Among Alzheimer's Disease Research Articles

Similar brain proteomic signatures in Alzheimer’s disease and epilepsy

The prevalence of epilepsy is increased among Alzheimer’s Disease (AD) patients and cognitive impairment is common among people with epilepsy. Epilepsy and AD are linked but the shared pathophysiological changes remain poorly defined. We aim to identify protein differences associated with epilepsy and AD using published proteomics datasets. We observed a highly significant overlap in protein differences in epilepsy and AD: 89% (689/777) of proteins altered in the hippocampus of epilepsy patients were significantly altered in advanced AD. Of the proteins altered in both epilepsy and AD, 340 were altered in the same direction, while 216 proteins were altered in the opposite direction. Synapse and mitochondrial proteins were markedly decreased in epilepsy and AD, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Notably, many of the proteins altered in epilepsy interact with tau or are regulated by tau expression. This suggests that tau likely mediates common protein changes in epilepsy and AD. Immunohistochemistry for Aβ and multiple phosphorylated tau species (pTau396/404, pTau217, pTau231) showed a trend for increased intraneuronal pTau217 and pTau231 but no phosphorylated tau aggregates or amyloid plaques in epilepsy hippocampal sections. Our results provide insights into common mechanisms in epilepsy and AD and highlights the potential role of tau in mediating common pathological protein changes in epilepsy and AD.

Electroacupuncture improves cognitive function in APP/PS1 mice by inhibiting oxidative stress related hippocampal neuronal ferroptosis

BackgroundElectroacupuncture, recognized as a crucial non-pharmacological therapeutic approach, has demonstrated notable efficacy in enhancing cognitive function among Alzheimer's disease (AD) patients. This study aimed to investigate the neuroprotective properties of electroacupuncture in APP/PS1 mice with AD. MethodsA total of thirty APP/PS1 mice were randomly assigned to three groups: the Alzheimer's disease group (AD), the electroacupuncture treatment group (EA), and the ferroptosis inhibitor deferasirox treatment group (DFX). Additionally, ten C57BL/6 mice were included as a control group (Control). In the EA group, mice underwent flat needling at Baihui and Yintang, as well as point needling at Renzhong, once daily for 15 min each time. In the DFX group, mice received intraperitoneal injections of deferasirox at a dosage of 100 mg/kg/day. Following the 28-day treatment period, behavioral evaluation, morphological observation of neurons, and detection of neuronal ferroptosis were conducted. ResultsThe electroacupuncture treatment demonstrated a significant improvement in spatial learning, memory ability, and neuronal damage in mice with AD. Analysis of neuronal ferroptosis markers indicated that electroacupuncture interventions reduced the elevated levels of malondialdehyde, iron, and ptgs2 expression, while also increasing superoxide dismutase activity, Ferroportin 1 and glutathione peroxidase 4 expression. Moreover, the regulatory impact of electroacupuncture on ferroptosis may be attributed to its ability to enhance the expression and nuclear translocation of Nrf2. ConclusionsThis study suggested that electroacupuncture could inhibit the neuronal ferroptosis by activating the antioxidant function in neurons through p62/Keap1/Nrf2 signal pathway, thereby improve the cognitive function of AD mice by the neuronal protection effect.

Pathogenesis of Depression in Alzheimer's Disease.

Depression is a prevalent occurrence among Alzheimer's disease (AD) patients, yet its underlying mechanism remains unclear. Recent investigations have revealed that several pathophysiological changes associated with Alzheimer's disease can lead to mood disorders. These alterations include irregularities in monoamine neurotransmitters, disruptions in glutamatergic synaptic transmission, neuro-inflammation, dysfunction within the hypothalamic-pituitary-adrenocortical (HPA) axis, diminished levels of brain-derived neurotrophic factor (BDNF), and hippocampal atrophy. This review consolidates research findings from pertinent fields to elucidate the mechanisms underlying depression in Alzheimer's disease, aiming to provide valuable insights for the study of its mechanisms and clinical treatment.

60 Are all Embedded Measures Created Equal? A look at Embedded PVTs in Major Neurocognitive Disorder

Objective:Although performance validity is critical in determining the quality and accuracy of test data, research suggests not all neuropsychologists incorporate performance validity tests (PVTs) in dementia evaluations (McGuire et al., 2019). Furthermore, well-validated embedded measures, such as Reliable Digit Span (RDS) from the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV), have evidenced an unusually high number of failures in a dementia population when utilizing typical clinical cut-offs (Zenisek et al., 2016). The objective of this study is to explore performance on embedded PVTs among older adults who have a major neurocognitive disorder (MND), specifically among Alzheimer disease (AD) and non-AD patients.Participants and Methods:Archival data from outpatient neuropsychological evaluations were analyzed. All participants were at least 65 years of age, diagnosed with a MND, and completed Digit Span from the WAIS-IV, Brief Visuospatial Memory Test- Revised (BVMT-R), and Hopkins Verbal Learning Test-Revised (HVLT-R). In total, 84 participants, aged 67-96 (M=78.44, SD=6.11) with 6-20 years of education (M=13.47, SD=3.30), were included. The sample predominantly identified as female (n=60) and White (n=61). More individuals were diagnosed with AD (n=50) than non-AD dementia (n=34). Common non-AD diagnoses included Vascular (n=44), Lewy bodies (n=8), and Parkinson’s (n=2) dementias. Fisher’s Exact Test of Independence was used to account for the smaller sample to determine if there was a nonrandom association between diagnosis (AD vs non-AD) and embedded PVT performance: RDS< 7, BVMT-R Hits<4, BVMT-R Recognition Discrimination (RD) < 4, and HVLT-R RD < 5 (Bailey et al., 2018).Results:The Fisher’s Exact Test of Independence revealed a statistically significant association between neurocognitive diagnosis and RDS (p= .008), BVMT-R RD (p<.001), and HVLT-R RD (p<.001). BVMT-R Hits were not significantly associated with diagnosis (p = 0.10). These measures evidenced opposite patterns with RDS demonstrating a higher percentage of fails for the non-AD (63%) versus AD (20%) group. The AD group had a higher percentage of fails for BVMT-R RD (58% for AD and 13% for non-AD groups) and HLVT-R RD (66% for AD and 29% for non-AD group).Conclusions:The current study suggests performance on embedded PVTs vary across MND diagnoses. Individuals with a non-AD diagnosis were more likely to fail RDS than those with AD. This is likely secondary to attention and working memory demands that are mediated by the frontal-subcortical networks, which are less impacted by AD pathology (Bonelli & Cummings, 2022; Loring et al., 2016). In contrast, AD patients were more likely to fail embedded PVTs within memory measures, which are largely mediated by the mesial temporal cortex associated with AD (Pluta, 2022). These results suggest embedded measures operate differently based on diagnosis and neuroanatomical systems affected. The clinical relevance of these findings includes potentially using alternative PVTs or different cut-offs based on diagnosis. Future research should attempt to better delineate more appropriate, as well as time efficient, PVTs among the dementia population.

NcRNAs: A synergistically antiapoptosis therapeutic tool in Alzheimer's disease.

The aim of this review is to systematically summarize and analyze the noncoding RNAs (ncRNAs), especially microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the cell apoptosis among Alzheimer's disease (AD) in recent years to demonstrate their value in the diagnosis and treatment of AD. We systematically summarized in vitro and in vivo studies focusing on the ncRNAs in the regulation of cell apoptosis among AD in PubMed, ScienceDirect, and Google Scholar. We discover three patterns of ncRNAs (including 'miRNA-mRNA', 'lncRNA-miRNA-mRNA', and 'circRNA-miRNA-mRNA') form the ncRNA-based regulatory networks in regulating cell apoptosis in AD. This review provides a future diagnosis and treatment strategy for AD patients based on ncRNAs.

Sex-heterogenous effect on Alzheimer's disease risk at the BIN1 locus.

Among Alzheimer's Disease (AD) tier 1 genes, BIN1 shows the greatest sex-biased expression in GTEx RNASeq, notably in brain tissues. Fine-mapping studies suggest that the BIN1 locus harbors at least two independent risk variants. We considered a region ±200kb around BIN1 and performed sex-stratified analyses to identify genome-wide significant variants with a sex-heterogenous effect in imputed data from the AD Genetics Consortium. We ran conditional analyses on rs6733839 to show that variants with sex-heterogenous effects were independent from the lead variant at this locus. Additionally, we performed sex- and rs6733839-genotype-stratified analyses to understand which haplotype drives this sex-heterogenous effect on AD risk and on BIN1 expression in brain tissue from the ROSMAP study. Rs10200967 has a significant sex-heterogenous effect on AD risk and is genome-wide significant in females but not males (Table 1). In the conditional analysis the association remains significant (pfemale = 6.5×10-3 , Table 2). The linkage disequilibrium between these two variants is low (r2 = 0.12). The protective association of rs10200967 is strongest in females homozygous for the major allele of rs6733839 (p = 1.1×10-3 ). Among individuals homozygous for the major allele of rs6733839, the effect of the interaction between rs10200967 dosage and sex on AD risk is significant (p = 3.2×10-3 ). In the full sample, the three-way interaction between these two variants and sex is significant (p = 0.021, Table 3). The rs10200967 minor allele is associated with an increased expression in GTEx (p = 6.0×10-15 , Figure 1) and ROSMAP (p = 9.1×10-3 , Table 4). Among rs6733839 reference allele homozygotes, the rs10200967 interaction with sex on BIN1 expression is significant (p = 0.0495). In the full ROSMAP sample, the three-way interaction is trending significant (p = 0.062, Table 5). Interestingly, rs10200967 is located in a histone peak and a start-exon of a BIN1 transcript (Figure 1) reinforcing its putative regulatory role. Our sex- and rs6733839-genotype stratified analyses, demonstrate that rs10200967 at the BIN1 locus is genome-wide significant, with a sex-heterogenous effect on AD risk and on BIN1 expression. These results support the growing consensus that there are two separate signals at the locus and suggest that rs10200967 contributes to the signal independent of rs6733839.

Pleiotropic meta-analysis of Alzheimer's disease and cognitive performance.

A major challenge in the discovery of genetic risk loci for many complex diseases is reaching a sufficient sample size to adequately power the genetic analysis to detect modest effect sizes. With the increased number of publicly available genome-wide association studies (GWAS) summary statistics data over the last decade, a number of approaches has received increasing attention for exploiting the pleiotropy between correlated traits to improve statistical power. Pleiotropy is the phenomenon of one locus influencing multiple traits and it can aid to the discovery of novel genetic associations and point to underlying shared biological pathways. In the current study we aimed to explore the use of the pleiotropic statistical methods for estimating the genetic overlap among Alzheimer's disease (AD) and Cognitive performance (CP) and to discover novel AD associated loci. We utilised publicly available GWAS summary statistics for each trait; the AD summary statistics data by Kunkle et al. (2019) (N=63,926) and the CP data by Lee et al. (2018) (N=257,828). We estimated the genetic correlation between the two traits using the LD Score regression (LDSC) and jointly analysed the traits by using a modification of the meta-analysis method; the multi-trait analysis of GWAS (MTAG). LDSC identified a significant correlation between AD and CP (rg =-0.28, p=1.4e-05). Using MTAG, results showed a power increase of 35% to detect AD-specific risk loci despite the moderate rg between the two traits. A novel association was identified with rs7208590 (pMTAG =2.56e-08) in PPM1E which is independent of a previously reported association to the region covering BZRAP1-AS1, TEX14, RAD51C, PPM1E, TRIM37 genes. Moreover, we replicated two associations that have been previously reported by a pleiotropic study among AD and bipolar disease (Drange et al, 2019) and by a transethnic GWAS (Jun et al,2017); MTSS1L (rs2864755, pMTAG =2.88e-09) and HBEGF (rs7268, pMTAG =2.52e-11), respectively. The current study leveraged the power of GWAS and the phenomenon of pleiotropy to identify novel genetic loci and to construct biological hypotheses about the AD pathogenesis. Our knowledge of pleiotropy can aid to the diagnosis, intervention and personalised treatment via precision medicine.

3D CNN based Alzheimer’s diseases classification using segmented Grey matter extracted from whole-brain MRI

A recent study from MRI has revealed that there is a minor increase in cerebral-spinal fluid (CSF) content in brain ventricles and sulci, along with a substantial decrease in grey matter (GM) content and brain volume among Alzheimer's disease (AD) patients. It has been discovered that the grey matter volume shrinkage may indicate the possible case of dementia and related diseases like AD. Clinicians and radiologists use imaging techniques like Magnetic Resonance Imaging (MRI), Computed Tomography (CT) scan, and Positron Emission Tomography (PET) to diagnose and visualize the tissue contents of the brain. Using the whole brain MRI as the feature is an on-going approach among machine learning researchers, however, we are interested only in grey matter content. First, we segment the MRI using the SPM (Statistical parameter mapping) tool and then apply the smoothing technique to get a 3D image of grey matter (later called as grey version) from each MRI. This image file is then fed into 3D convolutional neural network (CNN) with necessary pre-processing so that it can train the network, to produce a classifying model. Once trained, an untested MRI (i.e. its grey version) can be passed through the CNN to determine whether it is a healthy control (HC), or Mild Cognitive Impairment (MCI) due to AD (mAD) or AD dementia (ADD). Our validation and testing accuracy are reported here and compared with normal MRI and its grey version.

Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2

Among Alzheimer's disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are far from being completely elucidated. Another key role in AD pathogenesis is played by alterations in brain cholesterol metabolism. Oxysterols (cholesterol oxidation products) are crucial for brain cholesterol homeostasis, and we previously demonstrated that changes in the brain levels of various oxysterols correlate with AD progression. Moreover, oxysterols have been shown to contribute to various pathological mechanisms involved in AD pathogenesis. In order to deepen the role of oxysterols in AD, we investigated whether they could contribute to astrocyte reactivity, and consequently impact on neuronal health. Results showed that oxysterols present in mild or severe AD brains induce a clear morphological change in mouse primary astrocytes, accompanied by the upregulation of some reactive astrocyte markers, including lipocalin-2 (Lcn2). Moreover, astrocyte conditioned media analysis revealed a significant increase in the release of Lcn2, cytokines, and chemokines in response to oxysterols. A significant reduction of postsynaptic density protein 95 (PSD95) and a concurrent increase in cleaved caspase-3 protein levels have been demonstrated in neurons co-cultured with oxysterol-treated astrocytes, pointing out that mediators released by astrocytes have an impact on neurons. Among these mediators, Lcn2 has been demonstrated to play a major role on synapses, affecting neurite morphology and decreasing dendritic spine density. These data demonstrated that oxysterols present in the AD brain promote astrocyte reactivity, determining the release of several mediators that affect neuronal health and synapses. Lcn2 has been shown to exert a key role in mediating the synaptotoxic effect of oxysterol-treated astrocytes.

Biological Functions of Plasmalogens.

Plasmalogens (Pls) are one kind of phospholipids enriched in the brain and other organs. These lipids were thought to be involved in the membrane bilayer formation and anti-oxidant function. However, extensive studies revealed that Pls exhibit various beneficial biological activities including prevention of neuroinflammation, improvement of cognitive function, and inhibition of neuronal cell death. The biological activities of Pls were associated with the changes in cellular signaling and gene expression. Membrane-bound GPCRs were identified as possible receptors of Pls, suggesting that Pls might function as ligands or hormones. Aging, stress, and inflammatory stimuli reduced the Pls contents in cells, and addition of Pls inhibited inflammatory processes, which could suggest that reduction of Pls might be one of the risk factors for the diseases associated with inflammation. Oral ingestion of Pls showed promising health benefits among Alzheimer's disease (AD) patients, suggesting that Pls might have therapeutic potential in other neurodegenerative diseases.

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

IntroductionLarge variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. MethodsGenome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. ResultsWe classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DiscussionThe regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

The clinical and economic burden among caregivers of patients with Alzheimer's disease in Canada

To estimate the clinical and direct medical economic burden among Alzheimer disease (AD) caregivers using real-world, longitudinal patient-level data in Canada. This retrospective observational study assessed the clinical and direct medical economic burden among individuals who cohabitate with AD patients ("AD caregiver cohort") compared with older adults who were cohabiting with another adult without dementia ("comparison cohort") using real-world data from the Southwestern Ontario database, a representative Canadian electronic health record (EHR) longitudinal EHR. The AD caregiver cohort (n = 2749; mild AD: n = 2254, moderate AD: n = 302, and severe AD, n = 193) had a similar or higher level of clinical and economic burden than the comparison cohort (n = 12 152). The overall AD cohort and caregivers of patients with mild AD had a similar clinical burden to the comparison cohort. Those caregiving for more severely affected AD patients had an increased risk of comorbidities and required more medication, physician attention, and hospital encounters compared with caregivers of less severe AD patients and the comparison cohort. Mean annual costs were higher among the AD caregiver cohort than the comparison cohort, and those caregiving for moderate and severe AD patients incurred the highest costs. Overall mortality was higher in the AD caregiver cohort compared with the comparison cohort. Caregivers of patients with mild AD had a similar clinical and direct economic burden to older adults who were not dementia caregivers, whereas the burden among caregivers of moderate and severe AD patients was much greater.

Potentially modifiable factors associated with agitation and aggression in Alzheimer's disease: results of the ICTUS study.

To study potentially modifiable factors associated with the severity of agitation or aggression (A/A) symptoms among Alzheimer's disease (AD) patients. Data from the Impact of Cholinergic Treatment Use (ICTUS) study, European longitudinal prospective observational study. Community dwelling outpatients included in 29 European memory clinics. 1375 participants with probable AD (Mini-Mental State Examination score of 10-26) with an informal caregiver. At baseline and twice yearly over the two-year follow-up, patients underwent comprehensive clinical and neuropsychological assessments: sociodemographic data, cognitive status, functional impairment, and assessment of neuropsychiatric symptoms based on Neuro-Psychiatric Inventory (NPI). The ZARIT scale assessed the caregiver's burden. The variable of interest was the severity of the item of A/A of the NPI. To study factors associated to the severity of A/A symptoms six months later, a multivariate mixed regression model was used. Frequency of A/A symptom varied from 30% to 34% at each visit. Two factors were found to be independently associated with the severity of A/A: (1) the presence of affective disorder (anxiety, depression, and/or irritability) that increased the severity of the A/A by 0.89 point (coefficient:0.89; 95% Confidence Interval (CI) = [0.48,1.30], p < 0.001), and (2) a severe caregiver burden that increased the severity of the A/A by 1.08 point (coefficient:1.08; 95% CI = [0.69,1.47], p < 0.001). Research should evaluate whether the identification and treatment of an affective disorder along with the evaluation and optimal management of the caregiver would have a positive impact on the course of A/A in mild to moderate AD patients.

Effect of memantine combined with citalopram on cognition of BPSD and moderate Alzheimer's disease: A clinical trial

Among Alzheimer's disease (AD) patients, it is very common to develop behavioral and psychological symptoms of dementia (BPSD), which has a close relation to the excess morbidity and mortality, greater healthcare use, earlier institutionalization, and caregiver burden. With evaluation of AD patients, the present study mainly aims to investigate whether citalopram would be efficient for BPSD, and examines citalopram's effects on cognitive function, caregiver distress, safety and tolerability. Eighty patients diagnosed with moderate AD and clinically significant BPSD from April 2015 to January 2016 were enrolled in this study. Patients randomly received memantine plus either citalopram (n=40, study group) or placebo (n=40, control group) in a 12-week period. The target dose of memantine was 20 mg/day. The dose of citalopram was 10 mg/day in the beginning with planned titration to 30 mg/day over 2 weeks on the basis of response and tolerability. Blood routine, urine routine, biochemical tests, electrocardiogram and electroencephalogram were carried out for each patient every month routinely to check the change induced by using medication. Treatment Emergent Symptom Scale (TESS) was used to measure untoward effects every 2 weeks. All of the agitation/aggression, irritability/lability, night-time behavioral disturbances, caregiver distress and Neuropsychiatric Inventory (NPI) total scores after treatment were found to be dramatically lower than those before treatment in both groups. Apathy, dysphoria and anxiety received lower scores in participants who received memantine combined with citalopram, compared to those before treatment. QTc interval prolongation was observed in 2 patients who were treated with 30 mg/day citalopramin. In conclusion, memantine combined with citalopram can more effectively improve the cognitive function, and reduce behavioral and psychological symptoms in patients with moderate AD. Cardiac adverse effects of citalopram are not common when the dose is <30 mg/day, which does not limit its practical application. Thus, citalopram has shown potential efficacy in adjunctive therapy of AD patients with BPSD.

Visualization of Alzheimer's Disease Related α-/β-/γ-Secretase Ternary Complex by Bimolecular Fluorescence Complementation Based Fluorescence Resonance Energy Transfer.

The competitive ectodomain shedding of amyloid-β precursor protein (APP) by α-secretase and β-secretase, and the subsequent regulated intramembrane proteolysis by γ-secretase are the key processes in amyloid-β peptides (Aβ) generation. Previous studies indicate that secretases form binary complex and the interactions between secretases take part in substrates processing. However, whether α-, β- and γ-secretase could form ternary complex remains to be explored. Here, we adopted bimolecular fluorescence complementation in combination with fluorescence resonance energy transfer (BiFC-FRET) to visualize the formation of triple secretase complex. We show that the interaction between α-secretase ADAM10 and β-secretase BACE1 could be monitored by BiFC assay and the binding of APP to α-/β-secretase binary complex was revealed by BiFC-FRET. Further, we observed that γ-secretase interacts with α-/β-secretase binary complex, providing evidence that α-, β- and γ-secretase might form a ternary complex. Thus our study extends the interplay among Alzheimer’s disease (AD) related α-/β-/γ-secretase.

A Tetrahedron-based Heat Flux Signature for Cortical Thickness Morphometry Analysis.

Cortical thickness analysis of brain magnetic resonance images is an important technique in neuroimaging research. There are two main computational paradigms, namely voxel-based and surface-based methods. Recently, a tetrahedron-based volumetric morphometry (TBVM) approach involving proper discretization methods was proposed. The multi-scale and physics-based geometric features generated through such methods may yield stronger statistical power. However, several challenges, such as the lack of well-defined thickness statistics and the difficulty in filling tetrahedrons into the thin and curvy cortex structure, impede the broad application of TBVM. In this paper, we present a universal cortical thickness morphometry analysis approach called tetrahedron-based Heat Flux Signature (tHFS) to address these challenges. We define the tetrahedron-based weak form heat equation and Laplace-Beltrami eigen decomposition and give an explicit FEM-based discretization formulation to compute the tHFS. We further show a tHFS metric space with which cortical morphometric distances can be directly visualized. Additionally, we optimize the cortical tetrahedral mesh generation pipeline and fill dense high-quality tetrahedra in the grey matters without sacrificing data integrity. Compared with existing cortical thickness analysis approaches, our experimental results of distinguishing among Alzheimer's disease (AD), cognitively normal (CN) and mild cognitive impairment (MCI) subjects shows that tHFS yields a more accurate representation of cortical thickness morphometry. The tHFS metric experiment provides a more vivid visualization of tHFS's power in separating different clinical groups.

Integrated Biomarkers for Depression in Alzheimer's Disease: A Critical Review.

Depression is a common neuropsychiatric manifestation among Alzheimer's disease (AD) patients. It may compromise everyday activities and lead to a faster cognitive decline as well as worse quality of life. The identification of promising biomarkers may therefore help to timely initiate and improve the treatment of preclinical and clinical states of AD, and to improve the long-term functional outcome. In this narrative review, we report studies that investigated biomarkers for AD-related depression. Genetic findings state AD-related depression as a rather complex, multifactorial trait with relevant environmental and inherited contributors. However, one specific set of genes, the brain derived neurotrophic factor (BDNF), specifically the Val66Met polymorphism, may play a crucial role in AD-related depression. Regarding neuroimaging markers, the most promising findings reveal structural impairments in the cortico-subcortical networks that are related to affect regulation and reward / aversion control. Functional imaging studies reveal abnormalities in predominantly frontal and temporal regions. Furthermore, CSF based biomarkers are seen as potentially promising for the diagnostic process showing abnormalities in metabolic pathways that contribute to AD-related depression. However, there is a need for standardization of methodological issues and for replication of current evidence with larger cohorts and prospective studies.

Predicting the Rate of Cognitive Decline in Alzheimer Disease: Data From the ICTUS Study.

Different rates of cognitive progression have been observed among Alzheimer disease (AD) patients. The present study aimed at evaluating whether the rate of cognitive worsening in AD may be predicted by widely available and easy-to-assess factors. Mild to moderate AD patients were recruited in the ICTUS study. Multinomial logistic regression analysis was performed to measure the association between several sociodemographic and clinical variables and 3 different rates of cognitive decline defined by modifications (after 1 year of follow-up) of the Mini Mental State Examination (MMSE) score: (1) "slow" progression, as indicated by a decrease in the MMSE score ≤1 point; (2) "intermediate" progression, decrease in the MMSE score between 2 and 5 points; and (3) "rapid" progression, decrease in the MMSE score ≥6 points. A total of 1005 patients were considered for the present analyses. Overall, most of the study participants (52%) exhibited a slow cognitive course. Higher ADAS-Cog scores at baseline were significantly associated with both "intermediate" and "rapid" decline. Conversely, increasing age was negatively associated with "rapid" cognitive worsening. A slow progression of cognitive decline is common among AD patients. The influence of age and baseline cognitive impairment should always be carefully considered when designing AD trials and defining study populations.

Neuropathologic Heterogeneity Does Not Impair Florbetapir-Positron Emission Tomography Postmortem Correlates

Neuropathologic heterogeneity is often present among Alzheimer disease (AD) patients. We sought to determine whether amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinically and pathologically defined AD and 17 nondemented patients with quantitative florbetapir F-18 (F-AV-45) positron emission tomography (PET) imaging during life and postmortem histological β-amyloid quantification and neuropathologic examination were assessed. AD patients were divided on the basis of concurrent pathologies, including those with Lewy bodies (LBs) (n = 21), white matter rarefaction (n = 27), severe cerebral amyloid angiopathy (n = 11), argyrophilic grains (n = 5), and TAR DNA binding protein-43 inclusions (n = 18). Many patients exhibited more than 1 type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in 6 cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p μ 0.001). All AD subgroups had significantly greater amyloid measures versus nondemented patients, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with LBs had significantly lower SUVr measures versus AD cases without LBs (p = 0.002); there were no other paired comparison differences. These findings indicate that florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.

High degree of heterogeneity in Alzheimer's disease progression patterns.

There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4–6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline.