An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

Effect of Nordic Sensi® Chair on Behavioral and Psychological Symptoms of Dementia in Nursing Homes Residents: A Randomized Controlled Trial.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are present in most people with dementia (PwD), including Alzheimer's disease. There is consensus that non-pharmacological therapies represent the first line of treatment to address BPSD. OBJECTIVE: We explore the efficacy of the use of a rocking chair (Nordic Sensi® Chair, NSC) in the treatment of BPSD in nursing home residents with moderate and severe dementia. METHODS: We carried out a 16-week randomized, single-blind, controlled, clinical trial with PwD admitted to nursing homes. Participants were assigned to a treatment group (n = 40) that received three times a week one session per day of 20 minutes in the NSC and a control group (n = 37). The Neuropsychiatric Inventory-Nursing Home (NPI-NH) was used as primary efficacy outcome. Occupational distress for the staff was evaluated using the NPI-NH Occupational Disruptiveness subscale (NPI-NH-OD). Statistical analyses were conducted by means of a Mixed Effects Model Analysis. RESULTS: Treatment with the NSC was associated with a beneficial effect in most of BPSD, as reflected by differences between the treatment and control group on the NPI-NH total score (mean change score -18.87±5.56 versus -1.74±0.67, p = 0.004), agitation (mean change score -2.32±2.02 versus -0.78±1.44, p = 0.003) and irritability (mean change score -3.35±2.93 versus -1.42±1.31, p = 0.004). The NPI-NH-OD total score also improved the most in the treatment group (mean change score -9.67±7.67 versus -7.66±6.08, p = 0.003). CONCLUSIONS: The reduction in overall BPSD along with decreased caregiver occupational disruptiveness represent encouraging findings, adding to the potential of nonpharmacological interventions for nursing home residents living with dementia.

Efficacy of Souvenaid® Combined with Acetylcholinesterase Inhibitors in the Treatment of Mild Alzheimer's Disease.

BACKGROUND: Souvenaid® is a medical food that contains nutrients that can help synapse synthesis in Alzheimer's disease (AD). The potential effectiveness of combination therapy of Souvenaid with cholinesterase inhibitors (AChEI) is currently not well-known. OBJECTIVE: To look into the effect of combination therapy with Souvenaid plus AChEI in people with mild AD in the real-world. METHODS: We carried out a retrospective analysis in mild AD patients attending a memory clinic. Three groups were studied according to the treatment they received: Souvenaid alone (n = 66), AChEI alone (n = 84), and Souvenaid+AChEI (n = 70). Treatment effects were evaluated at baseline, 6 and 12 months. Cognitive functioning was assessed by Mini-Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit Modalities Test (SDMT), Boston Naming Test (BNT), Trail Making Test (TMT/A-B), Phonemic and Semantic Verbal Fluency Test (PVFT/SVFT); neuropsychiatric symptoms were evaluated by the Neuropsychiatric Inventory (NPI); functional capacity was assessed by the Bayer Activities Daily Living Scale (BAYER-S). A Mixed Model for Repeated Measures analysis was carried out to evaluate changes in outcome scores. RESULTS: After 12 months Souvenaid+AChEI showed significant improvement in MMSE (p < 0.001), RAVLT (p < 0.0001), SVFT (p = 0.002), PVFT (p = 0.007), TMTA (p = 0.039), TMTB (p = 0.001), and NPI (p < 0.0001) compared to AChEI alone. CONCLUSION: Souvenaid showed cognitive and behavioral benefits in mild AD patients. These effects increased when Souvenaid and AChEI were used in combination. This study can serve as a model for the design of prospective controlled trials that help to support the combined use of Souvenaid and antidementia drugs in AD.

Combined treatment with Ginkgo biloba extract EGb 761 plus acetylcholinesterase inhibitors improved cognitive function and neuropsychiatric symptoms in patients with mild cognitive impairment.

Introduction: Mild cognitive impairment (MCI) is a neurocognitive state between normal aging and dementia. There is currently no approved treatment for MCI, with acetylcholinesterase inhibitors (AChEI) being the commonly prescribed drugs. The Ginkgo biloba extract EGb 761 is an herbal remedy used for cognitive disorders, including dementia. This study aims to explore the potential synergistic effect of combination therapy with EGb 761 plus AChEI in patients with amnestic MCI in a real-life setting. Methods: We retrospectively identified 133 patients with amnestic MCI who were attending a memory clinic. Patients had received treatment with any of the following drugs: G. biloba extract EGb 761, donepezil, galantamine, or rivastigmine at their standard doses. Subjects were divided into three treatment groups: EGb 761, AChEI, and EGb 761+AChEI. Patients were assessed by Mini-Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit Modalities Test, Boston Naming Test, Trail Making Test (TMT Parts A and B), Letter and Category Fluency Test (LFT, CFT), Neuropsychiatric Inventory (NPI), and Interview for Deterioration in Daily Living. Mixed-effects model analysis was carried out to evaluate changes in cognitive, functional, and behavioral outcomes over a 12-month follow-up. Results: After 12 months, EGb 761+AChEI showed significant improvement in MMSE, RAVLT, CFT, TMT A-B, and NPI compared to AChEI and in MMSE and RAVLT compared to EGb 761. At 12 months, EGb 761 was superior to AChEI on the CFT, TMT A-B, and NPI. Discussion: Our findings suggest that combined therapy with EGb 761 plus AChEI may provide added cognitive and functional benefits in patients with MCI and provides additional real-world evidence for the combined use of EGb 761 and anti-dementia drugs in patients with MCI. This study can serve as a model for the design of clinical trials that help to support the combined use of EGb 761 and anti-dementia drugs in patients with MCI.

Effects of Tianeptine Treatment on Depression and Cognitive Function in Patients with Alzheimer's Disease: A 12-Month Retrospective Observational Study.

BACKGROUND: Depression is a common manifestation in Alzheimer's disease (AD). In clinical practice, antidepressant medication is often used for depression in AD. OBJECTIVE: We explore the effectiveness of the atypical antidepressant tianeptine compared with other conventional antidepressants in AD patients with depression in a real-life setting. METHODS: We retrospectively identified 126 AD patients who had received antidepressant treatment for 12 months with tianeptine or other antidepressants. Subjects were divided into two groups according to the treatment they had received: tianeptine group (n = 38) or other antidepressant group (n = 88). Drug effects on depression, cognition, behavior, and functional performance were evaluated at baseline, 6, and 12 months. A Mixed Effects Model Analysis was carried out to evaluate changes in performance scores. RESULTS: Both tianeptine and other antidepressants showed an antidepressant effect after 12 months with significant improvement on the Cornell Scale for Depression in Dementia, the Hamilton Depression Rating Scale, and the Neuropsychiatric Inventory-Depression subscale. A statistically significant improvement at 12 months was shown in the tianeptine group versus the other antidepressants group on most of the cognitive measures such as the Mini-Mental State Examination, the Letter and Category Fluency Test, the Rey Auditory Verbal Learning Test, and the Boston Naming Test. CONCLUSION: Our results suggest that tianeptine reduces depressive symptoms and improves cognition in AD patients. This could be considered clinically relevant and should inspire the design of future long-term randomized controlled trials that contribute to supporting the use of tianeptine for improving cognitive function in AD patients.

Benefits of Treatment with Ginkgo Biloba Extract EGb 761 Alone or Combined with Acetylcholinesterase Inhibitors in Vascular Dementia.

BACKGROUND: Vascular dementia (VaD) is the most severe manifestation of cognitive impairment caused by cerebrovascular disease. There are currently no specific drug treatments approved for VaD, with cholinesterase inhibitors (AChEI) being frequently used in VaD. However, the benefits they provide are small and short-lived. The standardized extract of Ginkgo biloba EGb 761 has demonstrated protective properties against neuronal and vascular damage and has been used as a pharmacological treatment for VaD. OBJECTIVES: This study aims to study the efficacy of EGb 761 alone and in combination with AChEI in a real-life setting. We carried out a retrospective analysis of data over a 12-month period in a sample of people suffering from VaD. METHODS: We retrospectively identified 77 patients with a diagnosis of VaD who had received treatment with any of the following drugs: Ginkgo biloba extract EGb 761 (240 mg daily), donepezil (10 mg daily), galantamine (16 or 24 mg daily), or rivastigmine patch (9.5 or 13.3 mg daily). Subjects were divided into three groups according to the treatment they had received: EGb 761 alone (n = 25), AChEI alone (n = 26), and EGb 761+AChEI (n = 26). Cognitive functioning was assessed by Mini-Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit Modalities Test (SDMT), Boston Naming Test (BNT), Trail Making Test forms A (TMTA) and B (TMTB), Letter (LFT) and Category Fluency Test (CFT); neuropsychiatric symptoms were assessed by the Neuropsychiatric Inventory (NPI); functional capacity was assessed by Interview for Deterioration in Daily Living (IDDD). RESULTS: A statistically significant improvement was observed in the EGb 761 group versus the AChEI group at 12 months' follow-up in CFT (+1.74, p < 0.001), TMTA (-17.91, p = 0.031) and NPI (-5.89, p < 0.001). With regard to the combined treatment, a statistically significant improvement was shown in the EGb 761 plus AChEI treatment group versus AChEI group at the 12-month follow-up in MMSE (+2.0, p = 0.001), RAVLT (+2.23, p = 0.007), CFT (+1.15, p = 0.013), TMTA (-19.92, p = 0.012), TMTB (-46.50, p < 0.001) and NPI (-6.77, p < 0.001). In the same line, a statistically significant improvement was observed in the EGb 761 plus AChEI treatment group versus EGb 761 at 12-month follow-up regarding MMSE (+2.11, p = 0.001), RAVLT (+2.35, p = 0.004) and TMTB (-25.25, p = 0.015). CONCLUSION: After 12 months of treatment EGb 761 alone or combined with AChEI showed cognitive and behavioral benefits in patients suffering from VaD. This study thus provides additional real-world evidence for the combined use of EGb 761 and anti-dementia drugs in VaD patients.

The Genetic Research in Alzheimer Disease (GERALD) Initiative Finds rs9320913 as a Neural eQTL of lincRNA AL589740.1.

Alzheimer's disease is the most common cause of dementia worldwide, and longitudinal studies are crucial to find the factors affecting disease development. Here, we describe a novel initiative from southern Spain designed to contribute in the identification of the genetic component of the cognitive decline of Alzheimer's disease patients. The germline variant rs9320913 is a C>A substitution mapping within a gene desert. Although it has been previously associated to a higher educational achievement and increased fluid intelligence, its role on Alzheimer's disease risk and progression remains elusive. A total of 407 subjects were included in the study, comprising 153 Alzheimer disease patients and 254 healthy controls. We have explored the rs9320913 contribution to both Alzheimer disease risk and progression according to the Mini-Mental State Exams. We found that rs9320913 maps within a central nervous system lincRNA AL589740.1. eQTL results show that rs9320913 correlated with the brain-frontal cortex (beta = -0.15, p value = 0.057) and brain-spinal cord (beta of -0.23, p value = 0.037). We did not find rs9320913 to be associated to AD risk, although AA patients seemed to exhibit a less pronounced Mini-Mental State Exam score decline.

White matter lesions and temporal atrophy are associated with cognitive and neuropsychiatric symptoms in patients with hypertension and Alzheimer's disease.

OBJECTIVES: An increasing evidence suggests hypertension (HTN) could be linked to cognitive impairment and incident Alzheimer's disease (AD). The precise mechanisms linking HTN and AD are not well-known. The aim of this study was to assess the putative association between HTN and AD. METHODS: We assessed in patients with AD associations between HTN and demographic and clinical data, vascular risk factors, treatments, APOE genotypes, brain white matter hyperintensities (WMH), and medial temporal atrophy (MTA) in multivariate analysis of covariance. RESULTS: We studied 92 patients with AD (mean ± SD age: 72.12 ± 6.91; women: 66.30%). Patients with HTN had significantly worse cognitive and functional status and higher frequency and severity of neuropsychiatric symptoms (P = .010). Magnetic resonance imaging analyzes showed significant increases in WMH (P = .018) and in MTA (P = .012) in patients with AD with HTN compared with those without HTN. CONCLUSIONS: Neuroimaging burden (MTA and higher degree of severity of WMH) among patients with AD and HTN are associated with the impaired cognitive function and neuropsychiatric symptoms.

Neuropsychiatric Symptoms in Patients With Alzheimer's Disease: The Role of Caregiver Burden and Coping Strategies.

This study was conducted to obtain data regarding the association of caregiver burden (CB) and neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease. We conducted a series of multiple linear regressions to determine the relationship between CB and NPSs and whether the caregiver coping strategies mediated this relationship. The NPSs were assessed using the Neuropsychiatric Inventory, and caregivers were evaluated with the Caregiver Burden Interview and the Inventory and the Coping Strategies Inventory. Results show that patients with more frequent and severe NPS were more likely to be cared for by more burdened caregivers, and this was partially mediated by caregiver coping strategies. More disengagement (ß = .330,P< .001) and less engagement coping (ß = -.347,P< .001) were predictors for NPS after adjusting for patient and caregiver characteristics. These results may be useful with a view to designing treatment interventions that aim to modify the use of caregiver coping strategies and to reduce NPSs.

Sleep disturbances in Alzheimer's disease are associated with neuropsychiatric symptoms and antidementia treatment.

Sleep disturbances (SDs) in Alzheimer's disease (AD) may significantly affect the behavioral, functional, and cognitive capacities of patients to the point of becoming a major determinant of caregiver burden. We conducted a cross-sectional study in 125 patients with probable AD to assess the association of SDs with neuropsychiatric symptoms, cognitive and functional status of patients, and severity and duration of dementia and to ascertain the role of antidementia drugs in the treatment of SD. SDs were assessed using the questionnaire on sleep disorders in the Neuropsychiatric Inventory. The prevalence of SDs in this sample was 36%. SDs in patients with AD are significantly associated with depression (Wald's test, 3.983; p < 0.05), disinhibition (Wald's test, 5.522; p < 0.05), and aberrant motor behavior (Wald's test, 7.430; p < 0.01). The patients treated with memantine presented lower mean SDs scores (t = 2.76; p < 0.001). These results highlight the need for a standardized and validated approach to the assessment of SDs in AD.

The experience of caregiving: the influence of coping strategies on behavioral and psychological symptoms in patients with Alzheimer's disease.

OBJECTIVES: To determine whether caregiver coping strategies are independently associated with behavioral and psychological symptoms (BPS) in Alzheimer's disease (AD) after accounting for patient characteristics. METHODS: Cross-sectional data analysis of 80 patients with AD and their primary caregivers. The presence of BPS was recorded using the Neuropsychiatric Inventory (NPI). The relationship between caregiver characteristics and BPS was assessed through one-way analysis of variance, two-tailed student t-tests or correlation coefficients. Multivariate linear regression was used to determine the combined effect of all caregiver factors that were significant on bivariate analysis regarding coping and BPS controlling for patient characteristics. RESULTS: Caregivers were on average 62 years old, 77% female, and most were the children or the spouse of the patient. Over 50% had significant depression or anxiety. Patients were on average 77 years old and 62% were female, and most had moderate to severe dementia. After adjusting for patient characteristics, patients cared for by more depressed, more burdened, or those using more disengagement coping strategies showed higher NPI mean composite scores. CONCLUSION: Coping strategies are associated with BPS regardeless of patient characteristics. Interventions to reduce BPS should focus on which psychological coping strategies caregivers use. Understanding how coping strategies influence BPS may help tailor specific interventions for caregivers.

Anxiety and depression are associated with coping strategies in caregivers of Alzheimer's disease patients: results from the MÁLAGA-AD study.

BACKGROUND: Caregiving for people with Alzheimer's disease (AD) is highly stressful and has significant negative consequences, such as anxiety and depression. Previous research offers conflicting findings as to whether coping strategies are associated with greater psychological distress or not. We conducted this study with a view to obtaining new data regarding the association of coping strategies and psychological distress in AD caregivers. METHODS: Eighty people with AD and their primary caregivers living in the community were recruited from local health services. Purposive recruitment was carried out to ensure that the sample was representative of people living with dementia in terms of dementia severity, gender, and care setting. We used the State-Trait Anxiety Inventory to measure anxiety, the Beck Depression Inventory to measure depression, and the Coping Strategies Inventory to measure coping strategies. RESULTS: Most caregivers reported higher anxiety and depression levels. Use of disengagement coping strategies (Wald = 3.35, p = 0.01) and higher caregiver burden (Wald = 4.83, p = 0.02) predicted anxiety on logistic regression. In turn, use of disengagement coping strategies (Wald = 12.48, p = 0.001) and higher caregiver burden (Wald = 6.91, p = 0.009) predicted depression on logistic regression. CONCLUSION: These results may be useful for designing treatment interventions that aim to modify the use of coping strategies and thus reduces caregiver anxiety and depression.

Disengagement coping partially mediates the relationship between caregiver burden and anxiety and depression in caregivers of people with Alzheimer's disease. Results from the MÁLAGA-AD study.

BACKGROUND: Caring for people with Alzheimer's disease can be considered stressful and demand adjustment strategies. While various variables have been associated with caregiver anxiety and depression, a possible mediator role of coping strategies adopted by caregivers between caregiver burden and anxiety and depression is still unclear. We hypothesized that caregivers with clinically significant anxiety and depression were more likely to use disengagement coping strategies that non-anxious and non-depressed caregivers. METHODS: This study involved 80 Alzheimer disease patients and their primary caregivers. Patients were evaluated using the Mini Mental State Examination, the Bayer Activities of Daily Living Scale, the Global Deterioration Scale and the Neuropsychiatric Inventory. Caregivers were evaluated with the Caregiver Burden Interview, the Beck Depression Inventory, the State-Trait Anxiety Inventory and the Coping Strategies Inventory. We conducted a series of multiple linear regressions to determine the relationship between caregiver burden and caregiver anxiety and depression, and if the coping strategies mediated this relationship. RESULTS: Using more disengagement (ß=0.270, p<0.001) and less engagement coping (ß=-0.310, p<0.001) were predictors for anxiety scores. Using more disengagement (ß=0.250, p<0.001) and less engagement coping (ß=-0.261, p<0.001) were predictors for depression scores. LIMITATIONS: This study was a cross-sectional design, so the direction of causality should be strengthened by a longitudinal study. CONCLUSIONS: Most caregivers reported higher anxiety and depression levels and this was partially mediated by their dysfunctional coping strategies.