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Broadband Coherent anti-Stokes Raman (BCARS) microscopy is an imaging technique that can acquire full Raman spectra (400-3200 cm -1 ) of biological samples within a few milliseconds. However, the CARS signal suffers from an undesired non-resonant background (NRB), deriving from four-wave-mixing processes, which distorts the peak line shapes and reduces the chemical contrast. Traditionally, the NRB is removed using numerical algorithms that require expert users and knowledge of the NRB spectral profile. Recently, deep-learning models proved to be powerful tools for unsupervised automation and acceleration of NRB removal. Here, we thoroughly review the existing NRB removal deep-learning models (SpecNet, VECTOR, LSTM, Bi-LSTM) and present two novel architectures. The first one combines convolutional layers with Gated Recurrent Units (CNN + GRU); the second one is a Generative Adversarial Network (GAN) that trains an encoder-decoder network and an adversarial convolutional neural network. We also introduce an improved training dataset, generalized on different BCARS experimental configurations. We compare the performances of all these networks on test and experimental data, using them in the pipeline for spectral unmixing of BCARS images. Our analyses show that CNN + GRU and VECTOR are the networks giving the highest accuracy, GAN is the one that predicts the highest number of true positive peaks in experimental data, whereas GAN and VECTOR are the most suitable ones for real-time processing of BCARS images., (© 2024. The Author(s).)

Inflammation plays a crucial role in Alzheimer's disease (AD). AD neurodegeneration and concurrent involvement of the peripheral immune system may promote leukocyte division and telomere shortening. We examined genotypes and plasma levels of two proinflammatory cytokines, IL-1beta and IL-18, and leukocyte telomere length (LTL) in patients with mild cognitive impairment (MCI) and AD. We wanted to determine whether changes in plasma IL-1beta and IL-18 levels, together with LTL shortening, could be diagnostic for disease progression from MCI to AD. Median plasma IL-1beta levels were in the order MCI patients (2.2 pg/ml) < AD patients (4.0 pg/ml), both of which differed significantly from the controls (0.0 pg/ml). In the AD patients, the lowest IL-1beta levels were associated with the presence of the C allele of IL-1beta rs16944 SNP. Median plasma IL-18 levels were in the order MCI patients (116.3 pg/ml) > AD patients (85.8 pg/ml), both of which were significantly higher than in the controls (17.6 pg/ml). Analysis of LTL showed a progressive reduction in the order controls > MCI > AD patients (p < 0.0001). Overall LTL reduction was correlated with increased plasma IL-1beta levels, substantiating the hypothesis that inflammatory processes secondary to neuroinflammation may trigger telomere attrition. Changes in plasma IL-1beta and Il-18 levels, and LTL seem to reflect shifts in AD stage; they may have potential use as blood biomarkers to monitor disease onset and progression from MCI to AD., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Clinical competence is the term used to describe an individual's capacity to express a choice regarding their participation in clinical procedures or experimental studies. Understanding the information provided is a prerequisite but consent forms are often lengthy and complicated. Alzheimer's disease patients may be vulnerable in written comprehension, due to cognitive deficits, but unfortunately to date, a specific evaluation of this ability is not included in periodical assessments., Methods: One hundred thirty Italian patients with Alzheimer's disease were compared with 130 controls in a comprehension task involving a simplified informed consent form. Their performance in this task was compared with their performance with two other types of reading material (a testament and a history text). In addition, the performance of a subgroup of very mild patients in this test was compared with their performance in a widely used interview for the assessment of clinical competence (MacArthur Competence Assessment Tool for Clinical Research)., Results: Good sensitivity and specificity of the cut-offs identified consent form and the other texts as good instruments for evaluation of written comprehension. The comprehension of consent form may be compromised since the early stages of Alzheimer's disease. Nevertheless, a simplified, written text may help patients in comparison with interviews (MacCAT-CR). Better performance was correlated to the standard of education and better cognitive functions., Conclusion: Deficits regarding the comprehension of written texts and the consent form may be early in Alzheimer's disease patients and need to be investigated during periodical neuropsychological assessment. Comprehension may be facilitated by means of specific simplification strategies.

Numerous studies have reported an association between shortened leukocyte telomere length (LTL) and increased risk of Alzheimer's disease (AD). In this study we investigated the relationship between LTL and AD development, including in the analysis patients with amnestic mild cognitive impairment (aMCI), a clinical entity considered prodromal of AD. LTL (T/S ratio) was measured in patients with AD (n=61) or aMCI (n=46), and compared with LTL of age-matched controls (n=56). Significant LTL differences were observed between controls, aMCI and AD patients (p<0.0001), with mean LTL values (±s.d) in the order: AD patients (0.70±0.15)

Studies investigating telomere length in association with cognitive decline, dementia, and sporadic Alzheimer's disease (AD) have frequently found shorter telomeres to be associated with the development of AD and telomerase expression with pathological processes in AD. Human telomerase is constituted by two components: the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC). Genetic variation at the two loci has been investigated in relation to telomere length, longevity, and common diseases of advanced age, but not in relation to AD. We examined three polymorphisms of the TERT gene (VNTR MNS16A, rs2853691, rs33954691) and three polymorphisms of the TERC gene (rs12696304, rs3772190, rs16847897) in a sample of 220 AD patients and 146 controls. MNS16A LL genotype was found to be associated with an increased risk of AD only in males [interaction term adjusted OR=3.55 (95% CI 1.2-10.2)]. The three TERC single nucleotide polymorphisms are in strict linkage disequilibrium and their genotype combinations influenced the age at AD onset (AAO). The combined genotype GG-TT-CC was associated with a mean AAO six years lower (70.5±6.7) than that associated with the other genotype combinations (76.04±6.7, p=0.01). The fact that the MNS16 L allele has been reported to lower TERT expression, and that the TERC alleles G, T, C (rs12696304, rs3772190, rs16847897 in this order have been repeatedly found associated with shorter LTL, seems to corroborate the hypothesis of a role of telomere length and telomerase in AD susceptibility., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Mild cognitive impairment (MCI) is the transition stage between the normal aging process and dementia itself. The most common clinical phenotype is amnestic MCI (aMCI) [subtypes: single domain (sMCI) and multiple domains (mMCI)], which is considered prodromal to Alzheimer's disease (AD). The APOE (apolipoprotein E) e4 allele is the most important genetic risk factor for AD, but its association with MCI onset and conversion to AD is controversial. In this follow-up study of 88 aMCI patients (68% sMCI and 32% mMCI at baseline), we examined APOE genotypes and plasma levels in relation to MCI development and progression based on their clinical/cognitive data obtained at baseline and follow-up assessment (mean follow-up time = 6.6 ± 3.4 years). A control sample (n = 164) was collected in previous investigations. The overall conversion rate to mMCI or AD was 52.2%. The APOE e4 allele was associated with a higher risk of developing MCI (OR: 2.23; 95%CI: 1.22-4.08). The conversion rate in the e4 allele carriers (32% of the sample) was 71%, and the e4 allele was associated with a higher risk of conversion to mMCI/AD (OR: 4.1; 95%CI: 1.2-13.6). APOE e2 allele carriers were 7% (all sMCI) and none progressed to mMCI/AD. Among MCI subjects, e4 carriers had the lowest plasma apoE levels (37.8 ± 12.5 mg/L), and e2 carriers had the highest (78.6 ± 38.1 mg/L). APOE e4 is a risk allele for the development and progression of aMCI, the APOE e2 allele seems to be protective, and apoE levels associated to them are an integral part of their action. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Family history of dementia (FH) is a recognized risk factor for developing late-onset Alzheimer's disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FH+) or without (FH-). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FH+ than the FH- AD patients (49.6% vs. 38.9%; P = 0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FH+ and the FH- AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44-5.09; P = 0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53-4.44; P = 0.0004). Having a first-degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3-6.4; P = 0.009 and OR 2.7, 95%CI 1.1-6.2; P = 0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P = 0.6). Among the FH+ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P = 0.02) and greater cognitive impairment (P = 0.02) than having only an affected sibling, whereas having two or more affected relatives did not., (© 2015 Wiley Periodicals, Inc.)

Emotional and social cognitive deficits were investigated in a group of 24 individuals with mild cognitive impairment (MCI) and 24 healthy controls. Empathic and visual emotional responses were collected, analyzed and correlated to brain structural imaging data by means of: (i) a pictorial matching-to-sample task with facial and non-facial stimuli; (ii) self-reported questionnaires for cognitive and affective emotional components, and alexithymia; (iii) in-depth assessment of cognitive functions. Results indicated that visual processing of faces in MCI individuals did not benefit from fearful emotional content which in healthy controls facilitates stimulus' recognition (emotional enhancement effect). This implicit visuo-emotional disorder was specific for the faces, did not generalize to other categories, and did not correlate to explicit measures of empathy. Thus, our main finding indicates that in MCI individuals, deficits in visual recognition of facial emotions may arise already in the earliest stages of memorization, during the visual encoding of facial emotions. Voxel-based morphometry revealed its association with atrophy in frontal and occipito-temporal regions, mostly involving the anterior medial prefrontal cortex (P<0.05, multiple-comparison correction). Neural evidences were corroborated by clinical scores showing significant correlation between reduction of Emotion Enhancement Effect and deficits in frontal/executive functions. Crucially, the disorder did not appear to be related to the number of impaired cognitive domains (single or multiple-domain MCI) but rather to the involvement of frontal brain networks and frontal/executive functions. This suggests that in prodromal stages of dementia, frontal symptoms may represent a significant signal of emotional recognition disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Although the Anosognosia Questionnaire-Dementia (AQ-D) is one of the main instruments for assessing awareness in Alzheimer's disease (AD), the normative data were until now limited to people from Argentina and Japan. This study aims to validate this instrument in an European context, in particular in an Italian sample. In a multicenter project (Verona, Padova, and Trapani), 130 patients with AD and their caregivers participated in the study. Psychometric characteristics of AQ-D are confirmed indicating that the scale permits the early identification of anosognosia and the correct care management of patients. Indeed, anosognosia results to be present also in patients with very mild AD (moderate: 44.44%; mild: 47.17%; and very mild: 23.73%). Moreover, the results indicate that deficits in awareness may vary in severity and that different types of anosognosia may be identified., (© The Author(s) 2015.)

Executive functions play an important role in the maintenance of autonomy in day-to-day activities. Nevertheless, there is little research into specific cognitive training for Mild Cognitive Impairment (MCI). We present the results of a program which aims to teach specific strategies and metacognitive abilities in order for patients to be able to carry out attentional and executive tasks. Two groups (A and B) were compared in a cross-over design. After the first evaluation, Group A (but not B) participated in a six month cognitive stimulation program. After a second assessment, only Group B received treatment and then a final evaluation was carried out on both groups. The results show that: i) both groups improved their performance as an effect of training; ii) improvements generalized to memory and general cognitive tasks; iii) in the interval without training, Group B's performance worsened and iv) Group A partially maintained their results over time., (© The Author(s) 2014.)

The greater predisposition of women to Alzheimer's disease (AD), owing to the decrease in postmenopausal estrogen, may be influenced by polymorphic variation in genes regulating estrogen metabolism (e.g., COMT) and estrogen biosynthesis (e.g., CYP17). In order to better understand how the estrogen pathway genetic variation might affect AD onset, we conducted a case-control study of two single nucleotide polymorphisms (SNPs) of these two genes (COMT rs4680 and CYP17 rs743572) in a sample of AD patients of Italian origin. The COMT allele and genotype were found associated neither with AD onset nor with parameters of AD severity, such as cognitive impairment, age at onset, or disease duration. In contrast, CYP17 was found to affect the age at disease onset mainly in males and, as compared with noncarriers, people carrying the A2 (C) allele had a 2.2-fold increased risk for AD. These findings suggest that the CYP17 A2 allele influences AD susceptibility in a sex-specific way by acting not only on AD risk but also on the age at disease onset, an important parameter of AD severity., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Mild cognitive impairment (MCI) converts to Alzheimer's disease within a few years of diagnosis in up to 80% of patients. The identification among such a population of a rare form of epilepsy (transient epileptic amnesia [TEA]), characterized by mixed anterograde and retrograde amnesia with apparent preservation of other cognitive functions, excessively rapid decay of newly acquired memories, and loss of memories for salient personal events of the remote past, strongly affects prognosis and medical treatment. Our aim was to define the clinical utility of routine high-density electroencephalography (EEG) in patients with MCI for the detection of epilepsy, especially TEA. Using high-density EEG (256 channels), we were able to single out 3 cases of TEA previously misdiagnosed as MCI in this cohort of 76 consecutive patients with MCI diagnosed at our center. Antiepileptic treatment effectively stopped the acute episodes of memory loss. To our knowledge, this is the first report of an incidence of 4% of TEA recorded in such a cohort., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Many factors could be responsible for the different response to treatment with the cholinesterase inhibitors (ChEIs) donepezil and rivastigmine in Alzheimer's disease (AD) patients. Sex and the variants of the estrogen receptor α (ESR1) gene are reported to modulate AD susceptibility or the course of the disease. The aim of the present study was to verify whether patient's sex and ESR1 genotype could influence the response to ChEI treatment, as there is evidence that estrogens affect cholinergic system functioning., Methods: Two ESR1 intronic polymorphisms (PvuII, rs2234693; XbaI, rs9340799) were examined in 184 AD patients: 157 were receiving treatment with donepezil or rivastigmine and 27 were receiving no treatment. Cognitive status was assessed using the mini mental state examination at four time points (1, 3, 9, and 15 months into therapy)., Results: Among the patients under treatment with either ChEI, the women responded more markedly than the men. As compared with the untreated patients, the effects of treatment were statistically significant for both donepezil and rivastigmine. A significant effect of ESR1 genotypes was observed for the donepezil-treated patients, among which those carrying at least one copy of P and X alleles showed a significantly lower cognitive decline than the noncarriers., Conclusions: The present data seem to confirm a sex-related influence on treatment, as the women seemed to be more sensitive to therapy and to have experienced less cognitive decline. ESR1 may be another gene contributing to interindividual variability in response to treatment with ChEIs., (Copyright © 2013 John Wiley & Sons, Ltd.)

Awareness of cognitive deficits and clinical competence were investigated in 79 mild to moderate Alzheimer's disease patients. Awareness was assessed by the anosognosia questionnaire for dementia, and clinical competence by specific neuropsychological tests such as trail making test-A, Babcock story recall test, semantic and phonemic verbal fluency. The findings show that 66 % of the patients were aware of memory deficits, while the 34 % were unaware. Deficit in awareness correlated with lower scores on the Mini Mental State Examination test that, in the score range from 24.51 to 30 and from 19.50 to 24.50, appeared to be a significant predictor of level of awareness. None of the AD patients had fully preserved clinical competence, only 7 patients (9 %) had partially preserved clinical competence and 72 patients (91 %) had completely lost clinical competence. All the patients with partially preserved clinical competence (9 %) were aware of their memory deficit. The study indicates that neuropsychological tests used for the assessment of executive functions are not suitable for investigating clinical competence. Therefore, additional and specific tools for the evaluation of clinical competence are necessary. Indeed, these might allow clinicians to identify AD patients who, despite their deficits in selected functions, retain their autonomy of choice as well as recognize those patients who should proceed to the nomination of a legal representative.

Background: The higher prevalence of sporadic Alzheimer's disease (AD) in women may be explained by their longer life expectancy, but also by biological gender-specific factors such as a woman's past fertility., Methods: We investigated the relationship between fertility and susceptibility to AD in women by studying two polymorphisms at codons 307 and 680 of the follicle-stimulating hormone receptor gene (FSHR) involved in determining human fertility. The role of age at menopause (AM) as a gender-specific AD susceptibility determinant was also examined. The study population comprised 291 AD patients (70.1% women) and 134 controls (63.4% women)., Results: Logistic regression analysis showed that only among the women the FSHR AS/AS genotype was associated with a significantly lower risk of AD (OR = 0.36, 95% CI: 0.15-0.85), suggesting a gender-specific protective role of the FSHR genotype against AD susceptibility. A lower age at natural menopause was observed in the AD patients (49.7 ± 2.53) than in the controls (50.7 ± 2.53, p = 0.02) and on linear regression analysis an association emerged between an earlier AM and an earlier AD onset (p = 0.004)., Conclusions: Genetic and non-genetic gender-specific factors may contribute to the AD pathogenesis in women, although further investigations are required to clarify their actual role., (2011 S. Karger AG, Basel.)

The human endothelin-converting enzyme (ECE) is involved in beta-amyloid synthesis and regulation of the endothelin-1 (ET-1) vasoconstricting peptide. We investigated the distribution of the C-338A polymorphism of the ECE-1b gene in sporadic late-onset Alzheimer's disease (LOAD) and in coronary artery disease (CAD) to verify its role in the onset of these two complex diseases. Two cohorts of 458 Italian Caucasian LOAD patients and 165 CAD patients were examined for the C-338A polymorphism and compared with respective control samples (260 and 106 subjects, respectively) . The A allele was less present in LOAD patients than in controls, but an at limits statistically significant difference was achieved only in subjects aged less than 80 years, where only the AA genotypes appeared to have a protective role against the onset of the sporadic LOAD. For the overall CAD sample the pattern was similar and significant differences were observed only in subjects non carrying the apolipoprotein E (APOE) e*4 allele, where the A allele carrying genotypes had a protective role against the onset of the disease.

Background: Various risk factors influence the development of Alzheimer's disease (AD). Apolipoprotein E (APOE) e*4 allele has a major role in AD susceptibility and its presence reduces age at AD onset. APOE is also thought to influence human reproduction, and common APOE genotypes seem to be associated with differential fertility. With this study, we investigated possible relationships between APOE genotype, past fertility, and AD onset age., Methods: APOE genotypes were determined in a sample of 176 women with sporadic AD. The number of children each woman had delivered was recorded., Results: A comparison of APOE genotype distribution in parous and nulliparous AD women confirmed that the e*3/e*3 genotype is associated with higher fertility and the e*4-carrying genotypes with lower fertility. When the combined effects of fertility and APOE genotypes on AD onset age were analyzed, parity was found to be associated with a significantly lower AD onset age (73.8 +/- 6.2 years) than nulliparity (80.7 +/- 5.0 years; p = 0.0007) among subjects carrying e*3/e*3 and e*3/e*2 genotypes. A similar effect was absent among e*4 carriers. Considering the high frequency of e*3/e*3 plus e*3/e*2 genotypes in Europe (range: 63-87%), past fertility may influence AD onset age in many women., Conclusion: Past fertility may have a relevant effect on AD onset age and this effect is influenced by APOE genotype., ((c) 2007 S. Karger AG, Basel.)

A sample of 243 Italian patients affected by the sporadic late-onset form of Alzheimer's disease (AD) was studied for the HindIII intronic polymorphism of the lipoprotein lipase (LPL) gene and compared with a sample of 148 healthy subjects. Since this polymorphism has been reported to be associated with CAD and because the two pathologies share common aspects, we decided to study it in AD too. We found a difference in the allele distribution, in that the H+ allele was more frequent in patients (0.782) than in controls (0.720); this difference was not quite significant (P = 0.059). The odds ratio from the logistic regression analysis for the H+ carrying genotypes was 2.7 (95% CI = 1.01-7.21; P = 0.048). When the separate genotypes H+H+ and H+H- were entered into the analysis, only H+H+ was found to significantly increase the risk with respect to H-H- (P = 0.029). This means that carrying this allele significantly increases the risk of developing AD, and the risk is mostly associated with the H+H+ genotype.

The paraoxonase (PON1) Gln192-->Arg polymorphism was examined in a group of sporadic late-onset Alzheimer's disease (AD) patients, in a group of coronary artery disease (CAD) patients, and in normal subjects. The AD sample showed a PON1*R allele frequency significantly lower than the control group (0.225 vs. 0.281, P=0.049). In the CAD patients the *R allele was more frequent than in the controls (0.230 vs. 0.213), though not significantly (P=0.28). The odds ratios (OR) adjusted for age, gender, and APOE polymorphism by logistic regression analysis highlighted that in AD the PON1 RR genotype was significantly protective (OR=0.41, 95% CI=0.19-0.90; P=0.025), whereas in CAD it appeared to be a significant risk factor (OR=5.11, 95% CI=1.09-23.9; P=0.038) limited to younger patients.

Alzheimer s disease is the most frequent cause of dementia in elderly people and it is one of the leading causes of death among older individuals. Weight loss is a frequent clinical finding in Alzheimer s disease patients, and it is actually listed as a symptom consistent with the diagnosis of Alzheimer s disease, but its significance has not been clearly understood until now. This review examines the role of the components of energy balance in determining weight loss in AD patients, on the basis of data collected from the literature. We also considered the possible causes of anorexia in AD patients. In the last years many researchers investigated the possible role of abnormally high energy expenditure, or low energy intakes, or both, to explain weight loss in these patients. Studies on energy intake, energy expenditure and body composition in AD patients have been reviewed. The results of published studies do not seem to support the hypothesis of an hypermetabolic state or inadequate energy intake in AD patients, but further studies, with greater samples are necessary in the future to investigate weight loss in AD patients. A better understanding of this finding could be important to obtain the maximal lifespan of demented patients.

We conducted a study of Alzheimer's disease focusing on taste impairment to determine at which step of gustatory information processing (discriminative or perceptive, gnosic or associative, gustatory-verbal) possible perturbations might be located. We used various foods found in a normal diet. Twenty patients and a matched control group participated in this study. The patients were divided into two subgroups according to disease severity (mild, moderate or severe). The study showed that patients with Alzheimer's disease exhibited an impairment at all three levels of gustatory information processing. Impairment of discriminative and gustatory-verbal stages was more obvious in the group of patients with severe Alzheimer's disease. Our study also showed that the gustatory deficiency can be described as an associative agnosia in the mild stage of Alzheimer's disease. This concept is in line with the notion of a dissociation between preservation of olfactory and gustatory thresholds and an alteration in odor identification in patients with mild stage Alzheimer's disease, suggesting that the alteration is central rather than peripheral. Our findings suggest that an alteration of the associative level of gustatory information processing can be found in Alzheimer's disease early stage.