Diffusion abnormality in posterior cingulate fiber tracts in Alzheimer’s disease: tract-specific analysis

Purpose

The aim of this study was to determine diffusion abnormalities in the posterior cingulate fiber tracts (PCFTs) in patients with Alzheimer’s disease (AD) by diffusion tensor tractography (DTT).

Materials and methods

We studied 23 AD patients and 18 age-matched normal controls who underwent magnetic resonance imaging using diffusion tensor imaging (DTI). DTT of PCFTs was generated from DTI. Mean diffusivity (MD) and fractional anisotropy (FA) were measured in co-registered voxels along with DTT of PCFTs. Student’s t-test was used to compare results between the AD patients and normal controls.

Results

The MD in PCFTs was significantly higher in AD patients than in normal controls (P = 0.019). The FA in PCFTs was significantly lower in AD patients than in normal controls (P = 0.007).

Conclusion

The abnormal MD increase and FA decrease, which is considered to indicate a net loss of barriers that restrict water molecular motion and tissue anisotropy of white matter, is consistent with neuropathological data that demonstrate partial loss of myelin, axons, and oligodendrial cells in white matter of AD brains. Our results suggest that MD and FA reflect progression of AD-related histopathological changes in the PCFTs and may represent a useful biological index for monitoring AD.     

Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer’s disease cases

Purpose

The activity of the glymphatic system is impaired in animal models of Alzheimer’s disease (AD). We evaluated the activity of the human glymphatic system in cases of AD with a diffusion-based technique called diffusion tensor image analysis along the perivascular space (DTI-ALPS).

Materials and methods

Diffusion tensor images were acquired to calculate diffusivities in the x, y, and z axes of the plane of the lateral ventricle body in 31 patients. We evaluated the diffusivity along the perivascular spaces as well as projection fibers and association fibers separately, to acquire an index for diffusivity along the perivascular space (ALPS-index) and correlated them with the mini mental state examinations (MMSE) score.

Results

We found a significant negative correlation between diffusivity along the projection fibers and association fibers. We also observed a significant positive correlation between diffusivity along perivascular spaces shown as ALPS-index and the MMSE score, indicating lower water diffusivity along the perivascular space in relation to AD severity.

Conclusion

Activity of the glymphatic system may be evaluated with diffusion images. Lower diffusivity along the perivascular space on DTI-APLS seems to reflect impairment of the glymphatic system. This method may be useful for evaluating the activity of the glymphatic system.

     

Evaluation of white matter damage in patients with Alzheimer’s disease and in patients with mild cognitive impairment by using diffusion tensor imaging

Purpose

The objective of this study was to evaluate white matter tissue damage in patients with Alzheimer’s disease (AD) and in patients with mild cognitive impairment (MCI) using diffusion tensor imaging (DTI).

Materials and methods

Forty-seven subjects were evaluated: 14 patients with AD, 15 with MCI and 18 healthy volunteers. All subjects were studied using conventional magnetic resonance imaging (MRI) and DTI (32 directions) with a 1.5 T magnet. Fractional anisotropy (FA) was measured in the following regions: frontal, occipital, parietal and temporal white matter and in the genu and splenium of the corpus callosum. The results were compared between the different groups and correlated with the Mini-Mental State Evaluation (MMSE) scores.

Results

A statistically significant difference was obtained between controls and MCI patients (p<0.007) and between controls and AD patients (p<0.05) with regard to FA of the white matter in the splenium. A statistically significant difference was obtained between controls and AD patients with regard to FA in the genu (p<0.016). Moreover, there was a statistically significant difference between controls and AD patients considering the genu (p<0.016) and the frontal white matter on the right side (p<0.024). The MMSE scores correlated with the FA values measured in the genu, the splenium and frontal white matter on the right side. No significant differences were identified between patients with AD and those with MCI.

Conclusions

DTI could be of value in the early detection of white-matter damage in patients with MCI and AD. The DTI values correlate with the neuropsychological tests.     

Amyloid PET imaging in Alzheimer’s disease: a comparison of three radiotracers

Purpose

The increasing use of amyloid PET in Alzheimer’s disease research and clinical trials has motivated efforts to standardize methodology. We compared retention of the ¹¹C radiotracer Pittsburgh Compound B (PiB) and that of two ¹⁸F amyloid radiotracers (florbetapir and flutemetamol) using two study populations. We also examined the feasibility of converting between tracer-specific measures, using PiB as the common link between the two ¹⁸F tracers.

Methods

One group of 40 subjects underwent PiB and flutemetamol imaging sessions and a separate group of 32 subjects underwent PiB and florbetapir imaging sessions. We compared cortical and white matter retention for each ¹⁸F tracer relative to that of PiB, as well as retention in several reference regions and image analysis methods. Correlations between tracer pairs were used to convert tracer-specific threshold values for amyloid positivity between tracers.

Results

Cortical retention for each pair of tracers was strongly correlated regardless of reference region (PiB–flutemetamol, ρ?=?0.84–0.99; PiB–florbetapir, ρ?=?0.83–0.97) and analysis method (ρ?=?0.90–0.99). Compared to PiB, flutemetamol had higher white matter retention, while florbetapir had lower cortical retention. Two previously established independent thresholds for amyloid positivity were highly consistent when values were converted between tracer pairs.

Conclusion

Despite differing white and grey matter retention characteristics, cortical retention for each ¹⁸F tracer was highly correlated with that of PiB, enabling conversion of thresholds across tracer measurement scales with a high level of internal consistency. Standardization of analysis methods and measurement scales may facilitate the comparison of amyloid PET data obtained using different tracers.     

An enhanced voxel-based morphometry method to investigate structural changes: application to Alzheimer’s disease

Introduction  

When characterizing regional cerebral gray matter differences in structural magnetic resonance images (sMRI) by voxel-based morphometry (VBM), one faces a known drawback of VBM, namely that histogram unequalization in the intensity images introduces false-positive results.     

Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease

Purpose

The cannabinoid type 2 receptor (CB₂R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB₂R is primarily found on microglia. CB₂R upregulation has been reported in animal models of Alzheimer’s disease, with a preferential localization near amyloid beta (Aβ) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB₂R tracer [¹¹C]NE40 in healthy controls (HC) and in patients with Alzheimer’s disease (AD) to investigate whether higher CB₂R availability regionally colocalized to Aβ deposits is present in vivo.

Methods

Dynamic 90-min [¹¹C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [¹¹C]PIB scan 40 min after injection. In four HC, a retest scan with [¹¹C]NE40 PET was performed within 9 weeks to investigate test–retest characteristics.

Results

[¹¹C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time–activity curves best; both binding potential (BP_ND) and distribution volume (V _T) parameters could be used. Brain uptake was generally low with an average K ₁ value of 0.07 ml/min/ml tissue. V _T and BP_ND were in the range of 0.7 – 1.8 and 0.6 – 1.6, respectively. Test values in HC were about 30 % for V _T and BP_ND. AD patients showed overall significantly lower CB₂R binding. No relationship was found between regional or global amyloid load and CB₂R availability.

Conclusion

Kinetic modelling of [¹¹C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [¹¹C]NE40 PET shows lower CB₂R availability in vivo in AD patients, with no relationship to Aβ plaques. A possible explanation for these findings is that [¹¹C]NE40 binds to CB₂R with lower affinity and/or selectivity than to CB₁R.

     

Quantitative analysis of the effects of donepezil on regional cerebral blood flow in Alzheimer’s disease by using an automated program, 3DSRT

INTRODUCTION: Donepezil, an acetylcholinesterase inhibitor, has been reported to have an effect that improves cerebral blood flow (CBF) alongside its primary effect on memory function. The aim of this study was to investigate the effects of long-term, low-dose donepezil therapy on blood perfusion in Alzheimer's disease (AD) by using a fully automated regional CBF quantification program named 3DSRT. MATERIALS AND METHODS: Fifteen subjects with mild to moderate AD according to NINCDS/ADRDA criteria underwent 99mTc-ethylcysteinate dimer (ECD) brain perfusion single photon emission computed tomography (SPECT) twice with an interval of 55.1 +/- 11.0 weeks. The dose of donepezil was fixed at 5 mg/day following the induction period (3 mg/day) of 2 weeks. Clinical efficacy of donepezil was assessed by using the Mini-Mental State Examination (MMSE). The results of SPECT imaging under exactly identical conditions were analyzed by 3DSRT, which enables us to perform a very objective assessment. RESULTS: Despite a decrease of the MMSE score from 20.9 +/- 4.7 to 18.7 +/- 5.7, CBF was increased in almost all cerebral areas except the left temporal segment. The increase was statistically significant in the left callosomarginal, right central, and bilateral pericallosal and lenticular nucleus segments. CONCLUSION: Thus far, no direct cerebrovascular effects have been reported for donepezil. We hypothesize that these CBF-promoting effects of donepezil might be related to increased neuronal activity and enhanced connection of neurons.     

Alteration of putaminal fractional anisotropy in Parkinson’s disease: a longitudinal diffusion kurtosis imaging study

Purpose

In Parkinson’s disease (PD), pathological microstructural changes occur that may be detected using diffusion magnetic resonance imaging (dMRI). However, there are few longitudinal studies that explore the effect of disease progression on diffusion indices.

Methods

We prospectively included 76 patients with PD and 38 healthy controls (HC), all of whom underwent diffusion kurtosis imaging (DKI) as part of the prospective Swedish BioFINDER study at baseline and 2 years later. Annualized rates of change in DKI parameters, including fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK), were estimated in the gray matter (GM) by placing regions of interest (ROIs) in the basal ganglia and the thalamus, and in the white matter (WM) by tract-based spatial statistics (TBSS) analysis.

Results

When adjusting for potential confounding factors (age, gender, baseline-follow-up interval, and software upgrade of MRI scanner), only a decrease in FA in the putamen of PD patients (β?=???0.248, P?<?.01) over 2 years was significantly different from the changes observed in HC over the same time period. This 2-year decrease in FA in the putamen in PD correlated with higher l-dopa equivalent dose at baseline (Spearman’s rho?=?.399, P?<?.0001).

Conclusion

The study indicates that in PD microstructural changes in the putamen occur selectively over a 2-year period and can be detected with DKI.

     

Precuneus atrophy in early-onset Alzheimer’s disease: a morphometric structural MRI study

Introduction Alzheimer’s disease (AD) usually first presents in elderly patients, but may also develop at an earlier age. Patients with an early age at onset tend to present with complaints other than memory impairment, such as visuospatial problems or apraxia, which may reflect a different distribution of cortical involvement. In this study we set out to investigate whether age at onset in patients with AD determines the pattern of atrophy on cerebral MRI scans. Methods We examined 55 patients with AD over a wide age range and analyzed their 3-D T1-weighted structural MRI scans in standard space using voxel-based morphometry (VBM). Regression analysis was performed to estimate loss of grey matter as a function of age, corrected for mini-mental state examination (MMSE) scores and sex. Results The VBM analyses identified multiple areas (including the temporal and parietal lobes), showing more atrophy with advancing age. By contrast, a younger age at onset was found to be associated with lower grey matter density in the precuneus. Regionalized volumetric analysis of this region confirmed the existence of disproportionate atrophy in the precuneus in patients with early-onset AD. Application of a multivariate model with precuneus grey matter density as input, showed that precuneal and hippocampal atrophy are independent from each other. Additionally, we found that a smaller precuneus is associated with impaired visuospatial functioning. Conclusion Our findings support the notion that age at onset modulates the distribution of cortical involvement, and that disproportionate precuneus atrophy is more prominent in patients with a younger age of onset.     

Role of DWI and MRS in diagnosis of Alzheimer’s and pre-Alzheimer’s disease

Background and purpose

Alzheimer’s disease (AD) is a major cause of dementia in elderly affecting about 30% above the age of 85 years, while mild cognitive impairment (MCI) is the impairment in cognitive functions with intact daily life activities which is described as the preclinical phase of AD.

Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease

The demographics of aging suggest a great need for the early diagnosis of dementia and the development of preventive strategies. Neuropathology and structural MRI studies have pointed to the medial temporal lobe (MTL) as the brain region earliest affected in Alzheimer's disease (AD). MRI findings provide strong evidence that in mild cognitive impairments (MCI), AD-related volume losses can be reproducibly detected in the hippocampus, the entorhinal cortex (EC) and, to a lesser extent, the parahippocampal gyrus; they also indicate that lateral temporal lobe changes are becoming increasingly useful in predicting the transition to dementia. Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging has revealed glucose metabolic reductions in the parieto-temporal, frontal and posterior cingulate cortices to be the hallmark of AD. Overall, the pattern of cortical metabolic changes has been useful for the prediction of future AD as well as in distinguishing AD from other neurodegenerative diseases. FDG-PET on average achieves 90% sensitivity in identifying AD, although specificity in differentiating AD from other dementias is lower. Moreover, recent MRI-guided FDG-PET studies have shown that MTL hypometabolism is the most specific and sensitive measure for the identification of MCI, while the utility of cortical deficits is controversial. This review highlights cross-sectional, prediction and longitudinal FDG-PET studies and attempts to put into perspective the value of FDG-PET in diagnosing AD-like changes, particularly at an early stage, and in providing diagnostic specificity. The examination of MTL structures, which has so far been exclusive to MRI protocols, is then examined as a possible strategy to improve diagnostic specificity. All told, there is considerable promise that early and specific diagnosis is feasible through a combination of imaging modalities.     

The effect of education on rCBF changes in Alzheimer’s disease: a longitudinal SPECT study

Purpose  To determine the relationship of differing levels of education on regional cerebral blood flow (rCBF) in patients with Alzheimer’s disease (AD). Methods  Fifty-three patients with AD followed-up for an average of 36 months were divided into the high-educated group (HE, ≥12 years of schooling) and low-educated group (LE, <12 years of schooling). The cognitive and functional impairment was assessed using the Mini-Mental State Examination (MMSE) and the Functional Assessment Staging (FAST), respectively. Initial and follow-up rCBF were assessed using SPECT with N-isopropyl-p-[¹²³I]-iodoamphetamine and the SPECT data were analyzed by 3D-stereotactic surface projections. Results  At initial evaluation, the HE group had greater rCBF deficits in the parietotemporal regions than did the LE group, even though both groups had comparable MMSE and FAST scores. When compared with initial SPECT, follow-up SPECT showed a significant rCBF reduction in widespread regions, including the frontal, parietal, temporal, and limbic lobes of the HE group, while it a significant rCBF reduction in scattered and small regions of the parietotemporal, cingulate, and occipital areas of the LE group, as the HE group had faster cognitive and functional decline than the LE group. Conclusion  The HE group showed lower rCBF at initial SPECT than the LE group, suggesting more advanced AD pathology. As a result, the HE group demonstrated a more extensive and severe reduction of rCBF on follow-up SPECT in association with faster cognitive and functional decline than the LE group. Our SPECT study provides stronger support for the cognitive reserve effects of education in AD.