole-brain 3D fast-spin-echo PCASL images of 20 FTD patients, 14 DLB patients, 48 AD patients and 50 controls from the Amsterdam Dementia Cohort. Regional CBF patterns were compared using analyses of variance for repeated measures. Permutation tests were used for voxel-wise comparisons. Analyses were performed using uncorrected and partial volume corrected (PVC) maps. All analyses were corrected for age and sex. RESULTS: There was an interaction between diagnosis and region (p < 0.001), implying differences in regional CBF changes between diagnostic groups. In AD patients, CBF was decreased in all supratentorial regions, most prominently so in the posterior regions. DLB patients showed lowest CBF values throughout the brain, but temporal CBF was preserved. Supratentorial PVC cortical CBF values were lowest in the frontal lobes in FTD patients, and in the temporal lobes in AD patients. CONCLUSIONS: Patients with AD, FTD and DLB display distinct patterns of quantitative regional CBF changes. 3D-PCASL may provide additional value in the workup of dementia patients. KEY POINTS: Patterns of regional CBF changes differ between AD, FTD and DLB patients. CBF is lower throughout the brain in DLB than AD and FTD. 3D-PCASL MRI is a potential non-invasive and easily accessible alternative to FDG-PET. 3D-PCASL MRI may be of additional value in the workup of dementia.

Functional segmentation of the hippocampus in the healthy human brain and in Alzheimer's disease.

In this study we segment the hippocampus according to functional connectivity assessed from resting state functional magnetic resonance images in healthy subjects and in patients with Alzheimer's disease (AD). We recorded the resting FMRI signal from 16 patients and 22 controls. We used seed-based functional correlation analyses to calculate partial correlations of all voxels in the hippocampus relative to characteristic regional signal changes in the thalamus, the prefrontal cortex (PFC) and the posterior cingulate cortex (PCC), while controlling for ventricular CSF and white matter signals. Group comparisons were carried out controlling for age, gender, hippocampal volume and brain volume. The strength of functional connectivity in each region also was correlated with neuropsychological measures. We found that the hippocampus can be segmented into three distinct functional subregions (head, body, and tail), according to the relative connectivity with PFC, PCC and thalamus, respectively. The AD group showed stronger hippocampus-PFC and weaker hippocampus-PCC functional connectivity, the magnitudes of which correlated with MMSE in both cases. The results are consistent with an adaptive role of the PFC in the context of progression of dysfunction in PCC during earlier stages of AD. Extension of our approach could integrate regional volume measures for the hippocampus with their functional connectivity patterns in ways that should increase sensitivity for assessment of AD onset and progression.

Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild cognitive impairment: a marker for disease severity.

PURPOSE: To compare quantitative cerebral blood flow (CBF) values in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and subjects with subjective complaints by using a whole-brain three-dimensional (3D) pseudocontinuous arterial spin-labeling (ASL) technique at 3.0 T. MATERIALS AND METHODS: The local institutional review board approved the study. All subjects provided informed consent. Whole-brain 3D fast spin-echo pseudocontinuous ASL images were acquired at 3.0 T in 71 patients with AD (mean age, 65 years ± 7; 55% women), 35 patients with MCI (mean age, 65 years ± 8; 42% women), and 73 subjects with subjective complaints (mean age, 60 years ± 9; 39% women) who visited a memory clinic. Analyses were performed by using both uncorrected maps and maps corrected for partial volume effects. Regional CBF was compared by using analyses of variance; permutation tests were used for voxel-wise comparisons. Associations with cognition (Mini-Mental State Examination) were investigated by using linear regression analyses. All analyses were corrected for age and sex. RESULTS: Uncorrected CBF was decreased in patients with AD compared with subjects with subjective complaints (27 mL/100 g/min ± 5 vs 33 mL/100 g/min ± 5; P < .001), with strongest reductions in the parietal lobes (22 mL/100 g/min ± 6 vs 30 mL/100 g/min ± 5; ie, decrease of 27%). Corrected cortical CBF showed similar results. In patients with MCI, CBF was decreased in the precuneus and the parietal and occipital lobes compared with subjects with subjective complaints. Voxel-wise comparisons confirmed the region of interest-based findings, showing the largest CBF differences in the precuneus and bilateral parietal cortex. Uncorrected and corrected cortical CBF were associated with cognition across diagnostic groups (ß = 0.46 and ß = 0.42, P < .001) and within the AD group (ß = 0.41 and ß = 0.42, P < .001). CONCLUSION: CBF measured with 3D pseudocontinuous ASL MR imaging helps detect functional changes in the prodromal and more advanced stages of AD and is a marker for disease severity.

Brain volume and white matter hyperintensities as determinants of cerebral blood flow in Alzheimer's disease.

To better understand whether decreased cerebral blood flow (CBF) in patients with Alzheimer's disease (AD) reflects neurodegeneration or cerebral small vessel disease, we investigated the associations of normalized brain volume (NBV) and white matter hyperintensity (WMH) volume with CBF. We included 129 patients with AD (66 ± 7 years, 53% female) and 61 age-matched controls (64 ± 5 years, 43% female). CBF was measured with pseudocontinuous arterial spin labeling at 3T in the whole brain and in partial volume corrected cortical maps. When NBV and WMH were simultaneously entered in age and sex adjusted models, smaller NBV was associated with lower whole brain (Stß: 0.29; p < 0.01) and cortical CBF (Stß: 0.28; p < 0.01) in patients with AD. Larger WMH volume was also associated with lower whole brain (Stß: -0.22; p < 0.05) and cortical CBF (Stß: -0.24; p < 0.05) in AD. Additional adjustments did not change these results. In controls, neither NBV nor WMH was associated with CBF. Our results indicate that in AD, lower CBF as measured using pseudocontinuous arterial spin labeling, reflects the combined disease burden of both neurodegeneration and small vessel disease.

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.

Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer's disease.

We investigated whether microbleeds and white matter hyperintensities (WMH) in Alzheimer's disease (AD) associate more with conventional vascular risk factors or with risk factors that reflect amyloid burden. A total of 371 patients with probable AD were included. WMH (Fazekas 2 or 3) were present in 107 (29%) patients and microbleeds were seen in 98 (26%). Patients with both microbleeds and WMH were older and presented more frequently with lacunes and multiple microbleeds than patients with microbleeds in isolation (all p < 0.05). Using multivariate regression models, we found that WMH presence showed independent associations with age, hypertension, current smoking, and lacune presence. Microbleeds were independently associated with male gender, higher blood pressure, lower cerebrospinal fluid Aß42, and apolipoprotein E ε4 homozygosity. Separate analyses for microbleeds according to their location showed that these associations were driven by microbleeds in lobar locations. Our results suggest that, unlike WMH, microbleeds in AD are particularly associated with additional amyloid burden, and as such, may relate to cerebral amyloid angiopathy.

Resting-state fMRI changes in Alzheimer's disease and mild cognitive impairment.

Regional functional connectivity (FC) of 39 patients with Alzheimer's disease (AD), 23 patients with mild cognitive impairment (MCI), and 43 healthy elderly controls was studied using resting-state functional magnetic resonance imaging (rs-fMRI). After a mean follow-up of 2.8 ± 1.9 years, 7 MCI patients converted to AD, while 14 patients remained cognitively stable. Resting-state functional magnetic resonance imaging scans were analyzed using independent component analysis (ICA), followed by a "dual-regression" technique to create and compare subject-specific maps of each independent spatiotemporal component, correcting for age, sex, and gray matter atrophy. AD patients displayed lower FC within the default-mode network (DMN) in the precuneus and posterior cingulate cortex compared with controls, independent of cortical atrophy. Regional FC values of MCI patients were numerically in between AD patients and controls, but only the difference between AD and stable MCI patients was statistically significant. Correlation with cognitive dysfunction demonstrated the clinical relevance of FC changes within the DMN. In conclusion, clinically relevant decreased FC within the DMN was observed in AD.