Elderly Controls Research Articles

Stereoscopic Depth Perception and Visuospatial Dysfunction in Alzheimer's Disease.

With visuospatial dysfunction emerging as a potential marker that can detect Alzheimer’s disease (AD) even in its earliest stages and with disturbance in stereopsis suspected to be the prime contributor to visuospatial deficits in AD, we assessed stereoscopic abilities of patients with AD and mild cognitive impairment (MCI). Whereas previous research assessing patients’ stereoacuity has yielded mixed results, we assessed patients’ capacity to process coarse disparities that can convey adequate depth information about objects in the environment. We produced two virtual cubes at two different distances from the observer by manipulating disparity type (absolute vs. relative), disparity direction (crossed vs. uncrossed) and disparity magnitude, then had participants judge the object that appeared closer to them. Two patient groups performed as well as, or even better than elderly controls, suggesting that AD patients’ coarse disparity processing capacity is capable of supporting common tasks involving reaching, grasping, driving, and navigation. Results may help researchers narrow down the exact cause(s) of visuospatial deficits in AD and develop and validate measures to assess visuospatial dysfunction in clinical trials and disease diagnosis.

Microstructural and Cerebral Blood Flow Abnormalities in Subjective Cognitive Decline Plus: Diffusional Kurtosis Imaging and Three-Dimensional Arterial Spin Labeling Study.

Objective: To explore microstructural and cerebral blood flow (CBF) abnormalities in individuals with subjective cognitive decline plus (SCD plus) using diffusional kurtosis imaging (DKI) and three-dimensional (3D) arterial spin labeling (ASL).Methods: Twenty-seven patients with SCD plus, 31 patients with amnestic mild cognitive impairment (aMCI), and 33 elderly controls (ECs) were recruited and underwent DKI and 3D ASL using a GE 3.0-T MRI. Mean kurtosis (MK), fractional anisotropy (FA), mean diffusivity (MD), and CBF values were acquired from 24 regions of interest (ROIs) in the brain, including the bilateral hippocampal (Hip) subregions (head, body, and tail), posterior cingulate cortex (PCC), precuneus, dorsal thalamus subregions (anterior nucleus, ventrolateral nucleus, and medial nucleus), lenticular nucleus, caput nuclei caudati, white matter (WM) of the frontal lobe, and WM of the occipital lobe. Pearson's correlation analysis was performed to assess the relationships among the DKI-derived parameters, CBF values, and key neuropsychological tests for SCD plus.Results: Compared with ECs, participants with SCD plus showed a significant decline in MK and CBF values, mainly in the Hip head and PCC, and participants with aMCI exhibited more significant abnormalities in the MK and CBF values than individuals with ECs and SCD plus in multiple regions. Combined MK values showed better discrimination between patients with SCD plus and ECs than that obtained using CBF levels, with areas under the receiver operating characteristic (ROC) curve (AUC) of 0.874 and 0.837, respectively. Similarly, the AUC in discriminating SCD plus from aMCI patients obtained using combined MK values was 0.823, which was also higher than the combined AUC of 0.779 obtained using CBF values. Moreover, MK levels in the left Hip (h) and left PCC positively correlated with the auditory verbal learning test-delayed recall (AVLT-DR) score in participants with SCD plus. By contrast, only the CBF value in the left Hip head positively correlated with the AVLT-DR score.Conclusions: Our results provide new evidence of microstructural and CBF changes in patients with SCD plus. MK may be used as an early potential neuroimaging biomarker and may be a more sensitive DKI parameter than CBF at the very early stage of Alzheimer's disease (AD).

Mitochondrial Oxidative Stress and Damage Is Associated with age-related Glandular Remodeling and Nasal Polyp Formation

Our microarray data demonstrate significant reduction of submucosal gland-related genes in nasal polyps (NP) subjects and elderly controls. We hypothesized that mitochondrial damage is an underlying mechanism of glandular remodeling in aging and NP formation.

Decoding the role of long noncoding RNAs in the healthy aging of centenarians.

Aging is the largest risk factor of major human diseases. Long noncoding RNAs (lncRNAs) as the key regulatory elements have shown a strong impact on multiple biological processes as well as human disease mechanisms. However, the roles of lncRNAs in aging/healthy aging processes remain largely unknown. Centenarians are good models for healthy aging studies due to avoiding major chronic diseases and disabilities. To illustrate their ubiquitous nature in the genome and the 'secrets' of healthy aging regulation from the perspective of lncRNAs, peripheral blood samples from two regions consisting 76 centenarians (CENs), 54 centenarian-children (F1) and 41 spouses of centenarian-children (F1SP) were collected for deep RNA-seq. We identified 11 CEN-specific lncRNAs that is particularly expressed in longevous individuals. By kmers clustering, hundreds of human lncRNAs show similarities with CEN-specific lncRNAs, especially with ENST00000521663 and ENST00000444998. Using F1SP as normal elder controls (age: 59.9 ± 6.6years), eight lncRNAs that are differentially expressed in longevous elders (CEN group, age: 102.2 ± 2.4years) were identified as candidate aging/health aging-related lncRNAs (car-lncs). We found that the expression of eight car-lncs in human diploid fibroblasts displayed dynamic changes during cell passage and/or H2O2/rapamycin treatment; of which, overexpression either of THBS1-IT1 and THBS1-AS1, two lncRNAs that highly expressed in CENs, can remarkably decrease p16, p21 and the activity of senescent related β-galactosidase, suggesting that THBS1-IT1 and THBS1-AS1 can inhibit cellular senescence. We provided the first comprehensive analysis of lncRNA expression in longevous populations, and our results hinted that dysregulated lncRNAs in CENs are potential protective factors in healthy aging process.

Vascular Contributions to Neurodegeneration: Protocol of the COMPASS-ND Study.

To describe the neuroimaging and other methods for assessing vascular contributions to neurodegeneration in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study, a Canadian multi-center, prospective longitudinal cohort study, including reliability and feasibility in the first 200 participants. COMPASS-ND includes persons with Alzheimer's disease (AD; n = 150), Parkinson's disease (PD) and Lewy body dementias (LBDs) (200), mixed dementia (200), mild cognitive impairment (MCI; 400), subcortical ischemic vascular MCI (V-MCI; 200), subjective cognitive impairment (SCI; 300), and cognitively intact elderly controls (660). Magnetic resonance imaging (MRI) was acquired according to the validated Canadian Dementia Imaging Protocol and visually reviewed by either of two experienced readers blinded to clinical characteristics. Other relevant assessments include history of vascular disease and risk factors, blood pressure, height and weight, cholesterol, glucose, and hemoglobin A1c. Analyzable data were obtained in 197/200 of whom 18 of whom were clinically diagnosed with V-MCI or mixed dementia. The overall prevalence of infarcts was 24.9%, microbleeds was 24.6%, and high white matter hyperintensity (WMH) was 31.0%. MRI evidence of a potential vascular contribution to neurodegeneration was seen in 12.9%-40.0% of participants clinically diagnosed with another condition such as AD. Inter-rater reliability was good to excellent. COMPASS-ND will be a useful platform to study vascular brain injury and its association with risk factors, biomarkers, and cognitive and functional decline across multiple age-related neurodegenerative diseases. Initial findings show that MRI-defined vascular brain injury is common in all cognitive syndromes and is under-recognized clinically.

Diffusion MRI harmonization enables joint-analysis of multicentre data of patients with cerebral small vessel disease

ObjectivesAcquisition-related differences in diffusion magnetic resonance imaging (dMRI) hamper pooling of multicentre data to achieve large sample sizes. A promising solution is to harmonize the raw diffusion signal using rotation invariant spherical harmonic (RISH) features, but this has not been tested in elderly subjects. Here we aimed to establish if RISH harmonization effectively removes acquisition-related differences in multicentre dMRI of elderly subjects with cerebral small vessel disease (SVD), while preserving sensitivity to disease effects. MethodsFive cohorts of patients with SVD (N = 397) and elderly controls (N = 175) with 3 Tesla MRI on different systems were included. First, to establish effectiveness of harmonization, the RISH method was trained with data of 13 to 15 age and sex-matched controls from each site. Fractional anisotropy (FA) and mean diffusivity (MD) were compared in matched controls between sites using tract-based spatial statistics (TBSS) and voxel-wise analysis, before and after harmonization. Second, to assess sensitivity to disease effects, we examined whether the contrast (effect sizes of FA, MD and peak width of skeletonized MD - PSMD) between patients and controls within each site remained unaffected by harmonization. Finally, we evaluated the association between white matter hyperintensity (WMH) burden, FA, MD and PSMD using linear regression analyses both within individual cohorts as well as with pooled scans from multiple sites, before and after harmonization. ResultsBefore harmonization, significant differences in FA and MD were observed between matched controls of different sites (p < 0.05). After harmonization these site-differences were removed. Within each site, RISH harmonization did not alter the effect sizes of FA, MD and PSMD between patients and controls (relative change in Cohen’s d = 4 %) nor the strength of association with WMH volume (relative change in R2 = 2.8 %). After harmonization, patient data of all sites could be aggregated in a single analysis to infer the association between WMH volume and FA (R2 = 0.62), MD (R2 = 0.64), and PSMD (R2 = 0.60). ConclusionsWe showed that RISH harmonization effectively removes acquisition-related differences in dMRI of elderly subjects while preserving sensitivity to SVD-related effects. This study provides proof of concept for future multicentre SVD studies with pooled datasets.

Prevalence and prognostic value of small fiber neuropathy assessed by Sudoscan ® in transthyretin wild-type cardiac amyloidosis

The prevalence of small-fiber neuropathy (SFN) is high in patients with hereditary transthyretin amyloidosis (ATTRv) but remains unknown in transthyretin wild-type cardiac amyloidosis (ATTRwt-CA). To determine the prevalence of SFN in patients with ATTRwt-CA using Sudoscan®, a non-invasive method used to provide evidence of SFN in clinical practice and based on measurement of electrochemical skin conductance at the hands (hESC) and feet (fESC). A series of 62 non-diabetic patients with ATTRwt-CA was prospectively included over 2 years and compared to healthy elderly subjects, matched on age, gender and body mass index. The presence of SFN was defined as hESC < 60 μS and/or fESC < 70 μS and conductances were analyzed according to clinical, biological, and echocardiographic data. Mean hESC and fESC were significantly lower in patients with ATTRwt-CA than in elderly controls: 61.5 vs. 70.0 μS ( P = 0.006) and 68.3 vs. 76.9 μS respectively ( P < 0.0001). Prevalence of hESC < 60 μS and fESC < 70 μS was higher in patients with ATTRwt-CA than in controls: 33.9% versus 16.7% and 48.4% versus 19.9%, P < 0.05. Univariate analysis showed that fESC, NT-proBNP, creatinine plasma levels, and echocardiographic global longitudinal strain were associated with decompensated cardiac failure and death. Multivariate analysis revealed that fESC was an independent prognostic factor and Kaplan-Meier estimator evidenced a larger occurrence of cardiac decompensation and death in patients with fESC < 70 μS, P = 0.046. A reduced fESC was observed in almost 50% of patients with ATTRwt-CA and was associated with a worse prognosis. Sudoscan® could be used easily to screen ATTRwt-CA patients for the presence of SFN and identify patients at higher risk of outcome.

Microglial reactivity in the prefrontal cortex in different types of schizophrenia

To estimate microglial density and the ultrastructural parameters of microglia in the prefrontal cortex in chronic attack-like and continuous schizophrenia as compared to healthy controls. Postmortem electron microscopic morphometric study of microglia was performed in the prefrontal cortex (layer 5, Brodmann' area 10). Ten cases of attack-like schizophrenia, 9 cases of continuous schizophrenia and 20 controls were studied. Microglial density, areas of cell and nucleus, nucleus/cytoplasm ratio, volume fraction and the number of mitochondria, vacuoles of endoplasmic reticulum and lipofuscin granules were estimated. ANCOVA was used for statistical analysis. A significant decrease in volume fraction and the number of mitochondria and increase in these parameters of lipofuscin granules were found in both groups as compared to the control group. The group of attack-like schizophrenia showed a significant increase in area of vacuoles as compared to the control group, a significant increase in microglial density as compared to controls and in the young (≤50 yrs.old) subgroup as compared to the elderly (>50 yrs.old) control subgroup. In this group, areas of cell and nucleus were significantly higher in the young subgroup as compared to elderly controls, the elderly subgroup of attack-like schizophrenia and the young subgroup of continuous schizophrenia. An increase in the areas of microglia and the nucleus of microglia in young patients was found in comparison with the elderly from the control group, elderly patients with attack-like schizophrenia and young patients with continuous schizophrenia. Significant negative correlations of areas of cell and nucleus and the number of mitochondria with age and positive correlations of area of lipofuscin granules with age and illness duration were found in attack-like schizophrenia in contrast to continuous schizophrenia. Chronic attack-like schizophrenia is associated with increased reactivity in young age and dystrophic changes of microglia progressive with age and illness duration. Continuous schizophrenia is associated with reduced microglial reactivity, dystrophic and non-progressive changes of microglia.

Orthostatic Hypotension in Elderly Patients with Essential Tremor

PurposeEssential tremor (ET) is the most common movement disorder in which dysautonomia symptoms can be present. We aimed to evaluate the presence of orthostatic hypotension (OH) and its relationship with the clinical features.Patients and MethodsForty-four elderly patients with ET and 118 healthy elderly controls were included. OH was assessed via the head-up tilt table test and defined, according to the change in position, as a drop of at least 20 mmHg in systolic blood pressure and/or 10 mmHg in diastolic blood pressure. Tremor severity was evaluated using the Fahn-Tolosa-Marin Tremor Rating (FTMTR) Scale. All patients underwent geriatric comprehensive assessment.ResultsThere were no differences between the controls and patients with ET regarding age and gender. The mean age was 72.8±6.1, the mean disease duration 19.1±13.5 years and the mean FTMTR score was 30.9±17.1 in patients with ET. The frequency of OH at the 1st minute in patients with ET was higher than in controls (31.8% vs 17.8%, p=0.046). Furthermore, the frequency of jaw tremor in patients with OH was higher than in those without OH (35.7% vs 6.7%, p=0.025). About 28.6% of ET patients with OH had orthostatic symptoms.ConclusionWe demonstrated that ET patients, particularly those with jaw tremors, had OH and that most of them were asymptomatic. Therefore, in order to protect patients from complications related to OH, it would be appropriate to evaluate OH in the follow-up and treatment of elderly patients with ET.

Association Between Homocysteine and Vitamin Levels in Demented Patients.

Although it is known that the nutritional status among elderly persons and, in particular, patients with dementia, is compromised, malnutrition that results in insufficient uptake of several vitamins is often not diagnosed. An elevated homocysteine level is a known strong risk factor for vascular dementia (VaD) and Alzheimer's disease (AD). Several B vitamins are involved in the metabolism of homocysteine. Therefore, we investigated the serum levels of vitamin B1, vitamin B6, folate, and vitamin B12 in 97 patients with mild cognitive impairment (MCI) or different forms of dementia and 54 elderly control persons without dementia. Compared to aged non-demented people, vitamins B1, B6, B12, and folate were decreased in serum of patients with AD, and patients with Lewy body dementia had reduced vitamin B12 level. Vitamin B6 was diminished in VaD. Patients with frontotemporal dementia showed no alterations in vitamin levels. Age was identified as an important factor contributing to the concentrations of vitamin B1 and B6 in serum, but not vitamin B12 and folate. Increased levels of total homocysteine were detected especially in MCI and AD. Homocysteine correlated negatively with levels of vitamins B6, B12, and folate and positively with Q Albumin. Our data suggest that despite increased homocysteine already present in MCI, vitamin levels are decreased only in dementia. We propose to determine the vitamin levels in patients with cognitive decline, but also elderly people in general, and recommend supplementing these nutrients if needed.

Prevalence and prognostic value of autonomic neuropathy assessed by Sudoscan® in transthyretin wild‐type cardiac amyloidosis

AimsThe prevalence of autonomic neuropathy (AN) is high in patients with hereditary transthyretin amyloidosis but remains unknown in transthyretin wild‐type cardiac amyloidosis (ATTRwt‐CA). This study aimed to determine the prevalence of AN in patients with ATTRwt‐CA using Sudoscan®, a non‐invasive method used to provide evidence of AN in clinical practice and based on measurement of electrochemical skin conductance at the hands and feet (fESC).Methods and resultsA series of 62 non‐diabetic patients with ATTRwt‐CA was prospectively included over 2 years and compared with healthy elderly subjects, matched by age, gender, and body mass index. The presence of AN was defined as electrochemical skin conductance at the hands <60 μS and/or fESC <70 μS, and conductances were analysed according to clinical, biological, and echocardiographic data. Mean fESC was significantly lower in patients with ATTRwt‐CA compared with elderly controls: 68.3 (64.1–72.5) vs. 76.9 (75.6–78.1) μS (P < 0.0001), respectively. Prevalence of fESC <70 μS was higher in ATTRwt‐CA patients than in controls: 48.4% vs. 19.9%, P < 0.05. Univariate analysis showed that fESC, N‐terminal pro‐B‐type natriuretic peptide, creatinine plasma levels, and echocardiographic global longitudinal strain were associated with decompensated cardiac failure and death. Multivariate analysis revealed that fESC was an independent prognostic factor, and Kaplan–Meier estimator evidenced a greater occurrence of cardiac decompensation and death in patients with fESC <70 μS, P = 0.046.ConclusionsReduced fESC was observed in almost 50% of patients with ATTRwt‐CA and was associated with a worse prognosis. Sudoscan® could easily be used to screen ATTRwt‐CA patients for the presence of AN and identify patients at higher risk for a poor outcome.

APOE Variants in an Iberian Alzheimer Cohort Detected through an Optimized Sanger Sequencing Protocol.

The primary genetic risk factor for late onset Alzheimer’s disease (LOAD) is the APOE4 allele of Apolipoprotein E (APOE) gene. The three most common variants of APOE are determined by single nucleotide polymorphisms (SNPs) rs429358 and rs7412. Our aim was to estimate allele and genotype frequencies of APOE variants in an Iberian cohort, thus helping to understand differences in APOE-related LOAD risk observed across populations. We analyzed saliva or buccal swab samples from 229 LOAD patients and 89 healthy elderly controls (≥68 years old) from Northern Portugal and Castile and León region, Spain. The genotyping was performed by Sanger sequencing, optimized to overcome GC content drawbacks. Results obtained in our Iberian LOAD and control cohorts are in line with previous large meta-analyses on APOE frequencies in Caucasian populations; however, we found differences in allele frequencies between our Portuguese and Spanish subgroups of AD patients. Moreover, when comparing studies from Iberian and other Caucasian cohorts, differences in APOE2 and APOE4 frequencies and subsequent different APOE-related LOAD risks must be clarified. These results show the importance of studying genetic variation at the APOE gene in different populations (including analyses at a regional level) to increase our knowledge about its clinical significance.

Gesturing helps memory encoding in aMCI.

Encoding in episodic memory is a step often impaired in patients with amnestic Mild Cognitive Impairment (aMCI). However, procedural memory processes are still relatively preserved. In line with previous research on the enactment effect, we investigated the potential benefit of encoding words combined with imitative gestures on episodic memory. Based on the Grober and Buschke's free/cued recall procedure, we developed the Symbiosis test in which 13 patients with aMCI and 16 healthy elderly participants learned 32 words belonging to 16 different semantic categories either in a verbal encoding (A) or a bimodal (B; verbal and motor imitation) condition, using a blocked ABBA/BAAB procedure. Overall, memory retrieval was better in healthy participants than in patients with aMCI, and better for cued retrieval in the bimodal encoding (gesture cues) than the verbal encoding (category cues) condition, but there was no interaction effect between group and encoding conditions. These results show that performing concomitant gestures can enhance cued episodic memory retrieval in patients with aMCI and in healthy elderly controls. The Symbiosis test broadens the scope of the enactment effect, from action phrases to isolated words learning in patients with aMCI. Future work should investigate how bimodal encoding provides novel perspectives for memory rehabilitation in patients with aMCI.

Usefulness of Muscle Synergy Analysis in Individuals With Knee Osteoarthritis During Gait.

To clarify whether there are any muscle synergy changes in individuals with knee osteoarthritis, and to determine whether muscle synergy analysis could be applied to other musculoskeletal diseases. Subjects in this study included 11 young controls (YC), 10 elderly controls (EC), and 10 knee osteoarthritis patients (KOA). Gait was assessed on a split-belt treadmill at 3 km/h. A non-negative matrix factorization (NNMF) was applied to the electromyogram data matrix to extract muscle synergies. To assess the similarity of each module, we performed the NNMF analysis assuming four modules for all of the participants. Further, we calculated joint angles to compare the kinematic data between the module groups. The number of muscle modules was significantly lower in the EC (2-3) and KOA (2-3) groups than in the YC group (3-4), which reflects the merging of late swing and early stance modules. The EC and KOA groups also showed greater knee flexion angles in the early stance phase. Contrarily, by focusing on the module structure, we found that the merging of early and late stance modules is characteristic in KOA. The lower number of modules in the EC and KOA groups was due to the muscle co-contraction with increased knee flexion angle. Contrarily, the merging of early and late stance modules are modular structures specific to KOA and may be biomarkers for detecting KOA. Describing the changes in multiple muscle control associated with musculoskeletal degeneration can serve as a fundamental biomarker in joint disease.

Relating Response Inhibition, Brain Connectivity, and Freezing of Gait in People with Parkinson's Disease.

Freezing of gait (FoG) in Parkinson's disease (PD) has been associated with response inhibition. However, the relationship between response inhibition, neural dysfunction, and PD remains unclear. We assessed response inhibition and microstructural integrity of brain regions involved in response inhibition [right hemisphere inferior frontal cortex (IFC), bilateral pre-supplementary motor areas (preSMA), and subthalamic nuclei (STN)] in PD subjects with and without FoG and elderly controls. Twenty-one people with PD and FoG (PD-FoG), 18 without FoG (PD-noFoG), and 19 age-matched controls (HC) completed a Stop-Signal Task (SST) and MRI scan. Probabilistic fiber tractography assessed structural integrity (fractional anisotropy, FA) among IFC, preSMA, and STN regions. Stop-signal performance did not differ between PD and HC, nor between PD-FoG and PD-noFoG. Differences in white matter integrity were observed across groups (.001 < p < .064), but were restricted to PD versus HC groups; no differences in FA were observed between PD-FoG and PD-noFoG (p > .096). Interestingly, worse FoG was associated with higher (better) mean FA in the r-preSMA, (β = .547, p = .015). Microstructural integrity of the r-IFC, r-preSMA, and r-STN tracts correlated with stop-signal performance in HC (p ≤ .019), but not people with PD. These results do not support inefficient response inhibition in PD-FoG. Those with PD exhibited white matter loss in the response inhibition network, but this was not associated with FoG, nor with response inhibition deficits, suggesting FoG-specific neural changes may occur outside the response inhibition network. As shown previously, white matter loss was associated with response inhibition in elderly controls, suggesting PD may disturb this relationship.

Do Patients With Dementia Benefit From Cochlear Implantation?

Do Patients With Dementia Benefit From Cochlear Implantation?

A novel visual short‐term memory task differentiates MCI and Alzheimer’s patients from healthy ageing

AbstractBackgroundWe developed a novel delayed reproduction task, the “What was where?” task, which obtains a continuous measure of localization error and is more sensitive compared to conventional span measures of Short‐term Memory (STM).MethodWe recruited 44 MCI (Mild Cognitive Impairment), 41 AD (Alzheimer’s Disease) patients and 109 healthy elderly controls (EHCs) from memory clinics in Oxford, UK and Jena, Germany, where they performed the “What was where?” task (Figure 1). We extracted the following metrics: Identification Accuracy (percentage correctly identified items), Absolute Localization Error (how far the object was misplaced), Misbinding rate (erroneously localizing an item to the remembered location of another item in memory) and Guessing response rate.ResultAbsolute Localization Error and Misbinding rates were greater in MCI and AD patients (p &lt; 0.001) compared to EHCs, while AD and MCI performed similarly on these metrics. However, Identification Accuracy as well as Guessing (p = 0.003) were greater in MCI (p &lt; 0.001) compared to AD patients. Moreover, EHCs identified the correct object more often (p &lt; 0.001) and guessed less (p &lt; 0.001) than MCI patients.ConclusionThis novel task is able to detect STM impairment in MCI cases on a continuous scale, and is a sensitive memory measure which might be a useful index of memory for future clinical trials in AD in its earliest stages.

Changes in anterior temporal and posterior medial hippocampal network connectivity in Alzheimer’s disease

AbstractBackgroundHippocampal connectivity is affected early in Alzheimer’s disease and plays a crucial role in episodic memory dysfunction. Different hippocampal subnetworks have been identified, namely the anterior temporal (AT) and the posterior medial (PM) networks that are specifically related to separate subregions of the medial temporal lobe (MTL) thought to be differentially affected in AD. The aim of this study was to assess the specific connectivity of these two networks and its changes in Alzheimer’s disease, using both a cross‐sectional and a longitudinal approach.MethodFifty‐three cognitively impaired patients on the Alzheimer’s continuum with mild cognitive impairment or dementia, all amyloid‐β (Aβ)‐positive, and 68 Aβ‐negative cognitively unimpaired elderly controls were included. They underwent structural T1‐MRI and resting‐state functional MRI (fMRI) scans at baseline and at 18‐month follow‐up as well for 30 patients. Seed‐based analyses were performed, using individual automatic segmentation of MTL subregions as seeds, to assess the functional connectivity within the AT (from the perirhinal cortex and anterior hippocampus seeds) and the PM (from the parahippocampal cortex and posterior hippocampus seeds) networks. First, we compared the functional connectivity of the two networks within the controls to highlight their specificities. Second, we compared MTL subregion connectivity within each network between groups, and between baseline and follow‐up in the patients, to assess AD‐related changes compared to controls and over time.ResultAT and PM networks showed distinct connectivity patterns in controls (Fig. 1). Patients showed decreased connectivity between the anterior hippocampus and regions of the PM network, and increased connectivity between anterior MTL subregions, compared to controls (Fig. 2). Over the 18‐month follow‐up period, decreased connectivity was found between both the anterior and posterior hippocampus and regions of the PM network, while increased connectivity was observed between several anterior MTL subregions and regions of the AT network (Fig. 3).ConclusionAD is characterized by both decreased MTL connectivity with the PM hippocampal network and increased connectivity with the AT hippocampal network. The specific assessment of the two main hippocampal subnetworks shed light on the overall pattern of AD‐related hippocampal changes involving both connectivity default and possible compensation or erroneous hyperactivity patterns.

Optimizing the memory binding test for detection of aMCI and dementia

AbstractBackgroundThe Memory Binding Test (MBT) Version 1 demonstrated good discriminative validity for distinguishing persons with dementia and amnestic mild cognitive impairment (aMCI) from cognitively normal elder controls (CN). Version 2 of the MBT test was developed to improve brevity, which is essential for screening. We aimed to compare these two versions in terms of cross‐sectional discriminative validity to distinguish A. aMCI vs. CN, B. aMCI and dementia vs. CN, and C. dementia vs. CN and aMCI.MethodVersion 1 and Version 2 (for differences see Table 1) of the MBT were administered to independent and systematically recruited samples between May 2003 and December 2007 (Age: 70+; Version 1: 20 dementia cases, 31 aMCI, 246 CN; Version 2: 13 dementia cases, 29 aMCI, 236 CN). Scores on the MBT indices were compared between the versions. The partial area under the receiver operating characteristic curve (ROC AUC) for specificities ≥ 0.70 was compared between indices and versions (Table 1). Specificities were compared between versions when the sensitivity values were comparable.ResultThe MBT indices were not significantly different between versions for the diagnosis groups of aMCI and dementia. In CN, Version 2 yielded higher scores on number of items Cued Recall for List 1 (CR‐L1), number of Pairs In the Paired condition (PIP), and number of Total Items recalled in the Paired condition (TIP) (14.8±1.5 vs. 14.4±1.7, 11.0±3.2 vs. 9.9±3.8, 26.3±4.0 vs. 24.9±5.0, respectively, p=0.005) and PIP and TIP remained higher (p=0.02) when adjusting for potential confounders of age, gender, education and global cognitive function. Partial AUC comparison shows that TIP was the optimal index for Version 1 and TIP partial AUCs were not significantly different between two versions (Figure 1, Table 2). The specificities were higher in Version 1 vs. Version 2 in Comparisons A and B, while the specificities were comparable in Comparison C (Table 3).ConclusionMBT Version 1 is better at distinguishing aMCI, or aMCI and dementia combined, from cognitively normal elderly. To distinguish dementia vs. cognitively normal elder controls and aMCI, Version 1 and Version 2 are comparable. We recommend using Version 1 for future studies.

Evaluation of the novel 18F‐labeled PET tracer SMBT‐1 for imaging astrogliosis in healthy elderly controls and A+/T+/(N+) Alzheimer's disease patients

AbstractBackgroundNeuroinflammatory changes, characterized by reactive astrocytes and activated microglia, contribute greatly to neurodegeneration throughout the course of Alzheimer’s diseases (AD). Reactive astrocytes overexpress monoamine oxidase‐B (MAO‐B) in the outer mitochondrial membrane. For imaging astrogliosis in the human brain, we developed the novel MAO‐B PET tracer named 18F‐SMBT‐1. We aimed to investigate the binding properties of 18F‐SMBT‐1 in healthy elderly controls and AD patients.MethodsAfter in silico preclinical evaluation were performed for the assessment of binding affinity and selectivity of 18F‐SMBT‐1, 9 participants, 5 healthy elderly controls (3F/2M, 78.5±6.0 yrs, 3 A‐/T‐/(N‐) and 2 A+/T‐/(N‐)) and 4 A+/T+/(N+) AD patients (3F/1M, 76.8±1.4 yrs), underwent 18F‐SMBT‐1 PET, amyloid PET with 18F‐NAV4694, tau PET with either 18F‐MK6240 (n=7) or 18F‐PI2620 (n=2), and 3D‐MPRAGE MRI. While Ab burden was expressed in Centiloids, tau tissue ratios were generated using the cerebellar cortex as reference region. 18F‐SMBT‐1 studies were expressed as SUV or as tissue ratios using the cerebellar white matter as reference region. To ascertain 18F‐SMBT‐1 selective binding to MAO‐B, participants underwent a second 18F‐SMBT‐1 scan after receiving 5mg selegiline twice daily for 5 days.ResultsSMBT‐1 showed strong and reversible binding to MAO‐B, and low binding affinity to other enzymes, receptors and misfolded proteins such as amyloid‐β and tau.18F‐SMBT‐1 yielded high contrast images at 60‐90 min post injection, with high tracer retention in basal ganglia, intermediate in neocortical regions, and lowest in cerebellum which tightly follows the known regional brain distribution of MAO‐B (R2=0.82). In AD patients, 18F‐SMBT‐1 retention was significantly higher in parahippocampus, fusiform and inferior temporal gyrus. More than 85% of 18F‐SMBT‐1 signal was blocked and no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO‐B.Conclusions18F‐SMBT‐1 is the highly selective MAO‐B tracer, which will enable the assessment of astrogliosis in the human brain. The confirmation of these preliminary findings with 18F‐SMBT‐1 will require examination of a much larger series, including participants with MCI and prodromal AD.