Prodromal Stage Of Alzheimer's Disease Research Articles

Circuitry and Synaptic Dysfunction in Alzheimer's Disease: A New Tau Hypothesis.

For more than five decades, the field of Alzheimer's disease (AD) has focused on two main hypotheses positing amyloid-beta (Aβ) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.

Endocytosis-pathway polygenic scores affects the hippocampal network connectivity and individualized identification across the high-risk of Alzheimer's disease.

The neural mechanisms underlying the polygenic effects of the endocytosis pathway on the brain function of Alzheimer's Disease (AD) remain unclear, especially in the prodromal stages of AD from early mild cognitive impairment (EMCI) to late mild cognitive impairment (LMCI). We used an imaging genetic approach to investigate the polygenic effects of the endocytosis pathway on the hippocampal network across the prodromal stages of AD. The subjects' data were selected from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal volumes were examined in subjects of cognitive normal (CN), EMCI and LMCI groups. Multivariate linear regression analysis was employed to measure the effects of disease and endocytosis-based multilocus genetic risk scores (MGRS) on the hippocampal network which was constructed using the bilateral hippocampal regions. We identified hippocampal volumes in LMCI group were smaller than those in CN and EMCI groups. Endocytosis-based MGRS was widely influenced the neural structures within the hippocampal network, especially in the prefrontal-occipital regions and striatum. Compared to low endocytosis-based MGRS carriers, high MGRS carriers showed the opposite trajectory of hippocampal network functional connectivity (FC) across the prodromal stages of AD. Further, a model composed of selected hippocampal FCs and hippocampal volume yielded strong classification powers of EMCI and LMCI. These findings expand our understanding of the pathophysiology of polygenic effects underlying brain network in the prodromal stages of AD.

Regional hyperperfusion in older adults with objectively-defined subtle cognitive decline

Although cerebral blood flow (CBF) alterations are associated with Alzheimer’s disease (AD), CBF patterns across prodromal stages of AD remain unclear. Therefore, we investigated patterns of regional CBF in 162 Alzheimer’s Disease Neuroimaging Initiative participants characterized as cognitively unimpaired (CU; n = 80), objectively-defined subtle cognitive decline (Obj-SCD; n = 31), or mild cognitive impairment (MCI; n = 51). Arterial spin labeling MRI quantified regional CBF in a priori regions of interest: hippocampus, inferior temporal gyrus, inferior parietal lobe, medial orbitofrontal cortex, and rostral middle frontal gyrus. Obj-SCD participants had increased hippocampal and inferior parietal CBF relative to CU and MCI participants and increased inferior temporal CBF relative to MCI participants. CU and MCI groups did not differ in hippocampal or inferior parietal CBF, but CU participants had increased inferior temporal CBF relative to MCI participants. There were no CBF group differences in the two frontal regions. Thus, we found an inverted-U pattern of CBF signal across prodromal AD stages in regions susceptible to early AD pathology. Hippocampal and inferior parietal hyperperfusion in Obj-SCD may reflect early neurovascular dysregulation, whereby higher CBF is needed to maintain cognitive functioning relative to MCI participants, yet is also reflective of early cognitive inefficiencies that distinguish Obj-SCD from CU participants.

Aberrant Hippocampal Functional Connectivity Is Associated with Fornix White Matter Integrity in Alzheimer's Disease and Mild Cognitive Impairment.

Alzheimer's disease (AD) is the most common cause of dementia in older individuals, and amnestic mild cognitive impairment (aMCI) is currently considered the prodromal stage of AD. The hippocampus and fornix interact functionally and structurally, with the fornix being the major efferent white matter tract from the hippocampus. The main aim of this study was to examine the impairments present in subjects with AD or aMCI and the relationship of these impairments with the microstructure of the fornix and the functional connectivity (FC) and gray matter volume of the hippocampus. Forty-four AD, 34 aMCI, and 41 age- and gender-matched normal controls (NCs) underwent neuropsychological assessments and multimode MRI. We chose the bilateral hippocampi as the region of interest in which gray matter alterations and FC with the whole brain were assessed and the fornix body as the region of interest in which the microstructural integrity of the white matter was observed. We also evaluated the relationship among gray matter alterations, the abnormal FC of the hippocampus and the integrity of the fornix in AD/aMCIResults:Compared to the NC group, the AD and aMCI groups demonstrated decreased gray matter volume, reduced FC between the bilateral hippocampi and several brain regions in the default mode network and control network, and damaged integrity of the fornix body (decreased fractional anisotropy and increased diffusivity). We also found that left hippocampal FC with some regions, the integrity of the fornix body, and cognition ability were significantly correlated. Therefore, our findings suggest that damage to white matter integrity may partially explain the reduced resting-state FC of the hippocampus in AD and aMCI. AD and aMCI are diseases of disconnectivity including not only functional but also structural disconnectivity. Damage to white matter integrity may partially explain the reduced resting-state FC in AD and aMCI. These findings have significant implications for diagnostics and modeling and provide insights for understanding the disconnection syndrome in AD.

Alzheimer's Disease in Down Syndrome: Progress in the Design and Conduct of Drug Prevention Trials.

Individuals with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD) pathology and this has provided significant insights into our understanding of the genetic basis of AD. The present review summarizes recent clinical, neuropathologic, imaging, and fluid biomarker studies of AD in DS (DSAD), highlighting the striking similarities, as well as some notable differences, between DSAD and the more common late-onset form of AD (LOAD) in the general population, as well as the much rarer, autosomal-dominant form of AD (ADAD). There has been significant progress in our understanding of the natural history of AD biomarkers in DS and their relationship to clinically meaningful changes. Additional work is needed to clearly define the continuum of AD that has been described in the general population, such as the preclinical, prodromal, and dementia stages of AD. Multiple therapeutic approaches, including those targeting not only β-amyloid but also tau and the amyloid precursor protein itself, require consideration. Recent developments in the field are presented within the context of such efforts to conduct clinical trials to treat and potentially prevent AD in DS.

Looking for a Treatment for the Early Stage of Alzheimer's Disease: Preclinical Evidence with Co-Ultramicronized Palmitoylethanolamide and Luteolin.

Background: At the earliest stage of Alzheimer’s disease (AD), although patients are still asymptomatic, cerebral alterations have already been triggered. In addition to beta amyloid (Aβ) accumulation, both glial alterations and neuroinflammation have been documented at this stage. Starting treatment at this prodromal AD stage could be a valuable therapeutic strategy. AD requires long-term care; therefore, only compounds with a high safety profile can be used, such as the new formulation containing palmitoylethanolamide and luteolin (co-ultra PEALut) already approved for human use. Therefore, we investigated it in an in vivo pharmacological study that focused on the prodromal stage of AD. Methods: We tested the anti-inflammatory and neuroprotective effects of co-ultra PEALut (5 mg/Kg) administered for 14 days in rats that received once, 5 µg Aβ(1–42) into the hippocampus. Results: Glial activation and elevated levels of proinflammatory mediators were observed in Aβ-infused rats. Early administration of co-ultra PEALut prevented the Aβ-induced astrogliosis and microgliosis, the upregulation in gene expression of pro-inflammatory cytokines and enzymes, as well as the reduction of mRNA levels BDNF and GDNF. Our findings also highlight an important neuroprotective effect of co-ultra PEALut treatment, which promoted neuronal survival. Conclusions: Our results reveal the presence of cellular and molecular modifications in the prodromal stage of AD. Moreover, the data presented here demonstrate the ability of co-ultra PEALut to normalize such Aβ-induced alterations, suggesting it as a valuable therapeutic strategy.

MRI Radiomics Classification and Prediction in Alzheimer's Disease and Mild Cognitive Impairment: A Review.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease that threatens the health of the elderly. Mild Cognitive Impairment (MCI) is considered to be the prodromal stage of AD. To date, AD or MCI diagnosis is established after irreversible brain structure alterations. Therefore, the development of new biomarkers is crucial to the early detection and treatment of this disease. At present, there exist some research studies showing that radiomics analysis can be a good diagnosis and classification method in AD and MCI. An extensive review of the literature was carried out to explore the application of radiomics analysis in the diagnosis and classification among AD patients, MCI patients, and Normal Controls (NCs). Thirty completed MRI radiomics studies were finally selected for inclusion. The process of radiomics analysis usually includes the acquisition of image data, Region of Interest (ROI) segmentation, feature extracting, feature selection, and classification or prediction. From those radiomics methods, texture analysis occupied a large part. In addition, the extracted features include histogram, shapebased features, texture-based features, wavelet features, Gray Level Co-Occurrence Matrix (GLCM), and Run-Length Matrix (RLM). Although radiomics analysis is already applied to AD and MCI diagnosis and classification, there still is a long way to go from these computer-aided diagnostic methods to the clinical application.

Effects of 1‐year Aerobic Exercise Training on Cerebral Blood Flow and Arterial Siffness in Amnestic Mild Cognitive Impairment

Aerobic exercise training (AET) may improve cerebralperfusion and reduce the risk of dementia. Changes in central arterialstiffness and pulsatile cerebral blood flow (CBF) associated with exercise training may be one of the underlying pathophysiological mechanism. The purpose of this study was to investigate: (1) The effects of AET on central arterialstiffness and CBF, and (2) whether pulsatile CBF mediates the association between changes in arterial stiffness and cerebral perfusion in amnestic mildcognitive impairment (aMCI), a prodromal stage of Alzheimer disease. Seventy aMCI patients were randomized to 12 months of moderate‐intensity AET (n=31) or stretching program (n=39). CBF and carotid β‐stiffness index were assessed by ultrasonography and applanation tonometry. Cerebral perfusion was calculated by normalizing total CBF to brain tissue mass measured by magnetic resonance imaging. Pulsatile CBF was measured from the middle cerebralartery using transcranial Doppler. Cardiorespiratory fitness was assessed by peak oxygen uptake (VO2peak). VO2peak and cerebralperfusion increased and carotid β‐stiffness index decreased in the AET group, while remained unchanged in the stretching group. The change in VO2peak was significantly associated with the change in cerebral perfusion, carotidβ‐stiffness index, and pulsatile CBF (Fig. 1). The decrease in carotidβ‐stiffness was associated with increased in cerebral perfusion (Fig. 2). Mediation analysis showed that changes in pulsatile CBF mediates the association between carotidβ‐stiffness index and cerebral perfusion (Fig. 2). These results suggest that AET decreases arterial stiffness and increases cerebral perfusion, which is mediated by pulsatile CBF in aMCI patients.Support or Funding InformationThis work was funded by the National Institutes of Health ((R01AG033106, R01HL102457, P30AG012300)Associations between the change (Δ) in relative peak oxygen uptake (VO2) and the change in cerebral perfusion, carotid β‐stiffness index and pulsatile cerebral blood flow (CBF).Figure 1Mediation analysis diagram of the effect of the change (Δ) in carotid β‐stiffness index on the change in cerebral perfusion through the change in pulsatile cerebral blood flow (CBF).Figure 2

An investigation of affective theory of mind ability and its relation to neuropsychological functions in Alzheimer's disease.

Although cognitive theory of mind (ToM) has been largely studied within neurodegenerative disorders including Alzheimer's disease (AD), studies focusing on affective ToM are relatively limited, yielding inconsistent findings. The current study aimed at investigating affective ToM abilities within different stages of AD (mild AD dementia [ADD], mild cognitive impairment [MCI], and subjective cognitive impairment [SCI]), together with its relationship with neuropsychological functioning. Eighty-one participants were tested with two different ToM tasks (Faux Pas Recognition Test [FPR] and Reading Mind in the Eyes Test [RMET]) and tests of attention, executive functions, episodic memory, and facial recognition. Our results showed two different affective ToM profiles in AD continuum: while ADD group performed poorly on both tasks of ToM, MCI group displayed deteriorated performance on RMET but not on FPR. In addition, ToM performance was significantly related to episodic memory and verbal fluency within the overall sample. These findings suggest that impairment in the decoding process of emotional cues could begin even in the prodromal stage of AD. In contrast, the reasoning process of emotional information, as measured with FPR, could be preserved until the dementia stage. Moreover, the relation of affective ToM with amnestic functions and verbal abilities could provide evidence of a domain-general ToM impairment in AD.

Multivariate Data Analysis and Machine Learning for Prediction of MCI-to-AD Conversion.

There has always been a need for discovering efficient and dependable Alzheimer's disease (AD) diagnostic biomarkers. Like the majority of diseases, the earlier the diagnosis, the most effective the treatment. (Semi)-automated structural magnetic resonance imaging (MRI) processing approaches are very popular in AD research. Mild cognitive impairment (MCI) is considered to be a stage between normal cognitive ageing and dementia. MCI can often be the prodromal stage of AD. Around 10-15% of MCI patients convert to AD per year. In this study, we used three supervised machine learning (ML) techniques to differentiate MCI converters (MCIc) from MCI non-converters (MCInc) and predict their conversion rates from baseline MRI data (cortical thickness (CTH) and hippocampal volume (HCV)). A total of 803 participants from the ADNI cohort were included in this study (188 AD, 107 MCIc, 257 MCInc and 156 healthy controls (HC)). We studied the classification abilities of three different WEKA classifiers (support vector machine (SVM), decision trees (J48) and Naive Bayes (NB)). We built six different classification models, three models based on CTH and three based on HCV (CTH-SVM, CTH-J48, CTH-NB, HCV-SVM, HCV-J48 and HCV-NB). For the classification experiments, we obtained up to 71% sensitivity and up to 56% specificity. The prediction of conversion showed accuracy for up to 84%. The value of certain multivariate models derived from the classification experiments has exhibited robust and effective results in MCIc identification. However, there was a limitation in this study since we could not compare the CTH with the HCV models seeing as the data used originated from different subjects. As future direction, we propose the creation of a model that would combine various features with data originating from the same subjects, thus being a far more reliable and accurate prognostic tool.

Convolutional Neural Network Based Prediction of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: A Technique using Hippocampus Extracted from MRI

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder. Mild Cognitive Impairment (MCI) is a prodromal stage of AD and its identification is very crucial for early trea ...

Molecular Subtyping of Mild Cognitive Impairment Based on Genetic Polymorphism and Gene Expression.

Alzheimer's Disease (AD) is a neurodegenerative brain disease in the elderly. Recent studies have revealed the heterogeneous nature of AD. Mild Cognitive Impairment (MCI) is the prodromal stage of AD. In this study, we identified subtypes of MCI based on genetic polymorphism and gene expression. We utilized the two types of omics data, namely genetic polymorphism and gene expression profiling, derived from 125 MCI patients' peripheral blood samples from the ADNI-1 dataset. Similarity network fusion (SNF) algorithm was implemented to cluster MCI patient subtypes. And 185 MCI patients in ADNI-2 were utilized to evaluate the effectiveness of this method. Two MCI subtypes were identified by implementing the SNF algorithm. We used Kaplan-Meier analysis and log-rank testing for the conversion from MCI to AD between two subtypes, and p-value is 4.58×10-3. In addition, we compared patients among two MCI subtypes by the following factors: the changes in Alzheimer's Disease cognitive scales and MRI image; significantly enriched pathways based on differentially expressed genes. This study proved that MCI is a heterogeneous disease by concluding that AD development in two MCI subtypes is significantly different. MCI patients with different molecular characteristics have different risks converting to AD. In addition to evaluating statistics, genetic polymorphism and gene expression profiling from MCI patients' peripheral blood are non-invasiveness and cost-effectiveness markers to identify MCI subtypes for clinical application.

Evolution of anosognosia in alzheimer's disease and its relationship to amyloid.

Unawareness, or anosognosia, of memory deficits is a challenging manifestation of Alzheimer's disease (AD) that adversely affects a patient's safety and decision-making. However, there is a lack of consensus regarding the presence, as well as the evolution, of altered awareness of memory function across the preclinical and prodromal stages of AD. Here, we aimed to characterize change in awareness of memory abilities and its relationship to beta-amyloid (Aβ) burden in a large cohort (N = 1,070) of individuals across the disease spectrum. Memory awareness was longitudinally assessed (average number of visits = 4.3) and operationalized using the discrepancy between mean participant and partner report on the Everyday Cognition scale (memory domain). Aβ deposition was measured at baseline using [18F]florbetapir positron emission tomographic imaging. Aβ predicted longitudinal changes in memory awareness, such that awareness decreased faster in participants with increased Aβ burden. Aβ and clinical group interacted to predict change in memory awareness, demonstrating the strongest effect in dementia participants, but could also be found in the cognitively normal (CN) participants. In a subset of CN participants who progressed to mild cognitive impairment (MCI), heightened memory awareness was observed up to 1.6 years before MCI diagnosis, with memory awareness declining until the time of progression to MCI (-0.08 discrepant-points/yr). In a subset of MCI participants who progressed to dementia, awareness was low initially and continued to decline (-0.23 discrepant-points/yr), reaching anosognosia 3.2 years before dementia onset. Aβ burden is associated with a progressive decrease in self-awareness of memory deficits, reaching anosognosia approximately 3 years before dementia diagnosis. ANN NEUROL 2020;87:267-280.

Brain Metabolic Dysfunction in Early Neuropsychiatric Symptoms of Dementia.

Neuropsychiatric symptoms (NPS) including behavioral and psychiatric symptoms are common in the dementia stages of Alzheimer's disease (AD) and are associated with poorer outcomes in cognition, functional states, quality of life, and accelerated progression to severe dementia or death. NPS are also increasingly observed in the mild cognitive impairment stage of AD and may predict incipient dementia. As such, there is an emerging conceptual framework, which support NPS as early non-cognitive symptoms of dementia. [18F]fluorodeoxyglucosepositron emission tomography is a technique that is sensitive in detecting resting metabolism associated with NPS in neuropsychiatric conditions, and there is a growing body of literature evaluating the role of NPS as early indicators of brain metabolic dysfunctions in AD. In this mini-review, we examine the frequency and associations of NPS with metabolic dysfunction in the AD continuum, including preclinical, prodromal, and dementia stages of AD. We will also present the validated neurobehavioral syndrome, mild behavioral impairment describes the later life emergence of sustained NPS as an at-risk state for incident cognitive decline and dementia, and an early presentation of neurodegenerative diseases in some. Lastly, we will discuss future directions in the field so as to better understand the neurobiological basis of NPS in the early stages of the AD continuum, and their role in predicting AD pathophysiological progression and incident dementia.

Multicenter Tract-Based Analysis of Microstructural Lesions within the Alzheimer's Disease Spectrum: Association with Amyloid Pathology and Diagnostic Usefulness.

Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer’s disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis (p < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aβ positive MCI cases from Aβ negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aβ positive SCD and control cases from Aβ negative controls. These findings suggest that in prodromal stages of AD, such as in Aβ positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aβ positive SCD and control cases.

Altered Cerebro-Cerebellar Limbic Network in AD Spectrum: A Resting-State fMRI Study.

Recent evidence suggests that the cerebellum is related to motor and non-motor cognitive functions, and that several coupled cerebro-cerebellar networks exist, including links with the limbic network. Since several limbic structures are affected by Alzheimer pathology, even in the preclinical stages of Alzheimer’s disease (AD), we aimed to investigate the cerebral limbic network activity from the perspective of the cerebellum. Twenty patients with mild cognitive impairment (MCI), 18 patients with AD, and 26 healthy controls (HC) were recruited to acquire Resting-state functional MRI (rs-fMRI). We used seed-based approach to construct the cerebro-cerebellar limbic network. Two-sample t-tests were carried out to explore the differences of the cerebellar limbic network connectivity. The first result, a sub-scale network including the bilateral posterior part of the orbitofrontal cortex (POFC) extending to the anterior insular cortex (AIC) and left inferior parietal lobule (L-IPL), showed greater functional connectivity in MCI than in HC and less functional connectivity in AD than in MCI. The location of this sub-scale network was in accordance with components of the ventral attention network. Second, there was decreased functional connectivity to the right mid-cingulate cortex (MCC) in the AD and MCI patient groups relative to the HC group. As the cerebellum is not compromised by Alzheimer pathology in the prodromal stage of AD, this pattern indicates that the sub-scale ventral attention network may play a pivotal role in functional compensation through the coupled cerebro-cerebellar limbic network in MCI, and the cerebellum may be a key node in the modulation of social cognition.

Decreased retinal thickness in patients with Alzheimer's disease is correlated with disease severity.

Background and purposeThe loss of retinal ganglion cells observed in Alzheimer’s disease (AD) may be attributable to a neurodegeneration of the neuro-retinal structure. Amnestic mild cognitive impairment (aMCI) has been considered a prodromal stage of AD. We evaluated retinal thicknesses in patients with aMCI and AD compared to healthy controls using spectral-domain optical coherence tomography (OCT) to investigate whether changes in retinal thickness are correlated with the clinical severity of dementia.MethodsPatients with aMCI (n = 14), mild to moderate AD (n = 7), severe AD (n = 9), and age-matched controls (n = 17) underwent neuro-ophthalmologic examinations. Global deterioration scale (GDS), clinical dementia rating (CDR), and mini-mental status examination (MMSE) were used to evaluate the clinical overall severity of dementia. The thicknesses of the peripapillary retinal nerve fiber layer (RNFL), total macula, and macular ganglion cell-inner plexiform layer (GC-IPL) were measured using Cirrus HD-OCT.ResultsThe severe AD group had overall significantly thinner GC-IPL, total macula, and peripapillary RNFL compared to the controls (p<0.05). In the mild to moderate AD group, the total macula, average RNFL, and superior RNFL thickness were each significantly reduced compared to controls (p<0.05). The aMCI group had reduced total macula, average RNFL, and inferior RNFL thickness, but there were no significant differences compared to the controls. The GDS and CDR scores had a negative correlation with the thickness of the GC-IPL and the total macula. The MMSE scores had a positive correlation with both the total macular and average RNFL thickness, when adjusted for age (p<0.05).ConclusionsThis study confirmed that retinal thickness is decreased in AD patients. There is a correlation between reduced retinal thickness and the clinical severity of dementia.

Personality Traits are Related to Selective Cognitive Impairment in Early Alzheimer's Disease.

A link between personality traits and cognitive performance has been shown in normal adults and elderly individuals. Very few studies have evaluated this link in Alzheimer's disease (AD). To better understand cognitive performance as regards to personality traits, our study was aimed to evaluate the role of premorbid personality on cognitive functioning in a population of patients presenting prodromal or mild AD. 181 elderly with prodromal or mild AD participated in a cross-sectional, prospective cohort study. The participants completed a personality inventory and a neuropsychological battery exploring memory, attention, executive function, language, and praxis. Cognitive performance were compared according to the level of each personality trait, using multivariate MANOVA models. A higher level of neuroticism was associated with lower performance at similarities test (D = 9.49, p = 0.003), delayed Free and Cued Selective Reminding test (D = 5.22, p = 0.02), and digit span score (D = 7.99, p = 0.006). A higher level of openness was related to better performance at similarities (D = 4.33, p = 0.04), letter fluency (D = 11.45, p = 0.001), and category fluency test (D = 5.85, p = 0.02). Neuroticism interfered negatively with cognitive functioning at the prodromal stage; the association between openness and cognitive function was observed at both prodromal and mild AD stage. These results suggest that personality traits, in particular neuroticism and openness, modulate cognitive abilities in patients with early AD. These results encourage the development of stress management programs to prevent its negative effects on cognitive aging.

Locus Coeruleus Degeneration Induces Forebrain Vascular Pathology in a Transgenic Rat Model of Alzheimer's Disease.

Noradrenergic locus coeruleus (LC) neuron loss is a significant feature of mild cognitive impairment and Alzheimer's disease (AD). The LC is the primary source of norepinephrine in the forebrain, where it modulates attention and memory in vulnerable cognitive regions such as prefrontal cortex (PFC) and hippocampus. Furthermore, LC-mediated norepinephrine signaling is thought to play a role in blood-brain barrier (BBB) maintenance and neurovascular coupling, suggesting that LC degeneration may impact the high comorbidity of cerebrovascular disease and AD. However, the extent to which LC projection system degeneration influences vascular pathology is not fully understood. To address this question in vivo, we stereotactically lesioned LC projection neurons innervating the PFC of six-month-old Tg344-19 AD rats using the noradrenergic immunotoxin, dopamine-β-hydroxylase IgG-saporin (DBH-sap), or an untargeted control IgG-saporin (IgG-sap). DBH-sap-lesioned animals performed significantly worse than IgG-sap animals on the Barnes maze task in measures of both spatial and working memory. DBH-sap-lesioned rats also displayed increased amyloid and inflammation pathology compared to IgG-sap controls. However, we also discovered prominent parenchymal albumin extravasation with DBH-sap lesions indicative of BBB breakdown. Moreover, microvessel wall-to-lumen ratios were increased in the PFC of DBH-sap compared to IgG-sap rats, suggesting that LC deafferentation results in vascular remodeling. Finally, we noted an early emergence of amyloid angiopathy in the DBH-sap-lesioned Tg344-19 AD rats. Taken together, these data indicate that LC projection system degeneration is a nexus lesion that compromises both vascular and neuronal function in cognitive brain areas during the prodromal stages of AD.

Neuropathological correlates of amyloid PET imaging in Down syndrome.

Down syndrome (DS) results in an overproduction of amyloid-β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12-30years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre-clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid-based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form.