Lisa Quenon

Classification of Non-Demented Patients Attending a Memory Clinic using the New Diagnostic Criteria for Alzheimer's Disease with Disease-Related Biomarkers

BACKGROUND New diagnostic criteria for predemential Alzheimers disease (AD) advocate the use of biomarkers. However, the benefit of using biomarkers has not been clearly demonstrated in clinical practice. OBJECTIVE To investigate whether a combination of biomarkers may be helpful in classifying a population of non-demented patients attending a Memory Clinic. METHODS Sixty non-demented patients were compared with 31 healthy elderly subjects. All subjects underwent a neuropsychological examination, brain 3T magnetic resonance imaging, [F18]-fluorodeoxyglucose and [F18]-flutemetamol positron emission tomography. According to their performance on memory, language, executive, and visuo-spatial domains, the patients were classified as mild cognitive impairment (amnestic, non-amnestic, single, or multiple domain) or subjective cognitive impairment. Patients were then classified according to the National Institute on Aging-Alzheimers Association (NIA-AA) criteria, using the normalized mean hippocampal volume (Freesurfer), [F18]-FDG PALZAD, and [F18]-flutemetamol standard uptake value ratio (SUVr) (cut-off at the 10th percentile of controls). The standard of truth was the clinical status at study entry (patient versus control). RESULTS The sensitivity/specificity of the clinical classification was 65/84%. The NIA-AA criteria were applicable in 85% of patients and 87% of controls. For biomarkers the best sensitivity (72%) at a fixed specificity of 84% was achieved by a combination of the three biomarkers. The clinical diagnosis was reconsidered in more than one third of the patients (42%) as a result of including the biomarker results. CONCLUSIONS Application of the new NIA-AA AD diagnostic criteria based on biomarkers in an unselected sample of non-demented patients attending a Memory Clinic was useful in allowing for a better classification of the subjects.

Targretin Improves Cognitive and Biological Markers in a Patient with Alzheimer's Disease.

We present the effects of Targretin® (bexarotene) on cognition and biomarkers in a patient with mild Alzheimers disease (AD). Targretin® is a Retinoic X Receptor (RXR) agonist shown to improve synaptic and cognitive functions in animal models of AD by increasing neuronal cholesterol efflux. After 6 months of treatment with Targretin® 300 mg/day, memory improved by about 40% and the tau protein in the cerebrospinal fluid decreased by about 20% . No significant side effects were noticed. This observation in a single patient indicates that Targretin® may improve memory performance and biological markers at an early stage of AD.

Unirhinal Olfactory Testing for the Diagnostic Workup of Mild Cognitive Impairment

BACKGROUND Olfactory dysfunction is associated with Alzheimers disease (AD), and already present at pre-dementia stage. OBJECTIVES Based on the assumption that early neurodegeneration in AD is asymmetrical and that olfactory input is primarily processed in the ipsilateral hemisphere, we assessed whether unirhinal psychophysical and electrophysiological assessment of olfactory function can contribute to the diagnostic workup of mild cognitive impairment (MCI). METHODS Olfactory function of 13 MCI patients with positive amyloid PET, 13 aged-matched controls (AC) with negative amyloid PET and 13 patients with post-infectious olfactory loss (OD) was assessed unirhinally using (1) psychophysical testing of olfactory detection, discrimination and identification performance and (2) the recording of olfactory event-related brain potentials. Time-frequency analysis was used to enhance the signal-to-noise ratio of the electrophysiological responses. Psychophysical and electrophysiological assessment of auditory and trigeminal chemosensory function served as controls. RESULTS As compared to AC and OD, MCI patients exhibited a significant asymmetry of olfactory performance. This asymmetry efficiently discriminated between MCI and AC (sensitivity: 85% , specificity: 77% ), as well as MCI and OD (sensitivity: 85% , specificity: 70% ). There was also an asymmetry of the electrophysiological responses, but not specific for MCI. In both MCI and OD, olfactory stimulation of the best nostril elicited significantly more activity than stimulation of the worse nostril, between 3-7.5 Hz and 1.2-2.0 s after stimulus onset. Trigeminal and auditory psychophysical testing did not show any difference between groups. CONCLUSION MCI patients exhibit a marked asymmetry of behavioral olfactory function, which could be useful for the diagnostic workup of MCI.

Patients with Amyloid-Negative Mild Cognitive Impairment have Cortical Hypometabolism but the Hippocampus is Preserved.

BACKGROUND Patients with mild cognitive impairment (MCI) are at risk for Alzheimers dementia but the presence of amyloid (Aβ) strongly increases this risk. In clinical settings, when Aβ status is not available, different neurodegenerative markers are used to characterize MCI. The accuracy of these markers to discriminate between Aβ-and Aβ+ MCI is not yet determined. OBJECTIVE To compare different markers of neurodegeneration in Aβ-and Aβ+ MCI, with an Aβ-elderly control (EC) group. METHODS Patients with MCI (n = 39) and EC (n = 28) underwent MRI, 18F-FDG PET, and Aβ PET (18F-flutemetamol). We compared FDG and MRI biomarker values in cortical and hippocampal regions of interest, and using voxel-wise surface maps. We computed ROC curves discriminating between the three groups for each biomarker. RESULTS All biomarker values were reduced in Aβ+ MCI compared to EC (p < 0.001). Aβ-MCI had low cortical metabolism (p = 0.002), but hippocampal volume, cortical thickness, and hippocampal metabolism were not significantly different between Aβ-MCI and EC (p > 0.40). Cortical metabolism best discriminated between MCI and EC (AUC = 0.92/0.86, Aβ+/Aβ-) while hippocampal volume best discriminated between Aβ-MCI and Aβ+ MCI (AUC = 0.79). CONCLUSIONS Cortical hypometabolism was observed in both Aβ-MCI and Aβ+ MCI whereas hippocampal atrophy was mostly found in Aβ+ MCI. For MCI patients without available Aβ information, hippocampal atrophy is thus more informative about Aβ status than cortical hypometabolism.

Prediction of Free and Cued Selective Reminding Test Performance Using Volumetric and Amyloid-Based Biomarkers of Alzheimer's Disease.

OBJECTIVES Relatively few studies have investigated relationships between performance on clinical memory measures and indexes of underlying neuropathology related to Alzheimers disease (AD). This study investigated predictive relationships between Free and Cued Selective Reminding Test (FCSRT) cue efficiency (CE) and free-recall (FR) measures and brain amyloid levels, hippocampal volume (HV), and regional cortical thickness. METHODS Thirty-one older controls without memory complaints and 60 patients presenting memory complaints underwent the FCSRT, amyloid imaging using [F18]-flutemetamol positron emission tomography, and surface-based morphometry (SBM) using brain magnetic resonance imaging. Three groups were considered: patients with high (Aβ+P) and low (Aβ- P) amyloid load and controls with low amyloid load (Aβ- C). RESULTS Aβ+P showed lower CE than both Aβ- groups, but the Aβ- groups did not differ significantly. In contrast, FR discriminated all groups. SBM analyses revealed that CE indexes were correlated with the cortical thickness of a wider set of left-lateralized temporal and parietal regions than FR. Regression analyses demonstrated that amyloid load and left HV independently predicted FCSRT scores. Moreover, CE indexes were predicted by the cortical thickness of some regions involved in early AD, such as the entorhinal cortex. CONCLUSIONS Compared to FR measures, CE indexes appear to be more specific for differentiating persons on the basis of amyloid load. Both CE and FR performance were predicted independently by brain amyloid load and reduced left HV. However, CE performance was also predicted by the cortical thickness of regions known to be atrophic early in AD. (JINS, 2016, 22, 991-1004).

Investigating Associative Learning Effects in Patients with Prodromal Alzheimer's Disease Using the Temporal Context Model.

The purpose of this study was to investigate associative learning effects in patients with prodromal Alzheimers disease (prAD) by referring to the Temporal Context Model (TCM; Howard, Jing, Rao, Provyn, & Datey, 2009), in an attempt to enhance the understanding of their associative memory impairment. TCM explains fundamental effects described in classical free-recall tasks and cued-recall tasks involving overlapping word pairs (e.g., A-B, B-C), namely (1) the contiguity effect, which is the tendency to successively recall nearby items in a list, and (2) the observation of backward (i.e., B-A) and transitive associations (i.e., A-C) between items. In TCM, these effects are hypothesized to rely on contextual representation, binding and retrieval processes, which supposedly depend on hippocampal and parahippocampal regions. As these regions are affected in prAD, the current study investigated whether prAD patients would show reduced proportions of backward and transitive associations in free and cued-recall, coupled to a reduced contiguity effect in free-recall. Seventeen older controls and 17 prAD patients performed a cued-recall task involving overlapping word pairs and a final free-recall task. Proportions of backward and transitive intrusions in cued-recall did not significantly differ between groups. However, in free-recall, prAD patients demonstrated a reduced contiguity effect as well as reduced proportions of backward and transitive associations compared to older controls. These findings are discussed within the hypothesis that the contextual representation, binding and/or retrieval processes are affected in prAD patients compared to healthy older individuals.

The classification of nondemented people attending a memory clinic according to the NIA and Alzheimer's Association guidelines on Alzheimer's disease-related biomarkers

Background: Alzheimer’s disease (AD) has been considered as a synaptic failure (Selkoe, 2002). Accordingly, a marker of synaptic integrity/function would be useful to understand the early physiopathology of AD. The synaptic vesicle protein SV2A, involved in vesicle trafficking, shows an ubiquitous distribution in the brain. Levetiracetam, an antiepileptic acting through SV2A, was recently shown to reverse synaptic deficit in a mice AD model (Sanchez, 2012) as well as to reduce hippocampal hyperactivity and to improve cognition in amnestic mild cognitive impairment (Bakker, 2012). Methods: Several SV2A ligands from UCB Pharma were screened as candidates for radiolabeling. [18F]UCB-H was radiosynthesized and the brain distribution was studied by both tissue dissection in mice and with microPET in rats. The first cerebral distribution was observed in male human healthy volunteers (EudraCT 2011-003413-42). Results: [18F]UCB-H was synthesized with a high specific activity (more than 100 GBq/mmol). The radioligand crossed the blood-brain barrier and showed a high brain uptake in male C57BL/6 mice (18% of injected dose 5 min post injection, measured by tissue dissection). Blocking of [18F]UCB-H brain uptake after pre-administration of brivaracetam, a recently described SV2A ligand (Gillard, 2011), was demonstrated with microPET experiments in male Sprague Dawley rats. The inactive diastereomer of brivaracetam did not inhibit [18F]UCB-H uptake. Administration of 180 MBq of [18F]UCB-H to human healthy volunteers was shown to be safe, and total body exposure (total body radiation effective/absorbed dose) was below FDA and European accepted limits. Brain uptake was important and the distribution of the biomarker was ubiquitous in grey matter structures. A relatively rapid washout allowed a very good fit to the standard 2-tissue compartment model with a total distribution volume greater than 6 ml/ cm3 and a specific distribution volume around 3 ml/cm3. Conclusions: [18F]UCB-H is a new PET biomarker of brain SV2A proteins, is suitable for human studies, and should aid exploration of early cerebral network dysfunction at different stages of AD.

IMPROVED PREDICTION OF COGNITIVE PERFORMANCE USING A WEIGHTED LINEAR COMPOSITE OF BIOMARKERS OF ALZHEIMER’S DISEASE

Background:The facial emotion recognition (FER) is impaired in frontotemporal dementia (FTD), but the specific profiles of these performances in other dementia and neural correlates of each emotion are still not well-known. The purpose of this study was to identify the performance profiles of six facial emotion recognition among healthy elders (NC), mild cognitive impairment (MCI), Alzheimer’s disease (AD) and FTD, and was to investigate the neuroanatomical correlates of facial emotions. Methods:A total of 110 (33 NC, 32 MCI, 32 AD, 13 FTD) older adults were administered FER test and brain MRI. Voxel-based morphometry (VBM) was used to examine associations between FER scores. Results: Negative emotion (i.e., Fear, anger, disgust, sadness) discriminated well the FTD from other groups, whereas positive emotion (i.e., surprise, happiness) did not. A VBM analysis showed negative emotions were correlated with temporal lobes, whereas positive emotions were related to pre and post central gyrus. Conclusions: Focusing on the negative emotion system which is related to temporal atrophy is the effective way to discriminate healthy aging, mild cognitive impairment, Alzheimer’s disease from frontotemporal dementia.