The effect of raloxifene on bone marrow adipose tissue and bone turnover in postmenopausal women with osteoporosis.

In patients with postmenopausal osteoporosis low bone volume is associated with high bone marrow adipose tissue (MAT). Moreover, high MAT is associated with increased fracture risk. This suggests an interaction between MAT and bone turnover, however literature remains equivocal. Estrogen treatment decreases MAT, but the effect of raloxifene, a selective estrogen receptor modulator (SERM) registered for treatment of postmenopausal osteoporosis, on MAT is not known. The aim of this study is 1] to determine the effect of raloxifene on MAT and 2] to determine the relationship between MAT and bone turnover in patients with osteoporosis. Bone biopsies from the MORE trial were analyzed. The MORE trial investigated the effects of raloxifene 60 or 120mg per day versus placebo on bone metabolism and fracture incidence in patients with postmenopausal osteoporosis. We quantified MAT in iliac crest biopsies obtained at baseline and after 2years of treatment (n=53; age 68.2±6.2years). Raloxifene did not affect the change in MAT volume after 2years compared to baseline (placebo: 1.89±10.84%, raloxifene 60mg: 6.31±7.22%, raloxifene 120mg: -0.77±10.72%), nor affected change in mean adipocyte size (placebo: 1.45 (4.45) µm, raloxifene 60mg: 1.45 (4.35) µm, raloxifene 120mg: 0.81 (5.21) µm). Adipocyte number tended to decrease after placebo treatment (-9.92 (42.88) cells/mm2) and tended to increase during raloxifene 60mg treatment (13.27 (66.14) cells/mm2) while adipocyte number remained unchanged in the raloxifene 120mg group, compared to placebo (3.06 (39.80) cells/mm2, Kruskal-Wallis p=0.055, post hoc: placebo vs raloxifene 60mg p=0.017). MAT volume and adipocyte size were negatively associated with osteoclast number at baseline (R2=0.123, p=0.006 and R2=0.098, p=0.016 respectively). Furthermore adipocyte size was negatively associated with osteoid surface (R2=0.067, p=0.049). Finally, patients with vertebral fractures had higher MAT volume (50.82 (8.80)%) and larger adipocytes (55.75 (3.14) µm) compared to patients without fractures (45.58 (12.72)% p=0.032, 52.77 (3.73) µm p=0.004 respectively). In conclusion, raloxifene did not affect marrow adipose tissue, but tended to increase adipocyte number compared to placebo. At baseline MAT volume and adipocyte size were associated with bone resorption, and adipocyte size was associated with osteoid surface, suggesting an interaction between bone marrow adipocytes and bone turnover. In addition, we found that high MAT volume and larger adipocyte size are associated with prevalent vertebral fractures in postmenopausal women with osteoporosis, indicating that adipocyte size affects bone quality independent of bone volume.

Correction to: Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline.

Upon publication of this article [1], it was noticed that there were some inconsistencies in Tables 1, 2 and 3. Some of the superscript letters were incorrectly assigned. Please see below the correct tables.

Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline.

BACKGROUND: Cerebrovascular disease (CVD) and amyloid-ß (Aß) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aß on neurodegenerative markers and cognition in patients without dementia. METHODS: We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aß1-42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aß and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (-) of Aß and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics. RESULTS: MTA and t-tau were elevated in the Aß - WMH+, Aß + WMH-, and Aß + WMH+ groups. MTA was most severe in the Aß + WMH+ group compared with the groups with a single pathology. Both WMH and Aß were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline. CONCLUSIONS: In the present study, we found an additive association of Aß and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up.

Predicting progression to dementia in persons with mild cognitive impairment using cerebrospinal fluid markers.

INTRODUCTION: We aimed to determine the added value of cerebrospinal fluid (CSF) to clinical and imaging tests to predict progression from mild cognitive impairment (MCI) to any type of dementia. METHODS: The risk of progression to dementia was estimated using two logistic regression models based on 250 MCI participants: the first included standard clinical measures (demographic, clinical, and imaging test information) without CSF biomarkers, and the second included standard clinical measures with CSF biomarkers. RESULTS: Adding CSF improved predictive accuracy with 0.11 (scale from 0-1). Of all participants, 136 (54%) had a change in risk score of 0.10 or higher (which was considered clinically relevant), of whom in 101, it was in agreement with their dementia status at follow-up. DISCUSSION: An individual person's risk of progression from MCI to dementia can be improved by relying on CSF biomarkers in addition to recommended clinical and imaging tests for usual care.

The Diagnostic and Prognostic Value of Neuropsychological Assessment in Memory Clinic Patients.

BACKGROUND: Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown. OBJECTIVE: To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients. METHODS: In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer's disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments. RESULTS: With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n = 1) correctly reclassified, etiology: NRI = -0.05, prognosis: NRI = -0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%. CONCLUSION: Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.

Cortical phase changes measured using 7-T MRI in subjects with subjective cognitive impairment, and their association with cognitive function.

Studies have suggested that, in subjects with subjective cognitive impairment (SCI), Alzheimer's disease (AD)-like changes may occur in the brain. Recently, an in vivo study has indicated the potential of ultra-high-field MRI to visualize amyloid-beta (Aß)-associated changes in the cortex in patients with AD, manifested by a phase shift on T2 *-weighted MRI scans. The main aim of this study was to investigate whether cortical phase shifts on T2 *-weighted images at 7 T in subjects with SCI can be detected, possibly implicating the deposition of Aß plaques and associated iron. Cognitive tests and T2 *-weighted scans using a 7-T MRI system were performed in 28 patients with AD, 18 subjects with SCI and 27 healthy controls (HCs). Cortical phase shifts were measured. Univariate general linear modeling and linear regression analysis were used to assess the association between diagnosis and cortical phase shift, and between cortical phase shift and the different neuropsychological tests, adjusted for age and gender. The phase shift (mean, 1.19; range, 1.00-1.35) of the entire cortex in AD was higher than in both SCI (mean, 0.85; range, 0.73-0.99; p < 0.001) and HC (mean, 0.94; range, 0.79-1.10; p < 0.001). No AD-like changes, e.g. increased cortical phase shifts, were found in subjects with SCI compared with HCs. In SCI, a significant association was found between memory function (Wechsler Memory Scale, WMS) and cortical phase shift (ß = -0.544, p = 0.007). The major finding of this study is that, in subjects with SCI, an increased cortical phase shift measured at high field is associated with a poorer memory performance, although, as a group, subjects with SCI do not show an increased phase shift compared with HCs. This increased cortical phase shift related to memory performance may contribute to the understanding of SCI as it is still unclear whether SCI is a sign of pre-clinical AD. Copyright © 2014 John Wiley & Sons, Ltd.

7T T2*-weighted magnetic resonance imaging reveals cortical phase differences between early- and late-onset Alzheimer's disease.

The aim of this study is to explore regional iron-related differences in the cerebral cortex, indicative of Alzheimer's disease pathology, between early- and late-onset Alzheimer's disease (EOAD, LOAD, respectively) patients using 7T magnetic resonance phase images. High-resolution T2(∗)-weighted scans were acquired in 12 EOAD patients and 17 LOAD patients with mild to moderate disease and 27 healthy elderly control subjects. Lobar peak-to-peak phase shifts and regional mean phase contrasts were computed. An increased peak-to-peak phase shift was found for all lobar regions in EOAD patients compared with LOAD patients (p < 0.05). Regional mean phase contrast in EOAD patients was higher than in LOAD patients in the superior medial and middle frontal gyrus, anterior and middle cingulate gyrus, postcentral gyrus, superior and inferior parietal gyrus, and precuneus (p ≤ 0.042). These data suggest that EOAD patients have an increased iron accumulation, possibly related to an increased amyloid deposition, in specific cortical regions as compared with LOAD patients.

Cortical phase changes in Alzheimer's disease at 7T MRI: a novel imaging marker.

BACKGROUND: Postmortem studies have indicated the potential of high-field magnetic resonance imaging (MRI) to visualize amyloid depositions in the cerebral cortex. The aim of this study is to test this hypothesis in patients with Alzheimer's disease (AD). METHODS: T2*-weighted MRI was performed in 16 AD patients and 15 control subjects. All magnetic resonance images were scored qualitatively by visual assessment, and quantitatively by measuring phase shifts in the cortical gray matter and hippocampus. Statistical analysis was performed to assess differences between groups. RESULTS: Patients with AD demonstrated an increased phase shift in the cortex in the temporoparietal, frontal, and parietal regions (P < .005), and this was associated with individual Mini-Mental State Examination scores (r = -0.54, P < .05). CONCLUSION: Increased cortical phase shift in AD patients demonstrated on 7-tesla T2*-weighted MRI is a potential new biomarker for AD, which may reflect amyloid pathology in the early stages.

The Dutch Parelsnoer Institute--Neurodegenerative diseases; methods, design and baseline results.

BACKGROUND: The Parelsnoer Institute is a collaboration between 8 Dutch University Medical Centers in which clinical data and biomaterials from patients suffering from chronic diseases (so called "Pearls") are collected according to harmonized protocols. The Pearl Neurodegenerative Diseases focuses on the role of biomarkers in the early diagnosis, differential diagnosis and in monitoring the course of neurodegenerative diseases, in particular Alzheimer's disease. The objective of this paper is to describe the design and methods of the Pearl Neurodegenerative Diseases, as well as baseline descriptive variables, including their biomarker profile. METHODS: The Pearl Neurodegenerative Diseases is a 3-year follow-up study of patients referred to a memory clinic with cognitive complaints. At baseline, all patients are subjected to a standardized examination, including clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. At present, in total more than 1000 patients have been included, of which cerebrospinal fluid and DNA samples are available of 211 and 661 patients, respectively. First descriptives of a subsample of the data (n = 665) shows that patients are diagnosed with dementia (45%), mild cognitive impairment (31%), and subjective memory complaints (24%). DISCUSSION: The Pearl Neurodegenerative Diseases is an ongoing large network collecting clinical data and biomaterials of more than 1000 patients with cognitive impairments. The project has started with data analyses of the baseline characteristics and biomarkers, which will be the starting point of future specific research questions that can be answered by this unique dataset.