Male Alzheimer's Disease Patients Research Articles

Sex-Specific Effects of Anxiety on Cognition and Activity-Dependent Neural Networks: Insights from (Female) Mice and (Wo)Men

Neuropsychiatric symptoms (NPS), such as depression and anxiety, are observed in 90% of Alzheimer's disease (AD) patients, two-thirds of whom are women. NPS usually manifest long before AD onset creating a therapeutic opportunity. Here, we examined the impact of anxiety on AD progression and the underlying brain-wide neuronal mechanisms. To gain mechanistic insight into how anxiety impacts AD progression, we performed a cross-sectional analysis on mood, cognition, and neural activity utilizing the ArcCreERT2 x enhanced yellow fluorescent protein (eYFP) x APP/PS1 (AD) mice. The ADNI dataset was used to determine the impact of anxiety on AD progression in human subjects. Female APP/PS1 mice exhibited anxiety-like behavior and cognitive decline at an earlier age than control (Ctrl) mice and male mice. Brain-wide analysis of c-Fos+ revealed changes in regional correlations and overall network connectivity in APP/PS1 mice. Sex-specific eYFP+/c-Fos+ changes were observed; female APP/PS1 mice exhibited less eYFP+/c-Fos+ cells in dorsal CA3 (dCA3), while male APP/PS1 mice exhibited less eYFP+/c-Fos+ cells in the dorsal dentate gyrus (dDG). In the ADNI dataset, anxiety predicted transition to dementia. Female subjects positive for anxiety and amyloid transitioned more quickly to dementia than male subjects. While future studies are needed to understand whether anxiety is a predictor, a neuropsychiatric biomarker, or a comorbid symptom that occurs during disease onset, these results suggest that there are sex differences in AD network dysfunction, and that personalized medicine may benefit male and female AD patients rather than a one size fits all approach.

An integrated approach to identifying sex-specific genes, transcription factors, and pathways relevant to Alzheimer's disease

BackgroundAge represents a significant risk factor for the development of Alzheimer's disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions. MethodsThe exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity. ResultsWe selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, Aβ aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD (https://bioinfo.cipf.es/metafun-ad/). ConclusionOur meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. These sex-based differences will represent the basis for new hypotheses and could significantly impact precision medicine and improve diagnosis and clinical outcomes in AD patients.

Activation of the hypoxia response in the aging cerebrovasculature protects males against cognitive impairment.

Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta-analysis of 335,803 single-nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex-dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex-biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex-stratified analysis of normal vascular aging revealed that angiogenesis and various stress-response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD.

The role of microRNAs in understanding sex-based differences in Alzheimer’s disease

BackgroundThe incidence of Alzheimer's disease (AD)—the most frequent cause of dementia—is expected to increase as life expectancies rise across the globe. While sex-based differences in AD have previously been described, there remain uncertainties regarding any association between sex and disease-associated molecular mechanisms. Studying sex-specific expression profiles of regulatory factors such as microRNAs (miRNAs) could contribute to more accurate disease diagnosis and treatment.MethodsA systematic review identified six studies of microRNA expression in AD patients that incorporated information regarding the biological sex of samples in the Gene Expression Omnibus repository. A differential microRNA expression analysis was performed, considering disease status and patient sex. Subsequently, results were integrated within a meta-analysis methodology, with a functional enrichment of meta-analysis results establishing an association between altered miRNA expression and relevant Gene Ontology terms.ResultsMeta-analyses of miRNA expression profiles in blood samples revealed the alteration of sixteen miRNAs in female and 22 miRNAs in male AD patients. We discovered nine miRNAs commonly overexpressed in both sexes, suggesting a shared miRNA dysregulation profile. Functional enrichment results based on miRNA profiles revealed sex-based differences in biological processes; most affected processes related to ubiquitination, regulation of different kinase activities, and apoptotic processes in males, but RNA splicing and translation in females. Meta-analyses of miRNA expression profiles in brain samples revealed the alteration of six miRNAs in female and four miRNAs in male AD patients. We observed a single underexpressed miRNA in female and male AD patients (hsa-miR-767-5p); however, the functional enrichment analysis for brain samples did not reveal any specifically affected biological process.ConclusionsSex-specific meta-analyses supported the detection of differentially expressed miRNAs in female and male AD patients, highlighting the relevance of sex-based information in biomedical data. Further studies on miRNA regulation in AD patients should meet the criteria for comparability and standardization of information.

Efficacy of Glucose Metabolism-Related Indexes on the Risk and Severity of Alzheimer's Disease: A Meta-Analysis.

Considering the strong correlation made between Alzheimer's disease (AD) and the pathology of glucose metabolism disorder, we sought to analyze the effects of fasting blood glucose (FBG) level, fasting plasma insulin (FINS) level, and insulin resistance index (HOMA-IR) on the risk and severity of AD. Reveal the pathological relationship between AD and insulin resistance. We searched 5 databases from inception through April 4, 2022. Meta-regression was conducted to identify if there were significant differences between groups. Shapiro-Wilk test and the Q-Q diagram were applied to evaluate the normality of variables. A multiple logistic regression model was employed to explore the association between FBG, FINS, HOMA-IR, and Mini-Mental State Examination scale score (MMSE). 47 qualified articles including 2,981 patients were enrolled in our study. FBG (p < 0.001), FINS (p < 0.001), and HOMA-IR (p < 0.001) were higher in AD patients than in controls. HOMA-IR was negatively correlated with MMSE (p = 0.001) and positively related to the sex ratio (male versus female) (p < 0.05). HOMA-IR obeyed lognormal distribution (p > 0.05), and the 95% bilateral boundary values were 0.73 and 10.67. FBG (p = 0.479) was positively correlated to MMSE, while FINS (p = 0.1657) was negatively correlated with MMSE. The increase in the levels of FBG, FINS, and HOMA-IR served as precise indicators of the risk of AD. HOMA-IR was found to be correlated to the increasing severity of AD, especially in male AD patients.

Nonobese Male Patients with Alzheimer's Disease Are Vulnerable to Decrease in Plasma Leptin.

Metabolic dysfunction links to cognitive deficits in Alzheimer's disease (AD). Leptin is an anti-obesity hormone that modulates energy homeostasis and memory function. Although leptin deregulation is implicated in mouse models of AD-like brain pathology, clinical studies have shown inconsistent results regarding an association of leptin with the development of this neurodegenerative disorder. We investigated the changes of plasma leptin and the correlation of sex-stratified circulating leptin with cognitive performance, AD-related biological markers, and metabolic status in patients with AD and cognitively unimpaired (CU) counterparts. We used nonobese AD patients and CU controls in a University of Kansas Medical Center (KUMC) cohort. Plasma leptin levels, circulating AD-related molecules and metabolic profiles were examined and analyzed. In contrast to unchanged circulating leptin in females, male patients exhibited decreased plasma leptin levels compared with male CU counterparts. Moreover, plasma leptin showed no correlation with cognitive performance and AD blood biomarkers in patients with either sex. Of note, females but not males demonstrated an association of plasma leptin with body mass index, high density lipoprotein-cholesterol and its ratio with total cholesterol and triglycerides. Our findings suggest that leptin deficiency is associated with nonobese male AD patients, supporting systemic dysmetabolism in the development of this neurodegenerative disorder in certain populations. Although plasma leptin may have limited capacity to reflect disease severity or progression, future mechanistic studies on the regulation of leptin in nonobese patients with AD would deepen our understanding of the sex-related disparity of AD etiopathogenesis.

A novel key driver gene of Alzheimer's disease impacts AD-related cognitive deficit, pathology and neuro-inflammation in sex- and APOE-specific manners.

Alzheimer's Disease (AD) has complex etiologies and the impact of sex on AD varies over the course of disease development. Literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex biased differences in AD remain elusive. Multi-omics data in tandem with systems biology approaches offer a new avenue to not only dissect sex-stratified molecular mechanisms of AD but also develop sex-specific diagnostic and therapeutic strategies for AD. We integrated RNA expression datasets from the para-hippocampal gyrus of the Mount Sinai Medical Center Brain Bank (MSBB) and the prefrontal cortex from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) to perform multiscale network analysis. The differentially expressed genes (DEGs) between AD and control, female and male, ApoE3 and ApoE4 genotype were rank-ordered based on their relevance to clinical dementia rating scale (CDR) and AD pathology (Braak stage, CERAD and plaque density). The trend analyses and gene co-expression network analysis were then performed to identify key drivers with sexually dimorphic expression patterns or differentially respond to APOE genotypes between sexes. In this study, we identified ldl receptor-related protein (lrp10), a receptor possibly involved in the uptake of ApoE and APP trafficking as the highest-ranked key driver gene candidate accounting for the sex differences in AD. Lrp10 mRNA was increased in female AD patients when compared to female controls or male AD patients. In contrast, LRP10 protein levels were reduced in AD when compared to controls, suggesting possible post-translational modifications of LRP10 in AD human brains. Gene perturbation studies in EFAD mouse hippocampal brain regions suggest that over-expression of lrp10 improved cognitive function, reduced Aβ42 and p-Tau, and increased microglial recruitment around amyloid plaques in female E4FAD mice. In contrast, down-regulation of lrp10 exacerbated cognitive impairment as well as increased brain Aβ42 and total tau levels in male E3FAD mice. These results strongly support our hypothesis that lrp10 is a causal regulator gene for AD, whose expression is strongly associated with cognition performance in sex- and APOE-specific manners. Our findings further implicate a role of lrp10 in regulating microglial function and neuro-inflammation in AD.

An Alzheimer's drug target only for men

Pharmacology β-Amyloid deposits in the brain are a hallmark of Alzheimer's disease. The binding of β-amyloid to the metabotropic glutamate receptor mGluR5 contributes to disease progression. Abd-Elrahman et al. found that β-amyloid was bound to mGluR5 in brain tissue samples only from male Alzheimer's disease model mice or male patients. Blocking the activity of mGluR5 reversed cognitive decline in male mice but not in their female counterparts, suggesting that mGluR5 inhibitors may be therapeutically beneficial only for male Alzheimer's disease patients. Sci. Signal. 13 , eabd2494 (2020).

The Association between Neprilysin gene polymorphisms and Alzheimer's disease in Tibetan population.

ObjectivesAlzheimer's disease (AD) is a well‐known neurodegenerative disease, of which the hallmark is the disposition of β‐amyloid (Aβ) in the form of plaque in the brain. Neprilysin (NEP) is the major enzyme to degrade Aβ and prevent accumulation of Aβ. The present study was undertaken to elucidate the correlation between the NEP gene polymorphisms and AD in Chinese Tibetan population.MethodsNinety‐nine sporadic AD Tibetan patients and 113 healthy Tibetan controls were enrolled in this study. The genotype frequencies and allele frequencies of multiple NEP gene loci were analyzed using the case–control association analysis.ResultsNo significant correlation was found between polymorphisms of NEP gene loci (rs9829757, rs1816558, rs6776185, rs3736187, rs701109, rs989692) and the occurrence of AD in Tibetan population. However, allele C of NEP gene locus (rs701109) and allele T of gene locus (rs3736187) were possible risk factors of male AD patients in Tibetan population.ConclusionsNEP gene loci (rs701109, rs989692, rs9829757, rs3736187, rs1816558, rs6776185) were polymorphic in Tibetan population. No difference was found between these loci but for that male gender combined with allele C of NEP gene locus (rs701109) and T of gene locus (rs3736187) might be risk factors for AD in Tibet.

Bone metabolic biomarkers and bone mineral density in male patients with early-stage Alzheimer's disease.

Alzheimer's disease (AD), osteoporosis, and osteopenia are the most common diseases in older individuals and share some similar pathophysiological processes of degeneration. The aim of this study is to investigate the association between bone metabolic biomarkers, bone mineral density (BMD), and early-stage AD in men. Forty-two male early-stage AD patients and 40 age-matched healthy older volunteers were enrolled. Serum calcium, osteocalcin, 1,25(OH)2D3, urine deoxypyridinoline/creatinine (DPD/Cr) ratio, urine calcium/creatinine (Ca/Cr) ratio, and BMD were measured. The correlation between early-stage AD and bone quality was evaluated. The urine DPD/Cr, urine Ca/Cr, and serum osteocalcin levels in the early-stage AD patients were significantly higher than those in the healthy control (HC) group (P < 0.05). The BMD data showed that the cortical and total BMD at 38% of the tibial length in the early-stage AD patients were lower than those in the HC group (P < 0.05). Furthermore, there was a negative correlation between the Montreal Cognitive Assessment score and serum osteocalcin or urine DPD/Cr levels. Abnormal urine DPD/Cr, urine Ca/Cr, and cortical BMD levels were independent risk factors in male patients with early-stage AD. Bone metabolic biomarkers and BMD are closely associated with early-stage AD in male patients. Our data indicated that the measurement of bone metabolic biomarkers and BMD may provide an alternative approach for screening AD patients at the early stage.

Altered Redox State in Whole Blood Cells from Patients with Mild Cognitive Impairment and Alzheimer's Disease.

Oxidative stress plays an essential and early role in the pathophysiology of Alzheimer's disease (AD). Alterations in the redox state in AD and in mild cognitive impairment (MCI) patients appear in the brain and at peripheral level. Given that it is easier to study the latter, most of the research has been focused on plasma. However, the analysis of redox parameters in whole blood cells (including erythrocytes and leukocytes) has not really been investigated. Moreover, the association of these parameters with Mini-Mental State Examination (MMSE) clinical scores, has scarcely been studied. Therefore, the aim of the present work was to analyze several redox markers in whole blood cells from male and female MCI and AD patients. Antioxidant (superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), and reductase (GR) activities, and reduced glutathione (GSH) concentration) together with oxidant parameters (oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS)) were investigated using MCI and AD (10 women and 10 men in each group) and their age-matched control groups (15 women and 15 men). The results show an altered redox state in whole blood cells from AD patients (higher CAT, GSSG/GSH, TBARS and lower GPx, GR, GSH). Some of these redox parameters are already affected in MCI patients (higher TBARS and lower GPx and GR activities) in both sexes and, consequently, they could be used as markers of prodromal AD. Since GR, GSH, GSSG, and GSSG/GSH were found to be associated with MMSE scores, they seem to be useful clinically to monitor cognitive decline in AD progression.

TOM1 Regulates Neuronal Accumulation of Amyloid-β Oligomers by FcγRIIb2 Variant in Alzheimer's Disease.

Emerging evidences suggest that intraneuronal Aβ correlates with the onset of Alzheimer's disease (AD) and highly contributes to neurodegeneration. However, critical mediator responsible for Aβ uptake in AD pathology needs to be clarified. Here, we report that FcγRIIb2, a variant of Fcγ-receptor IIb (FcγRIIb), functions in neuronal uptake of pathogenic Aβ. Cellular accumulation of oligomeric Aβ1-42, not monomeric Aβ1-42 or oligomeric Aβ1-40, was blocked by Fcgr2b knock-out in neurons and partially in astrocytes. Aβ1-42 internalization was FcγRIIb2 di-leucine motif-dependent and attenuated by TOM1, a FcγRIIb2-binding protein that repressed the receptor recycling. TOM1 expression was downregulated in the hippocampus of male 3xTg-AD mice and AD patients, and regulated by miR-126-3p in neuronal cells after exposure to Aβ1-42 In addition, memory impairments in male 3xTg-AD mice were rescued by the lentiviral administration of TOM1 gene. Augmented Aβ uptake into lysosome caused its accumulation in cytoplasm and mitochondria. Moreover, neuronal accumulation of Aβ in both sexes of 3xTg-AD mice and memory deficits in male 3xTg-AD mice were ameliorated by forebrain-specific expression of Aβ-uptake-defective Fcgr2b mutant. Our findings suggest that FcγRIIb2 is essential for neuropathic uptake of Aβ in AD.SIGNIFICANCE STATEMENT Accumulating evidences suggest that intraneuronal Aβ is found in the early step of AD brain and is implicated in the pathogenesis of AD. However, the critical mediator involved in these processes is uncertain. Here, we describe that the FcγRIIb2 variant is responsible for both neuronal uptake and intraneuronal distribution of pathogenic Aβ linked to memory deficits in AD mice, showing a pathologic significance of the internalized Aβ. Further, Aβ internalization is attenuated by TOM1, a novel FcγRIIb2-binding protein. Together, we provide a molecular mechanism responsible for neuronal uptake of pathogenic Aβ found in AD.

Sex Differences in Neuropsychological Test Performance in Alzheimer's Disease and the Influence of the ApoE Genotype.

Only few studies exist reporting sex differences in the Alzheimer disease (AD) patients regarding cognitive profile, brain damage, and risk factors. The present study investigated the influence of sex in combination with the Alzheimer risk allele, ε4-allele of apolipoprotein E, on cognitive performance. We examined the effect of sex and ApoE genotype on a range of neuropsychological markers from the German version of the Consortium to Establish a Registry in Alzheimer's Disease Neuropsychological Battery in a monocentric study of 399 AD patients. Male patients had significantly more years of school and occupational education compared with women. Male AD patients outperformed female patients in tasks of object naming, constructional praxis, and constructional praxis recall. There was no statistically significant interaction effect between sex and ε4-allele of apolipoprotein E for any of the examined variables. The superiority of healthy men compared with women in tasks of object naming, constructional praxis, and visual memory seems to remain stable when people develop AD, indicating larger cognitive reserves in men. In contrast, findings that cognitively healthy women outperform men in tests of verbal memory and verbal fluency are not stable in AD. Further studies are needed to gain insight in the reasons for sex differences.

Effects of Gender and Other Confounding Factors on Leptin Concentrations in Alzheimer's Disease: Evidence from the Combined Analysis of 27 Case-Control Studies.

Leptin, as a link between fat mass and the brain, has been reported to be associated with gender. The gender differences in leptin levels between Alzheimer's disease (AD) and healthy elderly controls are inconclusive so far. To quantitatively summarize the leptin data available from female and male patients with AD, we searched PubMed and EMBASE for articles published from inception to July 20, 2017. Data were extracted from 27 studies, consisting of 3,014 participants. The pooled results showed that the overall leptin levels were lower in AD (Hedges' g = -0.481; p = 0.002) than in controls, and the leptin levels in whole blood and serum were decreased with moderate and large effect sizes (g = -0.677, -0.839; respectively; both of p-values <0.001) in AD compared with controls. In blood, there were significantly lower concentrations of leptin in female AD than in female controls (g = -0.590; p = 0.014), but not in male case-control group (g = -0.666; p = 0.067). Meta-regression analysis demonstrated that the decreased extent of leptin levels in AD paralleled the degree of the severity of dementia symptoms, as well as the alterations of body mass index (p-values ≤0.002). The findings provide strong evidence that 1) the blood concentrations of leptin are lower in female AD patients than in female controls; and 2) the greater the severity of dementia symptoms, the greater the decreases in the blood leptin levels. But more future investigations on the blood leptin levels in male AD patients is warranted.

Gender-related increase of tropomyosin-1 abundance in platelets of Alzheimer's disease and mild cognitive impairment patients

The incidence of Alzheimer's disease (AD) is higher in elderly women than in men. The molecular background of this gender-related risk, however, is largely unknown. In a previous proteomics study, we identified significantly elevated levels of monoamine oxidase-B and tropomyosin-1 in AD patients, together with significant changes of the genetic AD risk factors apolipoprotein E4 (APOE4) and glutathione S-transferase omega 1 (GSTO1), in platelets - a promising source for AD blood biomarkers. The present study aimed to investigate the gender-specificity as well as the disease-stage dependency of these biomarkers in AD patients and those with mild cognitive impairment (MCI). Tropomyosin-1 and monoamine oxidase-B protein levels were quantified by 2-D DIGE and 1-D Western blotting. Here, for the first time, we revealed a significant increase of 38&39kDa tropomyosin-1 protein levels in female but not male AD (+56%; p=0.008) and MCI patients (+46%; p=0.041) measured by 1-D WB. In contrast, levels of monoamine oxidase-B were, independently of gender, elevated in AD patients (+52%; p=0.009) but unaltered in MCI compared to control subjects. Moreover, we confirmed that APOE4-positive females are at a higher risk (OR=18.7; p=9.7E−09) of developing AD compared to APOE4-positive males (OR=6.5; p=5.9E−04). No gender-related effects were observed for GSTO1. SignificancePlatelet tropomyosin-1 constitutes a gender-related and stage-dependent protein in cognitive impairment. In contrast, platelet monoamine oxidase-B, frequently described to be increased in platelets and brains of AD patients, shows a gender-independent but stage-related increase since it is unaltered in MCI subjects. A blood biomarker test for this preceding stage of AD that considers gender-specificity is not yet available. The newly described AD-related platelet protein profiles might refine and facilitate routine diagnosis and enable early as well as tailored interventions.

Anesthesia/Surgery Induces Cognitive Impairment in Female Alzheimer's Disease Transgenic Mice.

Anesthesia and/or surgery may promote Alzheimer's disease (AD) by accelerating its neuropathogenesis. Other studies showed different findings. However, the potential sex difference among these studies has not been well considered, and it is unknown whether male or female AD patients are more vulnerable to develop postoperative cognitive dysfunction. We therefore set out to perform a proof of concept study to determine whether anesthesia and surgery can have different effects in male and female AD transgenic (Tg) mice, and in female AD Tg plus Cyclophilin D knockout (CypD KO) mice. The mice received an abdominal surgery under sevoflurane anesthesia (anesthesia/surgery). Fear Conditioning System (FCS) was used to assess the cognitive function. Hippocampal levels of synaptic marker postsynaptic density 95 (PSD-95) and synaptophysin (SVP) were measured using western blot analysis. Here we showed that the anesthesia/surgery decreased the freezing time in context test of FCS at 7 days after the anesthesia/surgery in female, but not male, mice. The anesthesia/surgery reduced hippocampus levels of synaptic marker PSD-95 and SVP in female, but not male, mice. The anesthesia/surgery induced neither reduction in freezing time in FCS nor decreased hippocampus levels of PSD-95 and SVP in the AD Tg plus CypD KO mice. These data suggest that the anesthesia/surgery induced a sex-dependent cognitive impairment and reduction in hippocampus levels of synaptic markers in AD Tg mice, potentially via a mitochondria-associated mechanism. These findings could promote clinical investigations to determine whether female AD patients are more vulnerable to the development of postoperative cognitive dysfunction.

Differences between the behavioral and psychological symptoms of Alzheimer's disease and Parkinson's disease

AimWe compared the behavioral and psychological symptoms of Alzheimer's disease (AD) and Parkinson's disease (PD) in order to determine the characteristic features of each disorder. MethodsFor this retrospective cohort study, we compared the behavioral and psychological symptoms of 288AD patients and 189 PD patients (mean age, 74.6±5.9 and 73.0±8.7years respectively). Symptoms were evaluated using the geriatric depression scale (GDS), apathy scale (AS), and Abe's behavioral and psychological symptoms of dementia score (ABS). ResultsAD patients had higher AS and ABS scores than PD patients. A gender-dependent comparison showed that ABS scores were worse in female AD patients than in female PD patients (p=0.001). A subscale analysis of ABS scores revealed that male AD patients were only significantly different from male PD patients in 1 item, whereas female AD patients were significantly different from female PD patients in 4 items. Among patients with mild cognitive decline, no differences in affective scores were observed. Alternatively, among patients with moderate cognitive decline, affective scores on all 3 scales were worse in PD patients than in AD patients. ConclusionsThe present age- and gender-matched retrospective analysis identified greater behavioral and psychological disease severity in female AD patients relative to female PD patients, and greater affective severity in PD patients versus AD patients with a similar degree of cognitive decline.

Processing of Self versus Non-Self in Alzheimer's Disease.

Despite considerable evidence for abnormalities of self-awareness in Alzheimer’s disease (AD), the cognitive mechanisms of altered self-processing in AD have not been fully defined. Here we addressed this issue in a detailed analysis of self/non-self-processing in three patients with AD. We designed a novel neuropsychological battery comprising tests of tactile body schema coding, attribution of tactile events to self versus external agents, and memory for self- versus non-self-generated vocal information, administered in conjunction with a daily life measure of self/non-self-processing (the Interpersonal Reactivity Index). Three male AD patients (aged 54–68 years; one with a pathogenic mutation in the Presenilin 1 gene, one with a pathogenic mutation in the Amyloid Precursor Protein gene, and one with a CSF protein profile supporting underlying AD pathology) were studied in relation to a group of eight healthy older male individuals (aged 58–74 years). Compared to healthy controls, all patients had relatively intact tactile body schema processing. In contrast, all patients showed impaired memory for words previously presented using the patient’s own voice whereas memory for words presented in other voices was less consistently affected. Two patients showed increased levels of emotional contagion and reduced perspective taking on the Interpersonal Reactivity Index. Our findings suggest that AD may be associated with deficient self/non-self differentiation over time despite a relatively intact body image: this profile of altered self-processing contrasts with the deficit of tactile body schema previously described in frontotemporal dementia associated with C9orf72 mutations. We present these findings as a preliminary rationale to direct future systematic study in larger patient cohorts.

Adipose Tissue Distribution in Patients with Alzheimer's Disease: A Whole Body MRI Case-Control Study.

Total and central adiposity have been associated with increased risk of Alzheimer's disease (AD). Visceral and subcutaneous adipose tissues have different metabolic characteristics and could therefore be differentially associated with AD. To compare regional fat distribution determined by magnetic resonance imaging (MRI) in AD patients and healthy controls and investigate associations with stage of the disease and chemical markers. The investigation was performed in a prospective case-control study. We examined thirty patients with mild to moderate AD by whole-body MRI (1.5 T) and clinical questionnaires in comparison to thirty cognitively healthy age- and gender-matched study participants. Volumes of total, subcutaneous, and visceral body fat tissue were determined by an unbiased automatic analysis algorithm. Levels of leptin, ghrelin, and adiponectin were determined in serum, amyloid-β (Aβ)(1-42) and tau protein levels in cerebrospinal fluid (CSF). Male AD patients displayed significantly more total fat tissue than male controls. This difference was not observed in women. We observed a trend toward higher volume of visceral fat tissue in all patients (p = 0.13). Severity of disease was not associated with fat distribution in our study. Increased leptin levels correlated with lower CSF Aβ(1-42) in female, but not in male, AD patients. Fat volume is increased in male, but not in female AD patients. Negative correlation of leptin levels and CSF Aβ(1-42) in females might be one co-factor for the increased AD risk of females. Further studies are required to confirm this gender difference in fat volume during AD and evaluate its pathophysiological importance.

Gender-Specific Differences in Cognitive Profiles of Patients with Alzheimer's Disease: Results of the Prospective Dementia Registry Austria (PRODEM-Austria).

Alzheimer's disease (AD) is one of the most common age-related diseases in the western world. Gender differences in neuropsychological functions are seldom evaluated in AD. Recent investigations suggested that gender may be an important modifying factor in the development and progression of AD. We examined gender-specific differences in the pattern of cognitive dysfunction of patients with mild to moderate AD. We examined 113 males (mean age 78) and 173 females (mean age 80) of the prospective registry on dementia in Austria (PRODEM). We analyzed differences in the cognitive profile between male and female AD patients on the CERAD-Plus test battery. We found gender-related differences in the neuropsychological domains of verbal learning; the women tended to perform worse than men. Controlling for depression, stage and duration of dementia, and the level of education, there was still a significant effect of gender on verbal episodic memory. There is an interaction between gender and cognitive function, most notable in verbal episodic memory; female patients in the early stage of AD performed worse on verbal episodic memory than men. This indicates that the gender-specificities of neuropsychological functions should be given careful consideration in clinical diagnosis of dementia.