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For decades, mitochondrial dysfunctions and the generation of reactive oxygen species have been proposed to promote the development and progression of the amyloid pathology in Alzheimer's disease, but this association is still debated. It is unclear whether different mitochondrial dysfunctions, such as oxidative phosphorylation deficiency and oxidative stress, are triggers or rather consequences of the formation of amyloid aggregates. Likewise, the role of the different mitochondrial oxidative phosphorylation complexes in Alzheimer's patients' brain remains poorly understood. Previous studies showed that genetic ablation of oxidative phosphorylation enzymes from early age decreased amyloid pathology, which were unexpected results. To better model oxidative phosphorylation defects in aging, we induced the ablation of mitochondrial Complex III (CIII KO ) in forebrain neurons of adult mice with amyloid pathology. We found that mitochondrial Complex III dysfunction in adult neurons induced mild oxidative stress but did not increase amyloid beta accumulation. On the contrary, CIII KO -AD mice showed decreased plaque number, decreased Aβ42 toxic fragment, and altered amyloid precursor protein clearance pathway. Our results support the hypothesis that mitochondrial dysfunctions alone, caused by oxidative phosphorylation deficiency, is not the cause of amyloid accumulation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), currently represent major unmet medical needs. Therefore, novel therapeutic strategies are needed in order to improve patients' quality of life and prognosis. Since oxidative stress can be strongly involved in neurodegenerative diseases, the potential use of inosine, known for its antioxidant properties, in this context deserves particular attention. The protective action of inosine treatment could be mediated by its metabolite urate. Here, we review the current preclinical and clinical studies investigating the use of inosine in AD, PD, ALS, and MS. The most important properties of inosine seem to be its antioxidant action and its ability to raise urate levels and to increase energetic resources by improving ATP availability. Inosine appears to be generally safe and well tolerated; however, the possible formation of kidney stones should be monitored, and data on its effectiveness should be further explored since, so far, they have been controversial. Overall, inosine could be a promising potential strategy in the management of neurodegenerative diseases, and additional studies are needed in order to further investigate its safety and efficacy and its use as a complementary therapy along with other approved drugs.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and represents the most common form of senile dementia. Autophagy and mitophagy are cellular processes that play a key role in the aggregation of β-amyloid (Aβ) and tau phosphorylation. As a consequence, impairment of these processes leads to the progression of AD. Thus, interest is growing in the search for new natural compounds, such as Moringin (MOR), with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties that could be used for AD prevention. However, MOR appears to be poorly soluble and stable in water. To increase its solubility MOR was conjugated with α-cyclodextrin (MOR/α-CD). In this work, it was evaluated if MOR/α-CD pretreatment was able to exert neuroprotective effects in an AD in vitro model through the evaluation of the transcriptional profile by next-generation sequencing (NGS). To induce the AD model, retinoic acid-differentiated SH-SY5Y cells were exposed to Aβ 1-42 . The MOR/α-CD pretreatment reduced the expression of the genes which encode proteins involved in senescence, autophagy, and mitophagy processes. Additionally, MOR/α-CD was able to induce neuronal remodeling modulating the axon guidance, principally downregulating the Slit/Robo signaling pathway. Noteworthy, MOR/α-CD, modulating these important pathways, may induce neuronal protection against Aβ 1-42 toxicity as demonstrated also by the reduction of cleaved caspase 3. These data indicated that MOR/α-CD could attenuate the progression of the disease and promote neuronal repair.

MicroRNAs (miRNAs) are small RNAs involved in the post-transcriptional regulation of their target genes, causing a decrease in protein translation from the mRNA. Different miRNAs are found in the nervous system, where they are involved in its physiological functions, but altered miRNAs expression was also reported in neurodegenerative disorders, including Alzheimer's disease (AD). AD is characterized by memory loss, cognitive function abnormalities, and various neuropsychiatric disturbances. AD hallmarks are amyloid β (Aβ) aggregates, called senile plaques, and neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein. In this study, we performed an in silico analysis to evaluate altered patterns of miRNAs expression in the brains of AD patients compared to healthy subjects. We found 12 miRNAs that were differentially expressed in AD compared to healthy individuals. These miRNAs have target genes involved in AD pathogenesis. In particular, some miRNAs influence Aβ production, having as target secretase and amyloid precursor protein (APP). Some miRNAs were reported to be involved in nervous system functions, and their alteration can cause neuronal dysfunction.

Object: Alzheimer's disease is a progressive, irreversible neurodegenerative disorder associated with brain alterations. Diffusion tensor imaging (DTI) has contributed to identify degeneration in white matter cortical microstructural that can be considered an early and specific biomarker for Alzheimer's disease. This review aimed to provide a summary of DTI studies on white matter damage in Alzheimer's disease. Methods: On PubMed, Web of Science and Scopus databases, we reviewed the studies that used DTI for assessing fractional anisotropy in neurofiber tracts involved in Alzheimer's Disease progression: fornix, the cingulum, uncinate fasciculus, superior and inferior longitudinal fasciculus and corpus callosum. We included nine studies that met search criteria. Results: The results showed decreased fractional anisotropy value in mild cognitive impairment (MCI) patients. White matter diffusivity changes were associated with the progression of Alzheimer's disease. Conclusion: Microstructural alterations of the limbic and cortico-cortical tracts could be potential biomarkers for early diagnosis in preclinical disease phase.

miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3' and 5' untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain and some studies suggest that miRNAs are intimately involved in synaptic function and in specific signals during memory formation. More and more evidence demonstrates the possible involvement of miRNAs in Alzheimer's disease (AD). AD is the most common form of senile dementia, a disease that affects memory and cognitive functions. It is a neurodegenerative disorder characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated TAU protein. This review aims to provide an overview of the in vivo studies of the last 5 years in the literature describing the role of the different miRNAs involved in AD. miRNAs hold huge potential as diagnostic and prognostic biomarkers and, at the same time, their modulation could be a potential therapeutic strategy against AD.

Background: Vascular dementia and Alzheimer's disease are the most diffuse forms of dementia. Sometimes, they are difficult to distinguish due to overlaps in symptomatology, pathophysiology, and comorbidity. Visual constructive apraxia is very common in dementia and impairment in these abilities can provide clinical information for differential diagnosis., Materials and Methods: All patients underwent Mini Mental State Examination (MMSE) at basal visit (T0) and after 1 year (T1). We analyzed differences in Qualitative Scoring Method for the Pentagon Copying Test and we explored the visual constructive apraxia evolution in these 2 types of dementia., Results: In intragroup analysis, we found a significant difference in each group between T0 and T1 in MMSE score (P < .001) and total qualitative scores (P < .001). In intergroup analysis, at T0, we found significance difference in total qualitative scores (P < .001), in numbers of angles (P = .005), in distance/intersection (P < .001), in closure/opening (P = .01), in rotation (P < .001), and in closing-in (P < .001). At T1, we found significance difference in total qualitative scores (P < .001), in particular, in numbers of angles (P < .001), in distance/intersection (P < .001), in closure/opening (P < .001), in rotation (P < .001), and in closing-in (P < .001). The total score showed the highest classification accuracy (.90, 95%CI = .81-0.96) in differentiating patients with Alzheimer's disease from patients with vascular dementia. The optimal threshold value was k = 5. with .84 (95%CI = .69-0.93) sensitivity and .81 (95%CI = .64-0.93) specificity., Conclusion: Patients with vascular dementia showed more accuracy errors and graphic difficulties than patients with Alzheimer's disease. Qualitative analysis of copy provided a sensitive measure of visual constructive abilities in differentiating dementias, underlining a particularly vulnerability of visuoconstructive functions in vascular dementia compared with Alzheimer's disease., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Alzheimer's Disease (AD) is a neurodegenaritive disorder characterized by a progressive dementia, for which actually no cure is known. An early detection of patients affected by AD can be obtained by analyzing their electroencephalography (EEG) signals, which show a reduction of the complexity, a perturbation of the synchrony, and a slowing down of the rhythms., Methods: In this work, we apply a procedure that exploits feature extraction and classification techniques to EEG signals, whose aim is to distinguish patient affected by AD from the ones affected by Mild Cognitive Impairment (MCI) and healthy control (HC) samples. Specifically, we perform a time-frequency analysis by applying both the Fourier and Wavelet Transforms on 109 samples belonging to AD, MCI, and HC classes. The classification procedure is designed with the following steps: (i) preprocessing of EEG signals; (ii) feature extraction by means of the Discrete Fourier and Wavelet Transforms; and (iii) classification with tree-based supervised methods., Results: By applying our procedure, we are able to extract reliable human-interpretable classification models that allow to automatically assign the patients into their belonging class. In particular, by exploiting a Wavelet feature extraction we achieve 83%, 92%, and 79% of accuracy when dealing with HC vs AD, HC vs MCI, and MCI vs AD classification problems, respectively., Conclusions: Finally, by comparing the classification performances with both feature extraction methods, we find out that Wavelets analysis outperforms Fourier. Hence, we suggest it in combination with supervised methods for automatic patients classification based on their EEG signals for aiding the medical diagnosis of dementia.

In physiological conditions, different types of macrophages can be found within the central nervous system (CNS), i.e., microglia, meningeal macrophages, and perivascular (blood-brain barrier) and choroid plexus (blood-cerebrospinal fluid barrier) macrophages. Microglia and tissue-resident macrophages, as well as blood-borne monocytes, have different origins, as the former derive from yolk sac erythromyeloid precursors and the latter from the fetal liver or bone marrow. Accordingly, specific phenotypic patterns characterize each population. These cells function to maintain homeostasis and are directly involved in the development and resolution of neuroinflammatory processes. Also, following inflammation, circulating monocytes can be recruited and enter the CNS, therefore contributing to brain pathology. These cell populations have now been identified as key players in CNS pathology, including autoimmune diseases, such as multiple sclerosis, and degenerative diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer's disease. Here, we review the evidence on the involvement of CNS macrophages in neuroinflammation and the advantages, pitfalls, and translational opportunities of pharmacological interventions targeting these heterogeneous cellular populations for the treatment of brain diseases., Competing Interests: The authors declare no conflict of interest.

Aim: Cognitive impairment is present in several neurodegenerative disorders. The clock-drawing test (CDT) represents a useful screening instrument for assessing the evolution of cognitive decline. The aim of this study was to investigate the sensitivity of the CDT in monitoring and differentiating the evolution of cognitive decline in Alzheimer's dementia (AD), vascular dementia (VaD), and Parkinson's disease (PD)., Methods: This study involved 139 patients, including 39 patients with PD and mild cognitive impairment, 16 demented PD patients, 21 VaD patients with mild cognitive impairment, 17 patients with VaD, 33 patients with mild cognitive impairment due to AD, and 13 patients with probable AD. All participants completed the CDT. The Mini-Mental State Examination was administered to establish patients' cognitive functioning., Results: Comparisons of quantitative and qualitative CDT scores showed significant differences between the various diseases. Impairment of executive functioning seems to be more pronounced in PD and VaD than in AD. Patients with AD committed more errors related to a loss of semantic knowledge, indicating a severely reduced capacity in abstract and conceptual thinking., Conclusion: Results support the usefulness and sensitivity of the CDT in the detection of different dementia subtypes. Qualitative error analysis of the CDT may be helpful in differentiating PD, VaD, and AD, even in the early stages of each disease., (© 2018 Japanese Psychogeriatric Society.)

Background: Identifying the patients with mild cognitive impairment (MCI) who may develop dementia (MDC) is challenging. The study of peripersonal space (PPS) by using functional transcranial Doppler (fTCD) could be used for this purpose., Objective: To identify changes in cerebral blood flow (CBF) during motor tasks targeting PPS, which can predict MDC., Methods: We evaluated the changes in CBF in 22 patients with MCI and 23 with dementia [Alzheimer's disease (AD) and vascular dementia (VaD)] during a motor task (passive mobilization, motor imagery, and movement observation) in which the hand of the subject moved forward and backward the face., Results: CBF increased when the hand approached the face and decreased when the hand moved from the face in the healthy controls (HCs). CBF changed were detectable only in patients with MCI but not in those with the AD and those who were MDC after 8-month follow-up. On the other hand, the patients with VaD presented a paradoxical response to the motor task (i.e., a decrease of CBF rather than an increase, as observed in HCs and MCI). Therefore, we found a modulation of PPS-related CBF only in HCs and patients with stable MCI (at the 8-month follow-up)., Conclusions: fTCD may allow preliminarily differentiating and following-up the patients with MCI and MDC, thus allowing the physician to plan beforehand more individualized cognitive rehabilitative training.

Alzheimer's disease (AD) is a neurodegenerative disorder representing the major cause of dementia. It is characterized by memory loss, and cognitive and behavioral decline. In particular, the hallmarks of the pathology are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), formed by aggregated hyperphosphorylated tau protein. Oxidative stress plays a main role in AD, and it is involved in initiation and progression of AD. It is well known that Aβ induced oxidative stress, promoting reactive oxygen species (ROS) production and consequently lipid peroxidation, protein oxidation, tau hyperphosphorylation, results in toxic effects on synapses and neurons. In turn, oxidative stress can increase Aβ production. For these reasons, the administration of an antioxidant therapy in AD patients was suggested. The term vitamin E includes different fat-soluble compounds, divided into tocopherols and tocotrienols, that possess antioxidant action. α-Tocopherol is the most studied, but some studies suggested that tocotrienols may have different health promoting capacities. In this review, we focused our attention on the effects of vitamin E supplementation in AD animal models and AD patients or older population. Experimental models showed that vitamin E supplementation, by decreasing oxidative stress, may be a good strategy to improve cognitive and memory deficits. Furthermore, the combination of vitamin E with other antioxidant or anti-inflammatory compounds may increase its efficacy. However, even if some trials have evidenced some benefits, the effects of vitamin E in AD patients are still under debate., Competing Interests: The authors declare no conflict of interest.

Objective: In this work, we introduce Permutation Disalignment Index (PDI) as a novel nonlinear, amplitude independent, robust to noise metric of coupling strength between time series, with the aim of applying it to electroencephalographic (EEG) signals recorded longitudinally from Alzheimer's Disease (AD) and Mild Cognitive Impaired (MCI) patients. The goal is to indirectly estimate the connectivity between the cortical areas, through the quantification of the coupling strength between the corresponding EEG signals, in order to find a possible matching with the disease's progression., Method: PDI is first defined and tested on simulated interacting dynamic systems. PDI is then applied to real EEG recorded from 8 amnestic MCI subjects and 7 AD patients, who were longitudinally evaluated at time [Formula: see text]0 and 3 months later (time [Formula: see text]1). At time [Formula: see text]1, 5 out of 8 MCI patients were still diagnosed MCI (stable MCI) whereas the remaining 3 exhibited a conversion from MCI to AD (prodromal AD). PDI was compared to the Spectral Coherence and the Dissimilarity Index., Results: Limited to the size of the analyzed dataset, both Coherence and PDI resulted sensitive to the conversion from MCI to AD, even though only PDI resulted specific. In particular, the intrasubject variability study showed that the three patients who converted to AD exhibited a significantly ([Formula: see text]) increased PDI (reduced coupling strength) in delta and theta bands. As regards Coherence, even though it significantly decreased in the three converted patients, in delta and theta bands, such a behavior was also detectable in one stable MCI patient, in delta band, thus making Coherence not specific. From the Dissimilarity Index point of view, the converted MCI showed no peculiar behavior., Conclusions: PDI significantly increased, in delta and theta bands, specifically in the MCI subjects who converted to AD. The increase of PDI reflects a reduced coupling strength among the brain areas, which is consistent with the expected connectivity reduction associated to AD progression.

Brain imaging plays an important role in the study of Alzheimer's disease (AD), where atrophy has been found to occur in the hippocampal formation during the very early disease stages and to progress in parallel with the disease's evolution. The aim of the present study was to evaluate a possible correlation between "Small World" characteristics of the brain connectivity architecture-as extracted from EEG recordings-and hippocampal volume in AD patients. A dataset of 144 subjects, including 110 AD (MMSE 21.3) and 34 healthy Nold (MMSE 29.8) individuals, was evaluated. Weighted and undirected networks were built by the eLORETA solutions of the cortical sources' activities moving from EEG recordings. The evaluation of the hippocampal volume was carried out on a subgroup of 60 AD patients who received a high-resolution T1-weighted sequence and underwent processing for surface-based cortex reconstruction and volumetric segmentation using the Freesurfer image analysis software. Results showed that, quantitatively, more correlation was observed in the right hemisphere, but the same trend was seen in both hemispheres. Alpha band connectivity was negatively correlated, while slow (delta) and fast-frequency (beta, gamma) bands positively correlated with hippocampal volume. Namely, the larger the hippocampal volume, the lower the alpha and the higher the delta, beta, and gamma Small World characteristics of connectivity. Accordingly, the Small World connectivity pattern could represent a functional counterpart of structural hippocampal atrophying and related-network disconnection.

Endogenous glucocorticoids (eGCs) are steroid hormones with a wide spectrum of physiological effects. However, enhanced basal eGCs levels have been observed in patients affected by Alzheimer's disease (AD) and they have been correlated with dysregulation of the hypothalamic-pituitary-adrenocortical axis, hippocampal degeneration and reduced cognitive/memory performance. Therefore, it has been proposed that elevated concentration of eGCs might have a role in AD pathogenesis. AD is the most common form of dementia, characterized by the pathological accumulation of two proteins: the Amyloid Beta (Aβ) and the microtubule-associated protein tau in the neurons of the hippocampus and prefrontal cortex. In particular, the hippocampus, the cerebral area involved in learning and memory, is the brain region more vulnerable to chronic eGCs exposure. Although clinical studies have failed to establish a direct causative link between eGCs e and AD pathogenesis, evidences from pre-clinical studies have shown that increased eGCs levels accelerate the formation of Aβ in AD animal models by promoting the amyloidogenic pathway, and in parallel by reducing Aβ clearance, through transcriptional mechanisms involving the Glucocorticoid receptors. Instead, the effects of stress on tau phosphorylation seem to be mainly mediated bv the corticotropin-releasing factor receptor (CRFR1) and independent from stress-induced eGCs elevation.

Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of several neurodegenerative disorders, including Alzheimer's disease (AD). The main neuropathological hallmarks of AD are senile plaques, composed of amyloid beta (Aβ), and neurofibrillary tangles, formed by hyperphosphorylated tau. However, current therapies for AD have shown limited efficacy. In this study, we evaluated whether pre-treatment with cannabidiol (CBD), at 5 μM concentration, modulated the transcriptional profile of MSCs derived from gingiva (GMSCs) in order to improve their therapeutic potential, by performing a transcriptomic analysis by the next-generation sequencing (NGS) platform. By comparing the expression profiles between GMSCs treated with CBD (CBD-GMSCs) and control GMSCs (CTR-GMSCs), we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aβ generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3β, a central player in AD pathogenesis, by promoting PI3K/Akt signalling. In order to understand through which receptor CBD exerted these effects, we have performed pre-treatments with receptor antagonists for the cannabinoid receptors (SR141716A and AM630) or for the vanilloid receptor 1 (TRPVI). Here, we have proved that TRPV1 was able to mediate the modulatory effect of CBD on the PI3K/Akt/GSK3β axis. In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aβ production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD., Competing Interests: The authors declare no conflict of interest.

A complex network approach is combined with time dynamics in order to conduct a space-time analysis applicable to longitudinal studies aimed to characterize the progression of Alzheimer's disease (AD) in individual patients. The network analysis reveals how patient-specific patterns are associated with disease progression, also capturing the widespread effect of local disruptions. This longitudinal study is carried out on resting electroence phalography (EEGs) of seven AD patients. The test is repeated after a three months' period. The proposed methodology allows to extract some averaged information and regularities on the patients' cohort and to quantify concisely the disease evolution. From the functional viewpoint, the progression of AD is shown to be characterized by a loss of connected areas here measured in terms of network parameters (characteristic path length, clustering coefficient, global efficiency, degree of connectivity and connectivity density). The differences found between baseline and at follow-up are statistically significant. Finally, an original topographic multiscale approach is proposed that yields additional results.

In this study, we evaluated the levels of some of the most investigated metals (Cu, Se, Zn, Pb, and Hg) in the blood of patients affected by the most common chronic neurodegenerative diseases like Alzheimer's disease (AD) and multiple sclerosis (MS), in order to better clarify their involvement. For the first time, we investigated a Sicilian population living in an area exposed to a potentially contaminated environment from dust and fumes of volcano Etna and consumer of a considerable quantity of fish in their diet, so that this represents a good cohort to demonstrate a possible link between metals levels and development of neurodegenerative disorders. More specifically, 15 patients affected by AD, 41 patients affected by MS, 23 healthy controls, and 10 healthy elderly controls were recruited and subjected to a venous blood sampling. Quantification of heavy metals was performed by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). This technique has allowed us to establish that there is a concomitance of heavy metal unbalance associated with AD more than in other neurodegenerative pathologies, such as MS. Also, we can assess that the concentration of these elements is independent from the diet, especially from occasional or habitual consumption of fruits and vegetables, prevalence in the diet of meat or fish, possible exposure to contaminated environment due both to the occupation and place of residence.

Early detection of dementia can be useful to delay progression of the disease and to raise awareness of the condition. Alterations in temporal and spatial EEG markers have been found in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Herein, we propose an automatic recognition method of cognitive impairment evaluation based on EEG analysis using an artificial neural network (ANN) combined with a genetic algorithm (GA). The EEGs of 43 AD and MCI patients (aged between 62 and 88 years) were recorded, analyzed and correlated with their MMSE scores. Quantitative EEGs were calculated using discrete wavelet transform. The data obtained were analyzed by the means of the combined use of ANN and GA to determine the degree of cognitive impairment. The good recognition rate of ANN fed with these inputs suggests that the combined GA/ANN approach may be useful for early detection of AD and could be a valuable tool to support physicians in clinical practice.

The aim of this study was to investigate the neuronal network characteristics in physiological and pathological brain aging. A database of 378 participants divided in three groups was analyzed: Alzheimer's disease (AD), mild cognitive impairment (MCI), and normal elderly (Nold) subjects. Through EEG recordings, cortical sources were evaluated by sLORETA software, while graph theory parameters (Characteristic Path Length λ, Clustering coefficient γ, and small-world network σ) were computed to the undirected and weighted networks, obtained by the lagged linear coherence evaluated by eLORETA software. EEG cortical sources from spectral analysis showed significant differences in delta, theta, and alpha 1 bands. Furthermore, the analysis of eLORETA cortical connectivity suggested that for the normalized Characteristic Path Length (λ) the pattern differences between normal cognition and dementia were observed in the theta band (MCI subjects are find similar to healthy subjects), while for the normalized Clustering coefficient (γ) a significant increment was found for AD group in delta, theta, and alpha 1 bands; finally, the small world (σ) parameter presented a significant interaction between AD and MCI groups showing a theta increase in MCI. The fact that AD patients respect the MCI subjects were significantly impaired in theta but not in alpha bands connectivity are in line with the hypothesis of an intermediate status of MCI between normal condition and overt dementia.

Alzheimer's disease (AD) is a neurodegenerative disorder mainly characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, loss of synapses and neurons and chronic neuroinflammation. Emerging data highlight the involvement of innate immunity, that has been shown to play opposing roles during the AD progression. Activated microglia and reactive astrocytes exert neuroprotection mediated through Aβ phagocytosis in the early stage, whereas, as the disease progresses, they fail in Aβ clearance and exert detrimental effects, including neuroinflammation and neurodegeneration. Specific toll-like receptors (TLRs) and coreceptors can directly or indirectly be activated to induce Aβ uptake or inflammatory responses, depending on the disease stage. Fibrillar Aβ can directly interact with TLR2, TLR4, and CD14 to induce microglial Aβ phagocytosis in the beginning stages, and neuroinflammatory responses in the late stages. Early TLR3-mediated signal enhances neuronal Aβ autophagy, although it increases neuronal apoptosis in the late AD stage. Similarly, TLR7, TLR8 and TLR9 can enhance microglial Aβ uptake in the early stage, but over time they contribute to neuroinflammation. Therefore, TLRs, and in particular TLR2 and TLR4, represent a suitable target for therapeutic intervention within the disease progression and targeting them carefully could increase Aβ autophagy and phagocytosis or reduce inflammatory responses. Several modulators with selective TLR agonist or antagonist activity have been developed, and many of them could have a therapeutic benefit in AD patients. This paper outlines the role of specific TLRs in AD, also focusing on TLR-targeted compounds yet indicated for the treatment of other inflammatory diseases, that could be used to treat the different stages of the disease.

Background: Gray matter atrophy is regarded as a valid marker of neurodegeneration in Alzheimer's disease (AD), but few studies have investigated in detail the topographic changes associated with normal aging. In addition, few studies have compared the changes in the earliest clinical stage of AD (prodromal AD (pAD)) with those of healthy aging. Here we aimed to investigate the topographical distribution of age-related cortical atrophy and to compare it with that associated with prodromal and estabilished AD., Methods: Structural T1-weighted high-resolution brain magnetic resonance imaging scans were acquired from 60 healthy volunteers (20 young adults, YA: age 32.7 +/- 4.5 years; 40 elderly subjects, HE: age 71.3 +/- 6.2 years), 16 mild cognitive impairment subjects who converted to AD within 2 years (prodromal AD, pAD: age 72.8 +/- 5.4), and 20 mild to moderate AD patients (mAD, age 72.5 +/- 10.3). Cortical gray matter differences were investigated using a surface-based anatomical mesh modeling technique (cortical pattern matching) and region-of-interest (ROI) analyses based on hypothesized brain networks taught to have a functional and a structural link to each other. Differences in cortical atrophy were assessed between groups, as well as the effect of age within groups., Results: HE compared to YA showed a 10-30% deficit in cortical gray matter in widespread frontal, temporal, and parietal regions (p = 0.0001 by permutation testing), 6-13% loss in the visual and sensorimotor cortices (p < 0.01) and up to 13% loss in the direct hippocampal pathway ROIs (p < 0.001). pAD patients showed on average 8-9% cortical loss compared to HE (p < 0.0001), mainly in the left (up to 6% loss, p = 0.06) and right polysynaptic hippocampal pathway ROIs (up to 8% loss, p = 0.01), and in the left and right olfactory/orbitofrontal cortex (up to 12-15% loss, p < 0.001). The pattern of cortical atrophy in mAD versus HE was similar to that in pAD, but was more severe in the direct hippocampal pathway ROIs and sensorimotor, visual and temporal cortices (13-15% loss compared with HE, p < 0.0001)., Conclusion: Gray matter loss occurs during aging with rates of atrophy even more severe than that observed during the course of AD. These changes may be caused by normal mechanisms. In pAD, cortical atrophy due to disease is milder than that due to aging, maybe resulting from a slowed down velocity of cell loss, but affects specific brain areas. These findings are consistent with the view that AD is not merely accelerated aging.

Diagnosis and therapeutic strategies in Alzheimer's disease (AD) might greatly benefit of the present multidisciplinary approach for studying the molecular pathogenesis of the disorder. Gene expression profile at peripheral level could be a promising tool for pathogenic studies as well as for early diagnosis of AD. A dysregulated inflammatory response, as well as other systemic disorders, have been described in AD. Therefore, we investigated the expression, at peripheral level, of a number of genes involved in the inflammatory, oxidative stress and proliferative response of a well defined, small cohort of sporadic AD patients. Firstly, the mRNA expression of inflammatory, stress and proliferation/ differentiation genes were evaluated, using SuperArray, in mitogen-stimulated peripheral blood mononuclear cells (PBMC) from a group of 12 well-characterized, sporadic AD patients with various levels of dementia, by comparison with aged-matched controls. Real-time RT-PCR confirmed the trend of alteration in 16 genes out of the 36 supposed to be dysregulated in AD patients, by the preliminary screening. The expression level of the NFKB1(p105/50Kd) gene was significantly higher in AD with respect to adult age-matched controls (AA) and was related to the Mini-Mental State Examination (MMSE) score of the same patients. In addition, the expression of various NF-κB target genes and of both NF-κBp50 and NF-κBp65 DNA-binding activity were increased in PBMC from AD patients in comparison with those from AA. Our results suggest that NF-κB activation at peripheral blood cell level could be a potential new hallmark of AD progression and sustain a rationale to more deeply investigate the therapeutic potential of specific NF-κB inhibitors in AD.

Resting state electroencephalographic (EEG) rhythms do not deteriorate with the increase of white matter vascular lesion in amnesic mild cognitive impairment (MCI) subjects [1], although white matter is impaired along Alzheimer's disease (AD). Here we tested whether this is true even in AD subjects. Closed-eye resting state EEG data were recorded in 40 healthy elderly (Nold), 96 amnesic MCI, and 83 AD subjects. White matter vascular lesions were indexed by magnetic resonance imaging recorded in the MCI and AD subjects (about 42% of cases following ADNI standards). The MCI subjects were divided into two sub-groups based on the median of the white matter lesion, namely MCI+ (people with highest vascular load; n = 48) and MCI- (people with lowest vascular load; n = 48). The same was true for the AD subjects (AD+, n = 42; AD-, n = 41). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). LORETA software estimated cortical EEG sources. When compared to Nold group, MCI and AD groups showed well known abnormalities of delta and alpha sources. Furthermore, amplitude of occipital, temporal, and limbic alpha 1 sources were higher in MCI+ than MCI- group. As a novelty, amplitude of occipital delta sources was lower in AD+ than AD- group. Furthermore, central, parietal, occipital, temporal, and limbic alpha sources were higher in amplitude in AD+ than AD- group. Amplitude of these sources was correlated to global cognitive status (i.e., Mini Mental State Evaluation score). These results suggest that in amnesic MCI and AD subjects, resting state posterior delta and alpha EEG rhythms do not deteriorate with the increase of white-matter vascular lesion. These rhythms might be more sensitive to AD neurodegenerative processes and cognitive status rather than to concomitant lesions to white matter.

Serotonergic transmission impairment and abnormal phosphorylation of tau protein have been implicated in the physiopathology of Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Associations between a functional polymorphism (5-HTTLPR), in the promoter region of the serotonin transporter gene, and susceptibility to sporadic AD and FTLD have been reported. A polymorphism (Q7R) in saitohin gene inside the microtubule-associated protein tau gene has also been related to dementia. To determine the possible role of the two polymorphisms in susceptibility to AD and FTLD, we performed a case-control study collecting 218 Italian sporadic dementia patients and 54 controls. We found a significant excess of 5-HTTLPR short alleles and an interaction between 5-HTTLPR and Q7R polymorphisms in demented subjects. Our study confirms the role of 5-HTTLPR as a potential susceptibility factor for sporadic dementia in the Italian population, and suggests a possible interaction between 5-HTTLPR and Q7R polymorphisms in neurodegenerative diseases.