Relationship between herpes simplex virus-1-specific antibody titers and cortical brain damage in Alzheimer's disease and amnestic mild cognitive impairment

This work was supported by 2012–2014 Ricerca Corrente (Italian Ministry of Health).Alzheimer's disease (AD) is a multifactorial disease with a still barely understood etiology. Herpes simplex virus 1 (HSV-1) has long been suspected to play a role in the pathogenesis of AD because of its neurotropism, high rate of infection in the general population, and life-long persistence in neuronal cells, particularly in the same brain regions that are usually altered in AD. The goal of this study was to evaluate HSV-1-specific humoral immune responses in patients with a diagnosis of either AD or amnestic mild cognitive impairment (aMCI), and to verify the possible relation between HSV-1-specific antibody (Ab) titers and cortical damage; results were compared to those obtained in a group of healthy controls (HC). HSV-1 serum IgG titers were measured in 225 subjects (83 AD, 68 aMCI, and 74 HC). HSV-specific Ab avidity and cortical gray matter volumes analyzed by magnetic resonance imaging (MRI) were evaluated as well in a subgroup of these individuals (44 AD, 23 aMCI, and 26 HC). Results showed that, whereas HSV-1 seroprevalence and IgG avidity were comparable in the three groups, increased Ab titers (p < 0.001) were detected in AD and aMCI compared to HC. Positive significant correlations were detected in AD patients alone between HSV-1 IgG titers and cortical volumes in orbitofrontal (region of interest, ROI1 RSp0.56; p = 0.0001) and bilateral temporal cortices (ROI2 RSp0.57; p < 0.0001; ROI3 RSp0.48; p = 0.001); no correlations could be detected between IgG avidity and MRI parameters. Results herein suggest that a strong HSV-1-specific humoral response could be protective toward AD-associated cortical damage.Publisher PDFPeer reviewe

Immune and Imaging Correlates of Mild Cognitive Impairment Conversion to Alzheimer&apos;s Disease

Amnestic mild cognitive impairment (aMCI) conversion to Alzheimer's disease (AD) is seen in a sizable portion of aMCI patients; correlates predicting such conversion are poorly defined but neuroinflammation and the reactivation of chronic viral infections are suspected to play a role in this phenomenon. We analyzed these aspects in two homogeneous groups of aMCI who did or did not convert to AD over a 24-months period. Results showed that at baseline in those aMCI individuals who did not convert to AD: 1) A\uce\ub21-42stimulated production of the pro-inflammatory cytokines IL6 and IL1\uce\ub2 by CD14+cells was significantly reduced (p = 0.01), 2) CD14+/IL-33+cells were increased (p = 0.0004); 3) MFI of TLR8 and TLR9 was significantly increased, and 4) better preserved hippocampus volumes were observed and correlated with IL33+/CD14+cells. Notably, A\uce\ub21-42stimulated production of the antiviral cytokine IFN-\uce\ubb was increased as well in non-AD converters, although with a borderline statistical significance (p = 0.05). Data herein indicating that proinflammatory cytokines are reduced, whereas IFN-\uce\ubb production and TLR8 and 9 MFI are augmented in those aMCI in whom AD conversion is not observed suggest that the ability to mount stronger antiviral response within an antiiflammatory milieu associates with lack of AD conversion

Technology-enhanced multi-domain at home continuum of care program with respect to usual care for people with cognitive impairment: the Ability-TelerehABILITation study protocol for a randomized controlled trial

Background: According to the World Alzheimer Report (Prince, The Global Impact of Dementia: an Analysis of Prevalence, Incidence, Cost and Trends, 2015), 46.8 million people worldwide are nowadays living with dementia. And this number is estimated to approximate 131.5 million by 2050, with an increasing burden on society and families. The lack of medical treatments able to stop or slow down the course of the disease has moved the focus of interest toward the nonpharmacological approach and psychosocial therapies for people with/at risk of dementia, as in the Mild Cognitive Impairment (MCI) condition. The purpose of the present study is to test an individualized home-based multidimensional program aimed at enhancing the continuum of care for MCI and outpatients with dementia in early stage using technology. Methods: The proposed study is a single blind randomized controlled trial (RCT) involving 30 subjects with MCI and Alzheimer's disease (AD) randomly assigned to the intervention group (Ability group), who will receive the "Ability Program", or to the active control group (ACG), who will receive "Treatment As Usual" (TAU). The protocol provides for three steps of assessment: at the baseline (T_0), after treatment, (T_1) and at follow-up (T_2) with a multidimensional evaluation battery including cognitive functioning, behavioral, functional, and quality of life measures. The Ability Program lasts 6 weeks, comprises tablet-delivered cognitive (5 days/week) and physical activities (7 days/week) combined with a set of devices for the measurement and monitoring from remote of vital and physical health parameters. The TAU equally lasts 6 weeks and includes paper and pencil cognitive activities (5 days/week), with clinician's prescription to perform physical exercise every day and to monitor selected vital parameters. Discussion: Results of this study will inform on the efficacy of a technology-enhanced home care service to preserve cognitive and motor levels of functioning in MCI and AD, in order to slow down their loss of autonomy in daily life. The expected outcome is to ensure the continuity of care from clinical practice to the patient's home, enabling also cost effectiveness and the empowerment of patient and caregiver in the care process, positively impacting on their quality of lif

REST, a master regulator of neurogenesis, evolved under strong positive selection in humans and in non human primates

The transcriptional repressor REST regulates many neuronal genes by binding RE1 motifs. About one third of human RE1s are recently evolved and specific to primates. As changes in the activity of a transcription factor reverberate on its downstream targets, we assessed whether REST displays fast evolutionary rates in primates. We show that REST was targeted by very strong positive selection during primate evolution. Positive selection was also evident in the human lineage, with six selected sites located in a region that surrounds a VNTR in exon 4. Analysis of expression data indicated that REST brain expression peaks during aging in humans but not in other primates. Because a REST coding variant (rs3796529) was previously associated with protection from hippocampal atrophy in elderly subjects with mild cognitive impairment (MCI), we analyzed a cohort of Alzheimer disease (AD) continuum patients. Genotyping of two coding variants (rs3796529 and rs2227902) located in the region surrounding the VNTR indicated a role for rs2227902 in modulation of hippocampal volume loss, indirectly confirming a role for REST in neuroprotection. Experimental studies will be instrumental to determine the functional effect of positively selected sites in REST and the role of REST variants in neuropreservation/neurodegeneration

Subcortical amyloid load is associated with shape and volume in cognitively normal individuals

Amyloid-beta (Aβ) deposition is one of the main hallmarks of Alzheimer’s disease. The study assessed the associations between cortical and subcortical 11C-Pittsburgh Compound B retention, namely in the hippocampus, amygdala, putamen, caudate, pallidum, and thalamus, and subcortical morphology in cognitively normal individuals. We recruited 104 cognitive normal individuals who underwent extensive neuropsychological assessment, PiB-positron emission tomography (PET) scan and 3-tesla magnetic resonance imaging (MRI) acquisition of T1-weighted images. Global, cortical, and subcortical regional PiB retention values were derived from each scan and subcortical morphology analyses were performed to investigate vertex-wise local surface and global volumes, including the hippocampal subfields volumes. We found that subcortical regional Aβ was associated with the surface of the hippocampus, thalamus, and pallidum, with changes being due to volume and shape. Hippocampal Aβ was marginally associated with volume of the whole hippocampus as well as with the CA1 subfield, subiculum, and molecular layer. Participants showing higher subcortical Aβ also showed worse cognitive performance and smaller hippocampal volumes. In contrast, global and cortical PiB uptake did not associate with any subcortical metrics. This study shows that subcortical Aβ is associated with subcortical surface morphology in cognitively normal individuals. This study highlights the importance of quantifying subcortical regional PiB retention values in these individuals

HSV-1 Specific IgG3 Titers Correlate with Brain Cortical Thinning in Individuals with Mild Cognitive Impairment and Alzheimer&#8217;s Disease

Repeated reactivations of latent herpes simplex virus type-1 (HSV-1) in the central nervous system (CNS) may contribute to neurodegeneration in Alzheimer's disease (AD) patients. Immune response is a key element for the control of viral reactivation. HSV-1 uses a number of strategies to evade immune recognition, Immunoglobulin G 3 (IgG(3)) alone counteracts humoral immunoevasion, as it is the only IgG subclass that is not blocked by the HSV-1 Fc receptor, a protein that protects virion and infected cells from antibody-mediated effector mechanisms. We examined HSV-1-specific IgG(3) titers in serum of AD (n = 70) and mild cognitive impairment (MCI) (n = 61) subjects comparing the results to those of 67 age- and sex-matched healthy controls (HC); associations between MRI-determined brain cortical health and HSV-1-specific IgG(3) were analyzed in a subgroup of AD and MCI subjects. HSV-1-specific IgG(3) were more frequently detected in MCI compared to AD and HC subjects. Significant inverse correlations were found between IgG(3) titers and brain cortical thickness in areas typically involved in dementia and HSV-1 encephalitis in AD patients; interestingly, this negative correlation was much less important in MCI subjects. All together these results suggest that in AD an inefficient IgG(3) humoral immune response, failing to block viral replication, contributes to progressive neurodegeneration

Titers of herpes simplex virus Type 1 antibodies positively correlate with Grey Matter volumes in Alzheimer&apos;s disease

HSV-1 infection of the central nervous system targets the same brain regions most affected in Alzheimer's disease (AD) and could play a pathogenic role in AD. HSV-1 serum IgG titers were analyzed in patients with mild AD(n = 83) and healthy controls (HC, n = 51); results were correlated with cortical grey matter (GM) volumes as analyzed by MRI. Seroprevalence and antibody (Ab) titers were comparable between AD and HC; elevated Ab titers (>75th percentile) were nevertheless significantly more frequent in AD and were positively correlated with cortical bilateral temporal and orbitofrontal GM volumes. HSV-1-specific-Ab could possibly play a protective role in the early stages of AD

The shape of motor resonance: right- or left-handed?

The human Mirror Neuron System is a fronto-parietal neural pathway which, when activated by action observation, gives rise to an internal simulation of the observed action (motor resonance). Here we demonstrate how handedness shapes the resonant response, by engaging right-handed (RH) and left handed (LH) subjects in observation and execution of actions preferentially performed by the dominant hand. We hypothesize that since motor resonance reproduces subliminally the specific motor program for the observed action, it should be subject to motor constraints, such as handedness. A conjunction analysis for observed and executed actions revealed that handedness determines a lateralized activation of the areas engaged in motor resonance. Premotor-BA6 and parietal-BA40 are strongly left lateralized in RH subjects observing or moving their right hand, and to a lesser degree their left hand. Extremely LH subjects show a similar pattern of lateralization on the right, while more ambidextrous LH subjects show a more bilateral activation. The activation of a cortical network outside the Mirror Neuron System is also discusse