Search Results (174)

Alzheimer’s disease is a progressive neurodegenerative disorder marked by cognitive decline, and its global prevalence is expected to increase substantially in the coming decades. This review examines current therapeutic approaches and explores the potential role of medicinal plants and natural products in the treatment and prevention of Alzheimer’s disease. This review examines the pathophysiology of Alzheimer’s disease, with particular emphasis on the cholinergic, amyloid, and tau hypotheses. It evaluates currently approved therapeutic approaches, including cholinesterase inhibitors and NMDA receptor antagonists, as well as emerging immunotherapies. In addition, this review provides a comprehensive analysis of the pharmacological properties of various medicinal plants and explores innovative drug delivery systems. Research reveals that while conventional drugs like donepezil and memantine provide symptomatic relief, they do not halt disease progression. Recent immunotherapies, including lecanemab and donanemab, show potential to reduce amyloid-beta accumulation and slow cognitive decline; however, they face safety concerns, such as amyloid-related imaging abnormalities, and high costs. By comparison, several natural products—including huperzine A, curcumin, resveratrol, and epigallocatechin-3-gallate—demonstrate multi-target therapeutic potential through anti-inflammatory, antioxidant, and cholinergic-modulating mechanisms. This review offers a comprehensive contrast between natural products and traditional drugs as well as the safety and economic limitations of immunotherapies. Given the multifactorial nature of AD, therapeutic strategies that address multiple pathological pathways appear necessary. In this regard, plant-derived compounds, due to their broad pharmacological activity and generally favorable safety profiles, emerge as promising candidates for long-term management and may contribute meaningfully to the development of future therapeutic approaches for AD. Full article

Background: Alcohol Use Disorder (AUD) is a major contributor to global morbidity, mortality, and socioeconomic burden. Cravings, defined as intense urges to consume alcohol, play a central role in relapse and are recognized as a diagnostic criterion in DSM-5. Pharmacological strategies targeting cravings may offer immediate or short-term relief, complementing existing long-term approaches. However, evidence on short-term (up to approximately three months) anti-craving interventions remains fragmented. Objective: To systematically review randomized, double-blind, placebo-controlled trials (RCTs) assessing the short-term effects of pharmacological treatments on cue-induced alcohol cravings. Methods: A systematic search was conducted in PubMed and PsycINFO using terms related to alcohol, craving, and randomized controlled designs. Eligibility included clinical trials on alcohol-dependent participants that evaluated craving as an outcome. Exclusion criteria encompassed non-clinical studies, non-pharmacological interventions, animal studies, single-blind trials, and studies with psychiatric comorbidities. Study quality was appraised using Cochrane and Joanna Briggs Institute tools. Results: From 442 studies screened, 26 RCTs fulfilled the inclusion criteria. In total, 1097 participants were enrolled across the trials (range = 16–125 per study; mean = 44), predominantly male outpatients aged 15–65 years. Craving was assessed primarily with the Visual Analog Scale and Alcohol Urge Questionnaire. Intervention duration ranged from 1 to 98 days. Naltrexone consistently reduced cue-induced craving across four trials, with additional benefit observed when combined with ondansetron. Varenicline and acamprosate also demonstrated reductions in craving and drinking. Memantine showed efficacy in craving reduction but was not assessed for abstinence. Topiramate was effective, whereas gabapentin showed limited short-term benefit. Other agents (e.g., citalopram, oxytocin, ondansetron, quetiapine) yielded mixed findings, often limited to single studies. Overall, 58% of trials reported positive anti-craving effects, 23% no difference, and 8% increased craving versus placebo. However, these findings should be interpreted in light of important methodological limitations, including small sample sizes and heterogeneous experimental paradigms. Conclusions: This review suggests that naltrexone and varenicline appear to be the most consistently supported short-term pharmacotherapies for alcohol craving within the available evidence, with promising but less consistent findings for memantine, acamprosate, and topiramate. These results highlight potential candidates for immediate craving management in AUD, while underscoring the need for larger and longer-term trials to confirm their efficacy and safety. Full article

Background/Objectives: This study aimed to develop an ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method for quantifying amantadine (AMA) in rat plasma and to investigate its pharmacokinetics under simulated high-altitude hypoxia, contrasting its behavior with that of its structural analog memantine (MEM). Methods: The method entailed using memantine (MEM) as an internal standard. Sample preparation involved protein precipitation, followed by gradient elution with detection via positive electrospray ionization and selective reaction monitoring (SRM). The method validation complied with the International Conference on Harmonization (ICH) M10 guidelines. Pharmacokinetic studies were conducted in rats exposed to either low altitude (1500 m) or simulated high altitude (6500 m) after a single oral dose of AMA (10 mg/kg). Results: The assay demonstrated linearity from 5 to 1000 µg/L, with accuracy, precision, recovery, and stability all meeting the respective acceptance criteria. Hypoxia did not significantly alter systemic exposure to AMA, as measured by parameters such as the area under the concentration–time curve (AUC), maximum concentration (Cmax), and apparent clearance (CLz/F). However, hypoxia prolonged the elimination half-life by 55% and increased the variance in the mean residence time. This finding contrasts sharply with our previous results on MEM under identical hypoxic conditions, which showed a 72.15% increase in AUC and a 41.99% decrease in CLz/F. Conclusions: A robust UPLC-MS/MS method for quantifying AMA was successfully established. AMA exhibits unique pharmacokinetic resilience to acute hypoxia, characterized by increased variability in elimination without changes in overall exposure. This profile starkly differs from the heightened exposure and reduced clearance observed for drugs like MEM, which are predominantly cleared by hepatic metabolism (under the studied conditions). These findings are consistent with the concept that a drug’s primary elimination pathway (renal excretion vs. hepatic metabolism) critically determines its pharmacokinetic susceptibility to hypoxic stress. Full article

This narrative review integrates longitudinal cohort studies, neuroimaging and biomarker research, and major clinical trials to examine how depression and cognitive decline interact across the dementia continuum. Depression and cognitive impairment frequently co-occur in late life and exhibit substantial clinical and biological overlap. Meta-analytic and large population-based cohort studies consistently show that late-life depression increases the risk of mild cognitive impairment and dementia, with stronger associations observed for vascular dementia than for Alzheimer’s disease. Neurobiological studies implicate cerebrovascular pathology, neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and fronto-subcortical circuit dysfunction as key mechanisms linking depressive symptoms to later cognitive decline. In a subset of older adults, new-onset depression—particularly when accompanied by executive dysfunction, subjective cognitive decline, or high white-matter hyperintensity burden—are associated with an increased likelihood of near-term cognitive decline and dementia, although evidence for a definitive prodromal state remains limited. Depression is also highly prevalent as part of the behavioral and psychological symptoms of dementia, occurring in 30–50% of individuals with Alzheimer’s disease and even higher proportions in dementia with Lewy bodies or frontotemporal dementia. Comorbid depression in dementia accelerates cognitive and functional decline, increases neuropsychiatric burden, and worsens quality of life for patients and caregivers. Therapeutically, antidepressant treatment may confer modest benefits on mood and selected cognitive domains (e.g., processing speed and executive function) in non-demented older adults, whereas in established dementia, antidepressant efficacy is limited. In contrast, cholinesterase inhibitors, memantine, and multimodal non-pharmacological interventions yield small but measurable improvements in depressive or apathy-related symptoms. Emerging disease-modifying therapies for Alzheimer’s disease have demonstrated cognitive benefits, but current trial data provide insufficient evidence regarding effects on depressive symptoms, highlighting an important gap for future research. These findings underscore the need for stage-specific, integrative strategies to address the intertwined trajectories of mood and cognition in aging. Full article

Parkinson’s disease (PD) has been associated with some types of food and drugs. Here, we query PubMed for the association of PD with foods and drugs, using a list of 217,776 compounds derived from the Human Metabolome Database (HMDB). To calculate associations, a Python script was developed to query PubMed for co-citations of PD with each compound, and adjust this count for compound abundance. Notably, PD is found to be associated with small-molecule drugs, adjunctive therapies, contraindicated drugs, diagnostic agents, biomarkers, conditional essential molecules, and inducers. Drugs include L-dopa (49%), carbidopa (63%), benserazide (50%), entacapone (74%), tolcapone (56%), rasagiline (76%), selegiline (46%), pargyline (4%), ropinirole (61%), pramipexole (56%), lisuride (27%), cabergoline (16%), bromocriptine (12%), and zonisamide (9%). Adjunctive therapies include droxidopa (33%), trihexyphenidyl (28%), biperiden (17%), amantadine (24%), memantine (7%), rivastigmine (13%), donepezil (6%), galantamine (4%), domperidone (6%), clonazepam (4%), tetrabenazine (16%), mazindol (13%), quetiapine (6%), and clozapine (4%). Contraindicated drugs include haloperidol (4%), sulpiride (3%), and methyldopa (6%). Diagnostic agents include FP-CIT (60%) and beta-CIT (43%). Biomarkers include 3-methoxytyrosine (48%) and homovanillic acid (12%). Endogenous cofactors include tetrahydrobiopterin (4%) and Coenzyme Q10 (4%). Chemical inducers of PD include 6-hydroxydopamine (40%), N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 78%), tetrahydropyridine (77%), probenecid (4%), quinolinic acid (4%), 1,2,3,4-tetrahydroisoquinoline (TIQ, 16%), salsolinol (32%), rotenone (25%), and β-Methylamino-L-alanine (BMAA, 29%). Notably, our study highlights conditional essential endogenous cofactors associated with PD and emphasizes rational directions for investigation in PD. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by persistent memory impairment and complex molecular and cellular pathological changes in the brain. Current treatments, including acetylcholinesterase inhibitors and memantine, only help with symptoms for a short time and do not stop the disease from getting worse. This is mainly because these drugs do not reach the brain well and are quickly removed from the body. The blood–brain barrier (BBB) restricts the entry of most drugs into the central nervous system; therefore, new methods of drug delivery are needed. Nanotechnology-based drug delivery systems (NTDDS) are widely studied as a potential approach to address existing therapeutic limitations. Smart biosensing nanoparticles composed of polymers, lipids, and metals can be engineered to enhance drug stability, improve drug availability, and target specific brain regions. These smart nanoparticles can cross the BBB via receptor-mediated transcytosis and other transport routes, making them a promising option for treating AD. Additionally, multifunctional nanocarriers enable controlled drug release and offer theranostic capabilities, supporting real-time tracking of AD treatment responses to facilitate more precise and personalized interventions. Despite these advantages, challenges related to long-term safety, manufacturing scalability, and regulatory approval remain. This review discusses current AD therapies, drug-delivery strategies, recent advances in nanoparticle platforms, and prospects for translating nanomedicine into effective, disease-modifying treatments for AD. Full article

Background/Objectives: Empagliflozin (EMPA) was repurposed for Alzheimer’s disease (AD) treatment via buccal delivery, exploiting novel nanofibers (NFs) integrating chitosan (Cs), silk fibroin (Fb), and poly(lactic acid) (PLA). Methods: EMPA-loaded Cs/Fb/PLA NFs were electrospun in different formulations to optimize the formulation parameters. The optimized formulation was then investigated for its enhanced in vivo effect. Results: Optimized nanofiber diameters ranged from 459 ± 173 to 668 ± 148 nm, possessing bead-free morphology confirmed by SEM and satisfactory mechanical properties. EMPA was successfully well-dispersed in the polymer matrix as evidenced by FTIR, XRD, and drug content. The optimized NFs displayed a hydrophilic surface (contact angle < 90°), and biphasic drug release with sustained EMPA liberation (84.98% over 24 h). In vivo, buccal EMPA-Cs/Fb/PLA NFs in an AlCl₃-induced AD rat model significantly reduced brain-amyloid-β, phosphorylated tau, IL-1β, and AGER expression by 2.88-, 2.64-, 2.87-, and 2.50-fold, respectively, compared to positive controls, and improved locomotor activity (1.86-fold) and cognitive performance (T-maze) (4.17-fold). Compared to pure EMPA, the nanofiber formulation achieved further reductions in amyloid-β (1.78-fold), p-tau (1.42-fold), IL-1β (1.89-fold), and AGER (1.38-fold), with efficacy comparable to memantine. Histopathological examination revealed preservation of the hippocampal neuronal structure. Conclusions: The findings suggest EMPA-loaded Cs/Fb/PLA NFs as a promising non-invasive, sustained-release buccal delivery platform for AD therapy, offering multimodal neuroprotection through modulation of the Aβ–AGER–p-tau axis. Full article

Mild cognitive impairment (MCI) is a nosological entity that requires special attention from a therapeutic perspective, because annual conversion rates to dementia of 5–15% in these cases are considered typical. This narrative review aimed to identify available data supporting the efficacy and tolerability of various pharmacological therapeutic interventions by searching PubMed/MEDLINE, the Cochrane Database of Systematic Reviews, and the Web of Science (WoS) Core Collection for primary and secondary reports published over the last 25 years on the pharmacological treatment of MCI. The retrieved interventions were distributed in five large categories: (1) conventional cognitive enhancers; (2) disease-modifying therapeutic interventions; (3) strategies mitigating vascular risk and management of concomitant medications; (4) adjuvant and nootropic formulations; (5) case management of non-cognitive symptoms in MCI. The most broadly applicable pharmacological strategies in MCI include systematic deprescribing and optimisation of concomitant therapies, reducing anticholinergic and sedative load, avoiding iatrogenic hypoglycaemia and excessive blood pressure lowering, and careful, individualised treatment of vascular risk factors. Based on the randomised controlled trials, meta-analyses, and contemporary guidelines, a pragmatic pharmacological approach to MCI is suggested. Further trials with better design are urgently needed to document the efficacy and safety of pharmacological interventions in patients diagnosed with MCI. Full article

Objective: The objective of this study was to determine whether Non-Hispanic Black (NHB) or Non-Hispanic White (NHW) Alzheimer dementia patients with neuropsychiatric symptoms (ADNPS) differ regarding treatment with second-generation antipsychotics (SGAs), central acetylcholinesterase inhibitors (CAIs), and selective serotonin reuptake inhibitors (SSRIs). Methods: Pharmacologic and demographic factors associated with male and female ADNPS were examined using retrospective data collected from a registry from 2016 and 2020 in a regional AD care center. The logistic regression model was developed to generate odds ratios (OR) to determine factors that were associated with male or female ADNPS. Results: A total of 7031 AD patients were identified. Overall, 6237 patients were NHWs, and 794 were NHBs. Among the NHW AD patients, 1909 presented with behavioral disturbances or neuropsychiatric symptoms (NPS), and 168 NHB AD patients presented with NPS. In the adjusted analysis, NHW ADNPS patients were more likely to be treated with galantamine (OR = 1.538, 95% CI, 1.001–2.364, p = 0.049), memantine (OR = 1.222, 95% CI, 1.086–1.375, p < 0.001), olanzapine (OR = 2.323, 95% CI, 1.794–3.009, p < 0.001), risperidone (OR = 4.181, 95% CI, 3.539–4.939, p < 0.001), and escitalopram (OR = 1.401, 95% CI, 1.225–1.602, p < 0.001). In contrast, NHB ADNPS patients were more likely to be treated with memantine (OR = 2.601, 95% CI, 1.746–3.875, p < 0.001) and risperidone (OR = 5.526, 95% CI, 3.411–8.951, p < 0.001). Conclusions: Our findings show the use of memantine and risperidone to treat both NHB and NHW ADNPS patients. NHW ADNPS patients were more likely to be treated with galantamine, memantine, olanzapine, risperidone, and escitalopram. In contrast, NHB patients with ADNPS were more likely to be treated with memantine and risperidone. Full article

Protein glycation and oxidation contribute to the pathogenesis of neurodegenerative diseases. This study evaluated the antiglycative and antioxidative effects of donepezil, rivastigmine, galantamine, memantine, lamotrigine, sodium valproate, and carbamazepine using bovine serum albumin (BSA) as a model protein. Glycation was induced with fructose, ribose, or methylglyoxal (MGO), and oxidation with chloramine T (ChT). Concentrations of glycation products—Amadori products (APs), amyloid cross-β structure (βA), argpyrimidine (ARG), crossline (CRO), vesperlysine (VES), pentosidine (PEN), total AGEs and glycoxidation products—dityrosine (DT), kynurenine (KN), N-formylkynurenine (NFK) as well as oxidation biomarkers, total thiols (TTs), protein carbonyls (PCs), and advanced oxidation protein products (AOPPs), were determined via spectrophotometric and spectrofluorimetric methods. Molecular docking and a systematic literature review (PRISMA) complemented the experimental data. Lamotrigine showed the strongest antiglycative and antioxidative effects, surpassing aminoguanidine in reducing ARG, PEN, DT, and NFK levels. In contrast, donepezil markedly increased APs, βA, ARG, VES, DT, and PEN, suggesting proglycative and pro-oxidative activity. Docking revealed a high affinity of donepezil for RAGE (–7.2 kcal/mol), possibly explaining its impact on carbonyl stress. Overall, anti-dementia drugs showed weak to moderate antiglycative potential, with lamotrigine being the most effective. Full article

Hydrogen sulfide (H₂S) is a gasotransmitter that plays a crucial role in regulating pathological processes following injury to the central and peripheral nervous systems. This review systematizes current data on various classes of H₂S donors and inhibitors of its biosynthesis in neurotrauma and related experimental models. Inorganic donors (e.g., NaHS, Na₂S, and STS) rapidly suppress oxidative stress and inflammation, supporting the recovery of synaptic plasticity and cognitive function. Organic donors (e.g., GYY4137, ACS67, ACS84, SPRC, ADT-OH and its derivatives, S-memantine, and MTC) provide sustained H₂S release, stabilize the blood–brain barrier, and exhibit antiapoptotic activity. Natural donors (e.g., DADS, DATS, and SAMe) demonstrate high biocompatibility, inhibit pyroptosis, and enhance antioxidant defense mechanisms. Hybrid systems—including nanoparticles and hydrogels—enable targeted delivery and prolonged action, thereby stimulating regeneration and angiogenesis. Thiol-activated donors (e.g., COS/H₂S and AlaCOS) allow controlled H₂S release, offering broad opportunities for precise modulation of its concentration within target tissues. Inhibitors (e.g., AOAA, PAG, oxamic hydrazide 1, L-aspartic acid, benserazide, and NSC4056) of H₂S biosynthesis underscore the physiological importance of this gasotransmitter, as their administration enhances neuroinflammation and diminishes neuroprotection. The analysis reveals a general pattern: all classes of H₂S donors effectively modulate key pathological mechanisms, differing in their rate, duration, and specificity of action. These findings highlight the therapeutic promise of H₂S-based pharmacological agents in clinical neurotraumatology, while emphasizing the need for further research to optimize delivery systems, enhance efficacy, and minimize adverse effects. Full article

Background/Objectives: Interpersonal violence is an increasing public health concern, and its prediction and prevention remain global challenges. This study aimed to identify prescribed medications associated with interpersonal violence in Spain. Methods: A descriptive, longitudinal and retrospective study and case-non case study of spontaneous reports of adverse drug reactions corresponding to interpersonal violence recorded in the Spanish Pharmacovigilance Database (FEDRA^®) from 1984 to 31 March 2021. Results: 533 cases were reported in the study period. The mean age was 46.70 years with ages ranging from 1 to 99 years. There were no sex differences except in child and adolescent age group where most reports were from male. Main therapeutic groups involved were nervous system (62.3%), anti-infectives for systemic use (10%) and respiratory system (8.6%). Mostly drugs reported were montelukast, levetiracetam, bupropion, donepezil, perampanel, quetiapine, fluoxetine, and lorazepam. A statistically significant association/disproportion in the notification has been found in the reporting of interpersonal violence and different drugs according to the literature, notably atomoxetine, perampanel, memantine, donepezil, montelukast and methylphenidate. Conclusions: The results highlight that interpersonal violence, while rare, could occur as a clinically relevant adverse reaction to a small subset of medications. They underscore the importance of careful prescribing, especially in vulnerable populations and in individuals with a history of psychiatric disorders. Full article

Background: Alzheimer’s Disease (AD) is the most common form of dementia and is characterized by progressive cognitive decline and neurodegeneration. In Italy, AD represents a major public health and socio-economic challenge. This review aims to summarize current Italian research on pharmacological and non-pharmacological interventions, including preclinical studies, clinical trials, rehabilitative approaches, and emerging neuromodulation techniques, highlighting contributions and future directions. Methods: A narrative review of the literature was conducted, focusing on Italian preclinical and clinical studies, observational and real-world evidence, cognitive and physical interventions, music therapy, non-invasive brain stimulation (rTMS, tDCS, tACS), and digital or home-based rehabilitation programs. Results: Italian research has explored different pharmacological strategies, including multitarget compounds, eptastigmine, rotigotine, and combinatorial therapies (donepezil-memantine, citicoline addition). Non-pharmacological interventions, such as cognitive stimulation, motor rehabilitation, music therapy, and multidimensional programs, demonstrated benefits on cognition, behavior, daily functioning, and caregiver well-being. Non-invasive neuromodulation techniques, targeting the dorsolateral prefrontal cortex and precuneus, showed promising effects on memory, attention, and executive functions, especially when combined with cognitive training. Digital health technologies, including telerehabilitation and home-based brain stimulation programs, further enhanced accessibility and adherence. Challenges remain due to fragmented research, small sample sizes, and limited standardization. Conclusions: Italian research on AD reflects a growing emphasis on integrated, multidimensional, and technologically advanced approaches. Strengthening preclinical studies, promoting multicenter collaborations, and combining pharmacological, cognitive, and neuromodulatory strategies may enhance therapeutic efficacy and patient quality of life. Continued investment in innovation and multidisciplinary research positions Italy to contribute meaningfully to global AD management and prevention. Full article

Small cell lung cancer (SCLC) is an aggressive malignancy with a high incidence of brain metastases. Prophylactic cranial irradiation (PCI) was developed to reduce central nervous system (CNS) relapses and has been shown to improve survival, particularly in limited-stage disease. The pivotal Auperin meta-analysis and subsequent studies confirmed its role in patients achieving a complete response to initial therapy. In extensive-stage SCLC, earlier trials demonstrated reduced brain metastases and modest survival gains, but more recent studies incorporating routine magnetic resonance imaging (MRI) surveillance failed to show overall survival benefits, supporting MRI monitoring with salvage therapy as an alternative. Neurocognitive toxicity remains the major limitation of PCI, especially in older adults. Common effects include memory impairment, cognitive changes, and a reduced quality of life. Advances such as hippocampal avoidance PCI and neuroprotective strategies like memantine have shown the ability to mitigate long-term decline. Modern radiotherapy techniques, including intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT), enable the precise sparing of critical structures while maintaining intracranial control. The integration of immunotherapy has shifted treatment paradigms in SCLC. While checkpoint inhibitors have improved systemic outcomes, their impact on brain relapses and interactions with PCI remain uncertain. This review provides an overview of the evolution of PCI in SCLC, while emphasizing current challenges and future directions. Full article

Alzheimer’s disease (AD) and stroke have been identified as risk factors for each other. More than half of AD patients suffer stroke attacks and worse ischemic injuries. There has been a lack of research focus and clinical treatment for the comorbidity of these neurological disorders. AD and ischemic stroke share characteristic pathophysiology, including hyperactivities of excitatory neurons and NMDA receptors (NMDARs), excitotoxicity, and synapse/neurovascular destruction. Our recent investigations identified the deficiency of the NMDAR regulatory GluN3A (NR3A) subunit as a novel pathogenesis of sporadic AD. The present investigation tested a preemptive treatment to prevent AD development in two AD models and, in the meantime, to prime the susceptible brain against upcoming ischemic attacks. In the preclinical stage of 3-month-old GluN3A KO mice, an NMDAR-mediated sporadic AD model, and 5xFAD mice, an amyloid-based familial AD model, treatments with memantine (MEM), an NMDAR antagonist (10 mg/kg/day in drinking water) and a drug-free control were started when cognition of these mice was generally normal. Three months later, the mice were subjected to focal cerebral ischemic surgery, followed by continued 1.5–2.0 months of MEM or vehicle control. Morphological, pathological, and functional assessments were performed and compared at different time points. In both AD models, the early MEM treatment confined AD progression before and after stroke, reduced ischemia-induced brain injury, suppressed neuroinflammation, and improved locomotion, sensorimotor, psychological, and cognitive functions. This is the first report endorsing a shared mechanism of NMDAR hyperactivity in AD and stroke in AD models with distinctive risk factors. The dual therapeutic effects of the preemptive MEM treatment provide a disease-modifying possibility for individuals who are susceptible to sporadic or familial AD as well as ischemic stroke. Full article