Cognitive Symptoms Of Alzheimer's Disease Research Articles

Microwave-assisted synthesis of indoloquinoxaline derivatives as promising anti-alzheimer agents: DFT and molecular docking study

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. One of the major pathological features of AD is the degeneration of cholinergic neurons and associated loss of acetylcholine (ACh), a key neurotransmitter involved in memory and cognition. Reduced ACh levels correlate with the severity of cognitive symptoms in AD. Thus, inhibition of acetylcholinesterase (AChE), the enzyme responsible for breaking down ACh, is a leading treatment strategy. This study aimed to synthesize and evaluate novel AChE inhibitors based on an indolo[2,3-b]quinoxaline scaffold. A series of indolo[2,3-b]quinoxaline derivatives were designed by molecular hybridization of indole and quinoxaline privileged structures. Microwave-assisted synthesis improved the efficiency of obtaining the desired compounds. In vitro screening identified several potent AChE inhibitors, with IC50 values down to 0.02 µM. The most active compounds contained electron-withdrawing groups like nitro and benzoyl moieties. DFT calculations provided insights into geometrical, thermal, and electronic properties of the compounds. FMO analysis revealed variations in HOMO and LUMO energies that impact reactivity. Molecular docking elucidated binding modes, highlighting the pi-pi, pi-H, and H-bonding interactions with key amino acids in the catalytic gorge of AChE. Overall, the indole-quinoxaline hybrids represent promising candidates for development of novel dual binding site AChE inhibitors and multifunctional anti-Alzheimer agents.

Artemether Attenuates Aβ25-35-Induced Cognitive Impairments by Downregulating Aβ, BACE1, mTOR and Tau Proteins.

Alzheimer's disease (AD) is clinically characterized as a progressive cognitive impairment and behavioral disorder. Pathological hallmarks of AD include extracellular senile plaques (SPs), intracellular neurofibrillary tangles (NFTs) and massive neuronal loss. Although the exact cause of AD is not well understood, a mounting body of evidence has demonstrated that the pathogenesis of AD is associated with oxidative stress, neu-roinflammation, and amyloid beta (Aβ) induced neural apoptosis. Moreover, overexpression of β-secretase 1 (BACE1), Aβ, mammalian target of rapamycin (mTOR), and Tau proteins are closely related to cognitive symptoms in AD. Studies have demonstrated that artemether, an antimalarial drug with acceptable side effects, possesses protective effects against neuroinflammation and oxidative stress. Importantly, artemether can easily penetrate the blood brain barrier, thereby representing an ideal drug candidate for AD treatment. The effect of artemether on memory protection and the associated molecular mechanisms were investigated in an Aβ25-35 induced cognitive impairments rat model. Results of the in vivo study showed that oral administration of artemether significantly attenuated Aβ25-35-induced cognitive impairment in rats. Results of the in vitro study revealed that artemether significantly downregulated the endogenous expression of Aβ, BACE1, mTOR, and Tau proteins in N2a cells. The beneficial effect of artemether against Aβ 25-35-induced cognitive impairments was attributable to the downregulation of the expression of Aβ, BACE1, mTOR, and Tau proteins, suggesting the potential of artemether as an effective, neuronal protective, and multi-targeted drug candidate for AD treatment.

Monoaminergic System Modulation in Depression and Alzheimer's Disease: A New Standpoint?

The prevalence of depression has dramatically increased, and it has been estimated that over 300 million people suffer from depression all over the world. Depression is highly comorbid with many central and peripheral disorders. In this regard, depressive states have been associated with the development of neurological disorders such as Alzheimer’s disease (AD). Accordingly, depression is a risk factor for AD and depressive symptomatology is common in pre-clinical AD, representing an early manifestation of this disease. Neuropsychiatric symptoms may represent prodromal symptoms of dementia deriving from neurobiological changes in specific cerebral regions; thus, the search for common biological substrates is becoming an imperative and intriguing field of research. Soluble forms of beta amyloid peptide (Aβ) have been implicated both in the development of early memory deficits and neuropsychiatric symptoms. Indeed, soluble Aβ species have been shown to induce a depressive-like phenotype in AD animal models. Alterations in monoamine content are a common feature of these neuropathologies. Interestingly, serotonergic system modulation has been implicated in alteration of Aβ production. In addition, noradrenaline is considered crucially involved in compensatory mechanisms, leading to increased Aβ degradation via several mechanisms, including microglia modulation. In further agreement, antidepressant drugs have also been shown to potentially modulate cognitive symptoms in AD and depression. Thus, the present review summarizes the main knowledge about biological and pathological substrates, such as monoamine and related molecules, commonly involved in AD and depression pathology, thus shading light on new therapeutic approaches.

Transcranial direct current stimulation does not improve memory deficits or alter pathological hallmarks in a rodent model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive and debilitating degenerative disorder for which there are currently no effective therapeutic options. Non-invasive neuromodulation, including transcranial direct current stimulation (tDCS), has been investigated for the treatment of cognitive symptoms in AD. Results from clinical and preclinical studies, however, have been somewhat controversial. We investigate whether tDCS delivered to triple transgenic (3xTg) AD mice improves memory deficits and mitigates the development of AD-type neuropathology.3xTg AD mice and controls were implanted with paddle electrodes over the skull. The cathode was anterior to bregma and the anode anterior to lamda. tDCS was delivered for 20 min/day, 5 days/week over three weeks at 50 μA. Though this amplitude was lower than the one used in the preclinical literature, it generated a high current density compared to the clinical scenario. Memory testing was conducted during treatment weeks 2 and 3. Post-mortem pathological AD markers were studied. Our results show that performance of 3xTg mice in the novel object recognition and Morris water maze tests was significantly impaired compared to that of controls. In addition, AD transgenics had an increased expression of tau, phosphorylated-tau and amyloid precursor protein in the hippocampus. tDCS did not improve behavioural deficits or mitigated the development of AD neuropathology in 3xTg animals. In summary, we found that tDCS at the settings selected in our study was largely ineffective in improving memory performance or altering the expression of AD pathological hallmarks in a validated mouse model.

Differential effects of cognitive reserve and brain reserve on cognition in Alzheimer disease.

To examine cross-sectional effects of cognitive reserve (CR) and brain reserve (BR) on cognition across the spectrum of Alzheimer disease (AD). We included 663 AD biomarker-positive participants with dementia (probable AD, n = 462) or in the predementia stages (preclinical/prodromal AD, n = 201). Education was used as a proxy of CR and intracranial volume as a proxy of BR. Cognition was assessed across 5 domains (memory, attention, language, visuospatial, and executive functions). We performed multiple linear regression models to examine effects of CR and BR on cognitive domain Z scores, adjusted for cerebral atrophy. Furthermore, we assessed differences in effects according to disease stage and across degrees of total reserve using a 4-level variable (high CR/high BR, high CR/low BR, low CR/high BR, and low CR/low BR). We found positive, independent effects of both CR and BR across multiple cognitive domains. Stratification for disease stage showed that effects of CR on attention and executive functioning were greater in predementia than in dementia (β = 0.39 vs β = 0.21 [Welch t = 2.40, p < 0.01] and β = 0.46 vs β = 0.26 [t = 2.83, p < 0.01]). Furthermore, we found a linear trend for better cognitive performance in all domains in the high CR/high BR group, followed by high CR/low BR, low CR/high BR, and then low CR/low BR (p for trend <0.05). CR and BR both independently mitigate cognitive symptoms in AD. The positive effect of CR is most strongly expressed in the predementia stages and the additive effects of high CR and BR are most beneficial.

Nicotinic Acetylcholine Receptors in the Pathophysiology of Al zheimer's Disease: The Role of Protein-Protein Interactions in Current and Future Treatment.

Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets to treat cognitive dysfunction in Alzheimer's disease (AD) due to their positioning within regions of the brain critical in learning and memory, such as the prefrontal cortex and hippocampus, and their demonstrated role in processes underlying cognition such as synaptic facilitation, and theta and gamma wave activity. Historically, activity at these receptors is facilitated in AD by use of drugs that increase the levels of their endogenous agonist acetylcholine, and more recently nAChR selective ligands have undergone clinical trials. Here we discuss recent findings suggesting that the expression and function of nAChRs in AD may be regulated by direct interactions with specific proteins, including Lynx proteins, NMDA-receptors and the Wnt/β-catenin pathway, as well as β-amyloid. The ability of protein interactions to modify nAChR function adds a new level of complexity to cholinergic signaling in the brain that may be specifically altered in AD. It is currently not known to what degree current nAChR ligands affect these interactions, and it is possible that the difference in the clinical effect of nAChR ligands in AD is related to differences in their ability to modulate nAChR protein interactions, rather than their effects on ion flow through the receptors. Drugs designed to target these interactions may thus provide a new avenue for drug development to ameliorate cognitive symptoms in AD. Notably, the development of experimental drugs that specifically modulate these interactions may provide the opportunity to selectively affect those aspects of nAChR function that are affected in AD.

Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals.

Alzheimer's disease (AD), a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh). The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE), an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD.

Medication for Alzheimer’s Disease and Associated Fall Hazard: A Retrospective Cohort Study from the Alzheimer’s Disease Neuroimaging Initiative

Falls are common in the elderly, especially in those with cognitive impairment. The elderly are often treated with several medications, which may have both beneficial and deleterious effects. The use and type of medication in Alzheimer's disease (AD) patients and association with falls is limited. We examined the association between falls and medication use in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Diagnosis, demographics, medication use, apolipoprotein E4 allele status and functional activity level at baseline were gathered for 810 participants enrolled in the ADNI, including healthy controls and subjects with mild cognitive impairment or Alzheimer's. Reports detailing adverse event falls were tabulated. Baseline characteristics were compared between subjects with and without one or more falls. Cox proportional hazards models were conducted to evaluate the association between subject characteristics and hazard of the first fall. Age (p < 0.0001), Functional Activities Questionnaire (p = 0.035), Beers List (p = 0.0477) and medications for treating cognitive symptoms of Alzheimer's (p = 0.0019) were associated with hazard of fall in the univariate model. In the final multivariate model, after adjusting for covariates, Alzheimer's medication use (p = 0.0005) was associated with hazard of fall. Medication was changed by the clinician after an adverse fall event in 9% of the falls. About 7% of the falls were reported as serious adverse events and 6% were reported to be severe. We found a significant association between the use of symptomatic medication treating cognitive symptoms in AD and hazard of fall after adjusting for age and Beers List medication use. Additional pharmacovigilance of the association between falls and Alzheimer's medication use is warranted.

Is Drug Treatment for Dementia Followed Up in Primary Care? A Swedish Study of Dementia Clinics and Referring Primary Care Centres

PurposeIt is largely unknown how the medical treatment of patients diagnosed with dementia is followed up in primary care. Therefore, we studied patient medical records from two dementia clinics and from the referring primary care centres.MethodsA retrospective study of 241 patients was conducted from April to October 2011 in north west Stockholm, Sweden. Over half (51.5%) of the patients had Alzheimer’s disease (AD), the remainder had mixed AD/vascular dementia (VaD). Eighty-four medical reports from primary care (35% of the study group) were analysed at follow-up 18 months after diagnosis.ResultsAll four dementia drugs available on the Swedish market (three cholinesterase inhibitors [donepezil, rivastigmine and galantamine] and memantine) were prescribed at the two dementia clinics. The most commonly used dementia drug was galantamine. There were differences between the two dementia clinics in preference and combination of drugs and of treatment given to male and female patients. At follow-up, 84% were still on dementia medication. Drug use was followed up by the general practitioners (GPs) in two-thirds of the cases. Eighteen per cent of the GPs’ medical records made no reference to the patient’s dementia or treatment even though dementia drugs were included in the list of medications prescribed.ConclusionsThe results indicate that the Swedish guidelines for treatment of cognitive symptoms in AD are being followed in primary care. However, documentation of follow-up of drug treatment was sometimes insufficient, which calls for development of guidelines for complete medical records and medication lists.

The Structured Interview &amp; Scoring Tool–Massachusetts Alzheimer's Disease Research Center (SIST-M)

The Clinical Dementia Rating (CDR) and CDR Sum-of-Boxes can be used to grade mild but clinically important cognitive symptoms of Alzheimer disease. However, sensitive clinical interview formats are lengthy. To develop a brief instrument for obtaining CDR scores and to assess its reliability and cross-sectional validity. Using legacy data from expanded interviews conducted among 347 community-dwelling older adults in a longitudinal study, we identified 60 questions (from a possible 131) about cognitive functioning in daily life using clinical judgment, inter-item correlations, and principal components analysis. Items were selected in 1 cohort (n=147), and a computer algorithm for generating CDR scores was developed in this same cohort and re-run in a replication cohort (n=200) to evaluate how well the 60 items retained information from the original 131 items. Short interviews based on the 60 items were then administered to 50 consecutively recruited older individuals, with no symptoms or mild cognitive symptoms, at an Alzheimer's Disease Research Center. Clinical Dementia Rating scores based on short interviews were compared with those from independent long interviews. In the replication cohort, agreement between short and long CDR interviews ranged from κ=0.65 to 0.79, with κ=0.76 for Memory, κ=0.77 for global CDR, and intraclass correlation coefficient for CDR Sum-of-Boxes=0.89. In the cross-sectional validation, short interview scores were slightly lower than those from long interviews, but good agreement was observed for global CDR and Memory (κ≥0.70) as well as for CDR Sum-of-Boxes (intraclass correlation coefficient=0.73). The Structured Interview & Scoring Tool-Massachusetts Alzheimer's Disease Research Center is a brief, reliable, and sensitive instrument for obtaining CDR scores in persons with symptoms along the spectrum of mild cognitive change.

Donepezil Improves Obstructive Sleep Apnea in Alzheimer Disease: A Double-Blind, Placebo-Controlled Study

There is an association between Alzheimer disease and sleep-disordered breathing. Donepezil is the drug most frequently used to treat cognitive symptoms in Alzheimer disease. This study evaluates the effects of donepezil on obstructive sleep apnea in patients with Alzheimer disease. Randomized, double-blind, placebo-controlled design. Twenty-three patients with mild-to-moderate Alzheimer disease and apnea-hypopnea index (AHI) > 5/h were allocated to two groups: donepezil treated (n = 11) and placebo treated (n = 12). Polysomnography and cognitive evaluation using Alzheimer disease assessment scale-cognitive (ADAS-cog) subscale were performed at baseline and after 3 months. Cognitive and sleep data were analyzed using analysis of variance. AHI and oxygen saturation improved significantly after donepezil treatment compared to baseline and placebo (p < 0.05). Rapid eye movement (REM) sleep duration increased after donepezil treatment (p < 0.05). ADAS-cog scores improved after donepezil treatment, although they did not correlate with REM sleep increase and sleep apnea improvement (p < 0.01). Donepezil treatment improved AHI and oxygen saturation in patients with Alzheimer disease. Treatment also increased REM sleep duration and reduced ADAS-cog scores. ClinicalTrials.gov Identifier: NCT00480870.

Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis.

Cholinesterase inhibitors are the primary treatment for the cognitive symptoms of Alzheimer disease (AD). Cholinergic dysfunction is also associated with neuropsychiatric and functional deficits, but results from randomized controlled trials of cholinesterase inhibitors are conflicting. To conduct a systematic review and meta-analysis to quantify the efficacy of cholinesterase inhibitors for neuropsychiatric and functional outcomes in patients with mild to moderate AD. We performed a literature search of trials using MEDLINE (January 1966-December 2001), Dissertations Abstracts On-line, PSYCHINFO, BIOSIS, PubMed, and the Cochrane Controlled Trials Register. We retrieved English- and non-English-language articles for review and collected references from bibliographies of reviews, original research articles, and other articles of interest. We searched for both published and unpublished trials, contacting researchers and pharmaceutical companies. We included 29 parallel-group or crossover randomized, double-blind, placebo-controlled trials of outpatients who were diagnosed as having mild to moderate probable AD and were treated for at least 1 month with a cholinesterase inhibitor. Sixteen trials included neuropsychiatric and 18 included functional measures. Two investigators (N.H.T. and J.H.) independently extracted study methods, sources of bias, and outcomes. Neuropsychiatric outcomes were measured with the Neuropsychiatric Inventory (NPI, 0-120 points) and the Alzheimer Disease Assessment Scale, noncognitive (ADAS-noncog, 0-50 points) and were analyzed with the weighted mean difference method. Functional outcomes were measured with several activities of daily living (ADL) and instrumental activities of daily living (IADL) scales and analyzed with the standardized mean difference method. For neuropsychiatric outcomes, 10 trials included the ADAS-noncog and 6 included the NPI. Compared with placebo, patients randomized to cholinesterase inhibitors improved 1.72 points on the NPI (95% confidence interval [CI], 0.87-2.57 points), and 0.03 points on the ADAS-noncog (95% CI, 0.00-0.05 points). For functional outcomes, 14 trials used ADL and 13 trials used IADL scales. Compared with placebo, patients randomized to cholinesterase inhibitors improved 0.1 SDs on ADL scales (95% CI, 0.00-0.19 SDs), and 0.09 SDs on IADL scales (95% CI, 0.01 to 0.17 SDs). There was no difference in efficacy among various cholinesterase inhibitors. These results indicate that cholinesterase inhibitors have a modest beneficial impact on neuropsychiatric and functional outcomes for patients with AD. Future research should focus on how such improvements translate into long-term outcomes such as patient quality of life, institutionalization, and caregiver burden.

Selegiline in treatment of behavioral and cognitive symptoms of Alzheimer disease.

To evaluate the effects of selegiline on behavioral and cognitive symptoms of patients with Alzheimer disease. An English-language MEDLINE search (1982-1995) was used to identify the review articles and human clinical trials discussed in this article. Double- and single-blind and open-label trials were reviewed. Studies were also reviewed if selegiline was evaluated comparatively with other agents. Review articles were used for background information. Data were evaluated from human studies. Studies were critiqued on the basis of design, methodology, duration, sample size, and the degree to which neuropsychological tests used in each study were compared. Selegiline is a selective, irreversible inhibitor of monoamine oxidase type B. Eight of 11 controlled trials showed selegiline had a positive effect on cognition (e.g., word fluency, delayed recall, total recall). Two of 5 controlled trials evaluating selegiline's effect on behavior (e.g., anxiety, tension, excitement, depression) showed a positive effect. The role of selegiline remains to be determined by large well-controlled long-term clinical trials. Selegiline may be a useful agent in managing behavioral and cognitive symptomatology associated with Alzheimer disease. Given that the management of Alzheimer disease is symptomatic and no standard treatment exists, selegiline should be considered among the various options.

Biologic markers and neurochemical correlates of agitation and psychosis in dementia.

Behavioral and psychiatric symptoms frequently accompany the cognitive deterioration of dementia occurring in up to 80% of both community-based and nursing home patients. In Alzheimer's disease (AD), behavioral complications may develop at any stage of the disease process and tend to follow a more unpredictable course than the core cognitive symptoms. Over the past 15 years, our knowledge of the biologic and neurochemical basis of dementia, and of AD in particular, has increased significantly. Great emphasis has been placed on the cholinergic system abnormalities in the context of the cognitive impairment in AD and on the psychopharmalogic enhancement of cholinergic transmission in AD. However deficits in other neurotransmitter systems, such as the noradrenergic, serotonergic, and dopaminergic systems, also occur and may contribute to the core cognitive symptoms of AD. More recently, there has been increased interest in the biologic and neurochemical basis of behavioral and psychiatric disturbances in dementia. This article reviews the evidence for biologic and neurochemical correlates of psychosis and agitation in dementia, and discusses the treatment implications for these findings.

Treatment of Alzheimer Disease

Alzheimer disease (AD) and related dementias are major social problems threatening the lives of individuals and families and the viability of health care systems around the world. Advances in biological research are beginning to pay off with both short-term and long-term strategies for the development of more effective medications. Short-term strategies are aimed at treating the primary cognitive symptoms in AD as well as the secondary behavioral disturbances that occur frequently. Short-term strategies include drugs that act on cholinergic systems, including muscarinic agonists and cholinesterase inhibitors, to improve memory and perhaps attention. Drugs that act through bioaminergic systems may be useful in treating the behavioral symptoms. Long-term strategies for drug development are focusing on medications that may slow the progression of the disease. Growth factors and drugs that may act through other mechanisms to prevent alterations in cell metabolism offer the hope of actually preventing neural degeneration.