Spatial decrease of synaptic density in amnestic mild cognitive impairment follows the tau build-up pattern.

Next to amyloid and tau, synaptic loss is a key pathological hallmark in Alzheimer's disease, closely related to cognitive dysfunction and neurodegeneration. Tau is thought to cause synaptic loss, but this has not been experimentally verified in vivo. In a 2-year follow-up study, dual tracer PET-MR was performed in 12 amnestic MCI patients using 18F-MK-6240 for tau and 11C-UCB-J for SV2A as a proxy for synaptic density. Tau already accumulated in the neocortex at baseline with progression in Braak V/VI at follow-up. While synaptic loss was limited to limbic regions at baseline, it followed the specific tau pattern to stage IV/V regions two years later, indicating that tau spread might drive synaptic vulnerability. Moreover, synaptic density changes correlated to changes in cognitive function. This study shows for the first time in vivo that synaptic loss regionally follows tau accumulation after two years, providing a disease-modifying window of opportunity for (combined) tau-targeting therapies.

Diagnostic Performance of Automated MRI Volumetry by icobrain dm for Alzheimer's Disease in a Clinical Setting: A REMEMBER Study.

BACKGROUND: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer's disease (AD) dementia (ADD) patients in selected research cohorts. OBJECTIVE: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis. METHODS: The study population included HC (n = 90), subjective cognitive decline (SCD, n = 93), mild cognitive impairment (MCI, n = 357), and ADD (n = 280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n = 820) images from a retrospective, multi-center study (REMEMBER), icobrain dm's (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages. RESULTS: icobrain dm outperformed FreeSurfer in processing time (15-30 min versus 9-32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC = 0.914; Specificity 83.0%; Sensitivity 86.3%). CONCLUSION: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting.

In vivo synaptic density loss is related to tau deposition in amnestic mild cognitive impairment.

OBJECTIVE: To investigate in vivo whether synaptic loss and neurofibrillary tangle load spatially overlap and correlate with clinical symptoms in patients with amnestic mild cognitive impairment (aMCI). METHODS: In this cross-sectional study, 10 patients with aMCI and 10 healthy controls underwent triple PET-MRI with 11C-UCB-J (synaptic vesicle protein 2A), 18F-MK-6240 (tau deposition), and 11C-Pittsburgh compound B (ß-amyloid) and neuropsychological assessment. Gray matter atrophy was assessed by voxel-based morphometry with T1-weighted MRIs. Voxel-wise and volume-of-interest analyses were conducted on PET data. The interrelationship of synaptic density and tau deposition was investigated. We also investigated correlations of 18F-MK-6240 and 11C-UCB-J binding with cognitive performance. RESULTS: Compared to controls, patients with aMCI showed a decreased 11C-UCB-J binding mainly in substructures of the medial temporal lobe (MTL; 48%-51%, p cluster = 0.02). Increased 18F-MK6240 binding in the same region was observed (42%-44%, p cluster = 0.0003), spreading to association cortices. In the MTL, higher 18F-MK-6240 binding inversely related to lower 11C-UCB-J binding (p = 0.02, r = -0.76). Decreased performance on cognitive tests was associated with both increased 18F-MK-6240 and decreased 11C-UCB-J binding in the hippocampus (p < 0.01, r > 0.7), although in a multivariate analysis only 18F-MK-6240 binding was significantly related to cognitive performance. CONCLUSIONS: Patients with aMCI have high tau deposition and synaptic density loss mainly in key regions known to be involved in early cognitive impairment, indicating that these are interrelated in the MTL, while tau binding had already spread toward association cortices. Longitudinal data are needed to provide further insight into the temporal aspects of this relationship.

Use of Flutemetamol F 18-Labeled Positron Emission Tomography and Other Biomarkers to Assess Risk of Clinical Progression in Patients With Amnestic Mild Cognitive Impairment.

Importance: Patients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were ß-amyloid positive vs those who were ß-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression. Objective: To evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD. Design, Setting, and Participants: In this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18-labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018. Interventions: Flutemetamol F 18-labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures. Main Outcomes and Measures: Time from PET to probable AD or last follow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD. Results: Of 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients), 53.6% (52 of 97) for patients with positive results detected on PET scan, and 22.8% (29 of 127) for patients with negative results detected on PET scan. Hazard ratios for association with progression were 2.51 (95% CI, 1.57-3.99; P < .001) for a positive ß-amyloid scan alone (primary outcome measure), 5.60 (95% CI, 3.14-9.98; P < .001) with additional low hippocampal volume, and 8.45 (95% CI, 4.40-16.24; P < .001) when poorer cognitive status was added to the model. Conclusions and Relevance: A combination of positive results of flutemetamol F 18-labeled PET, low hippocampal volume, and cognitive status corresponded with a high probability of risk of progression from aMCI to probable AD within 36 months.

A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER).

BACKGROUND: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD). OBJECTIVE: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. METHODS: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available. RESULTS: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment. CONCLUSION: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial.

OBJECTIVE: The most widely studied positron emission tomography ligand for in vivo beta-amyloid imaging is (11)C-Pittsburgh compound B ((11)C-PIB). Its availability, however, is limited by the need for an on-site cyclotron. Validation of the (18)F-labeled PIB derivative (18)F-flutemetamol could significantly enhance access to this novel technology. METHODS: Twenty-seven patients with early-stage clinically probable Alzheimer disease (AD), 20 with amnestic mild cognitive impairment (MCI), and 15 cognitively intact healthy volunteers (HVs) above and 10 HVs below 55 years of age participated. The primary endpoint was the efficacy of blinded visual assessments of (18)F-flutemetamol scans in assigning subjects to a raised versus normal uptake category, with clinical diagnosis as the standard of truth (SOT). As secondary objectives, we determined the correlation between the regional standardized uptake value ratios (SUVRs) for (18)F-flutemetamol and its parent molecule (11)C-PIB in 20 of the AD subjects and 20 of the MCI patients. We also determined test-retest variability of (18)F-flutemetamol SUVRs in 5 of the AD subjects. RESULTS: Blinded visual assessments of (18)F-flutemetamol scans assigned 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly HVs to the raised category, corresponding to a sensitivity of 93.1% and a specificity of 93.3% against the SOT. Correlation coefficients between cortical (18)F-flutemetamol SUVRs and (11)C-PIB SUVRs ranged from 0.89 to 0.92. Test-retest variabilities of regional SUVRs were 1 to 4%. INTERPRETATION: (18)F-Flutemetamol performs similarly to the (11)C-PIB parent molecule within the same subjects and provides high test-retest replicability and potentially much wider accessibility for clinical and research use.

Acquiring a dataset of labeled video images showing discomfort in demented elderly.

One of the effects of late-stage dementia is the loss of the ability to communicate verbally. Patients become unable to call for help if they feel uncomfortable. The first objective of this article was to record facial expressions of bedridden demented elderly. For this purpose, we developed a video acquisition system (ViAS) that records synchronized video coming from two cameras. Each camera delivers uncompressed color images of 1,024 x 768 pixels, up to 30 frames per second. It is the first time that such a system has been placed in a patient's room. The second objective was to simultaneously label these video recordings with respect to discomfort expressions of the patients. Therefore, we developed a Digital Discomfort Labeling Tool (DDLT). This tool provides an easy-to-use software representation on a tablet PC of validated "paper" discomfort scales. With ViAS and DDLT, 80 different datasets were obtained of about 15 minutes of recordings. Approximately 80% of the recorded datasets delivered the labeled video recordings. The remainder were not usable due to under- or overexposed images and due to the patients being out of view as the system was not properly replaced after care. In one of 6 observed patients, nurses recognized a higher discomfort level that would not have been observed without the DDLT.

Safety and efficacy of galantamine (Reminyl) in severe Alzheimer's disease (the SERAD study): a randomised, placebo-controlled, double-blind trial.

BACKGROUND: The efficacy of galantamine has been shown in patients with mild, moderate, and advanced moderate Alzheimer's disease (AD). Here we report its efficacy in patients with severe AD. METHODS: Between December, 2003, and March, 2007, patients aged 84 (SD 6) years with severe AD (mini-mental state examination [MMSE] score 5-12 points), in a nursing home setting were randomly assigned to receive galantamine (n=207), titrated initially to 24 mg/day, or placebo (n=200). Co-primary efficacy measures for cognitive function and ability to undertake normal daily activities were the severe impairment battery (SIB) and the seven-item minimum data set-activities of daily living (MDS-ADL), respectively. Adverse events, vital signs, laboratory parameters, and electrocardiograms were monitored. This trial is registered with ClinicalTrials.gov, number NCT00216593. FINDINGS: 168 of 207 (81%) patients in the galantamine group and 161 of 200 (81%) in the placebo group completed the study. Mean SIB scores increased (improved) by 1.9 (95% CI -0.1 to 3.9) points with galantamine and decreased (worsened) by 3.0 (-5.6 to -0.5) points with placebo (between-group least squares mean difference 4.36, 1.3 to 7.5; p=0.006). Mean MDS-ADL self-performance score worsened by 1.2 (0.6 to 1.8) points and 1.6 (0.8 to 2.3) points, respectively (between-group least squares mean difference -0.41, -1.3 to 0.5; p=0.383). Nominally significant between-group differences in favour of galantamine occurred for the SIB domains of memory (p=0.006), praxis (p=0.010), and visuospatial ability (p=0.002), and for the MDS-ADL subitem locomotion on unit (p=0.021). 183 of 207 patients (88%) who received galantamine and 177 of 200 (89%) who received placebo had adverse events, which were mostly mild to moderate. Eight patients (4%) in the galantamine group and 21 patients (11%) in the placebo group died. ECG abnormalities were similar between the two groups. INTERPRETATION: Galantamine can be started and used safely in elderly patients with severe AD. Galantamine improved cognitive function but failed to significantly improve the co-primary parameter of overall activities of daily living.