Pharmacological management of behavioral disturbances in patients with Alzheimer’s disease

ABSTRACT

Neuropsychiatric symptoms (NPS) inevitably occur during the course of Alzheimer’s disease (AD) including psychosis, aggression, and depression. The effectiveness of pharmacological treatments for NPS has been limited because of their lack of efficacy, discontinuation due to undesirable adverse events, or poor adherence. In recent consensus guidelines, non-pharmacological treatments for NPS have been prioritized as first-line management strategies. Pharmacological treatments for severe NPS should be administrated as a second-line approach, and have been suggested to be started at a lower dosage followed by titration to a minimum effective dosage and for a limited time period. However, recent studies have shown that some patients receiving pharmacological treatments do not exhibit treatment efficacy in comparison with placebo. The concurrence of several sub-symptoms in NPS makes it difficult to target one symptom exclusively. Therefore, the current review focuses on a strategy for such refractory NPS in patients with AD. Recent randomized controlled trials have shown that the severity of NPS gradually reduces in a time-dependent manner regardless of active treatments. Therefore, clinicians should consider potential causes of NPS sub-symptoms from multifactorial aspects and select alternative treatments (e.g. neuromodulation or relocation into specialized care units) during the long-term disease course.     

Pharmacotherapeutic strategies for treating epilepsy in patients with Alzheimer’s disease

Introduction: Alzheimer’s disease (AD)-related epileptic comorbidity is now well documented and appears to have been previously underestimated. Prescribing antiepileptic drugs (AEDs) in AD patients aims at preventing seizure-related morbi-mortality and the occurrence of deleterious status epilepticus. At the earlier stages of the disease, some clinicians even expect a disease-modifying effect.

Areas covered: In this review, the author provides a brief overview of the epileptic comorbidity in AD, discusses the appropriate AEDs from a syndromic point of view, reviews the effectiveness and cognitive tolerability of the currently available drugs, and considers the influence of the comorbidities and the age of AD patients in the choice of an AED.

Expert opinion: Given the paucity of current empirical data, much remains to be done to provide good evidence of the efficacy and tolerability of AEDs in the area of AD-related seizures and epilepsy. To our knowledge, lamotrigine and levetiracetam are currently the two best therapeutic options as low-dose monotherapies.     

Vascular cognitive impairment and Alzheimer’s disease: role of cerebral hypoperfusion and oxidative stress

Cerebrovascular disease may lead to a wide range of cognitive changes, referred to collectively as vascular cognitive impairment. Stroke increases the risk of cognitive impairment and dementia, and may contribute to the progression of Alzheimer's disease (AD). Apart from clinical stroke itself, vascular risk factors are associated with the development of cognitive impairment and dementia. Animal models involving a temporary or permanent interruption of blood flow in the common carotid arteries develop nonprogressive cognitive impairment. Oxidative stress during cerebral hypoperfusion in animal models plays a key role in neuronal death and may thus contribute to the development of cognitive impairment in cerebrovascular disease. Genetic and pharmacological interventions to inhibit the major source of reactive oxygen species, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, are neuroprotective in experimental cerebral ischemia. Recent studies have demonstrated that inhibition of NADPH oxidase activity can mitigate cognitive impairment in rodent models of cerebral hypoperfusion. In this article, we review the evidence linking cognitive impairment and/or AD with NADPH oxidase-dependent oxidative stress, including the renin-angiotensin system.     

Memantine in Japanese patients with moderate to severe Alzheimer’s disease: meta-analysis of multiple-index responder analyses

Background: Responder analyses assessing clinical worsening have attempted to clarify clinically meaningful drug efficacy enhancements in patients with Alzheimer’s disease (AD).

Research design and methods: This was a meta-analysis of two multicenter, randomized, double-blind, parallel-group, 24-week studies of 633 Japanese patients with moderate to severe AD receiving memantine 20 mg/day (n = 318) or placebo (n = 315). The clinical trial registration number is UMIN000026013.

Results: Overall odds ratios (OR) for a reduced likelihood of clinical worsening (memantine versus placebo) were statistically significant on the following individual and combined rating scales: Severe Impairment Battery-Japanese version (SIB-J, OR 0.52; 95% CI: 0.37, 0.73; p = 0.0001); Behavioral Pathology in AD Rating Scale (BEHAVE-AD, OR 0.53; 95% CI: 0.37, 0.75; p = 0.0003); and SIB-J + Clinician’s Interview-Based Impression of Change-plus-Japanese version (SIB-J + CIBIC-plus-J; OR 0.53; 95% CI: 0.37, 0.77; p = 0.0009). A significantly reduced risk of triple worsening was evident in the memantine versus placebo group on the combined SIB-J + CIBIC-plus-J + BEHAVE-AD rating scales (OR 0.38; 95% CI: 0.22, 0.65; p = 0.0003).

Conclusions: Memantine is a viable treatment option for patients with AD presenting not only with cognitive impairment, but also with a broader range of symptoms, including the behavioral and psychological symptoms of dementia.     

Inflammation and Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia. It is characterized by extracellular deposition of a specific protein, beta-amyloid peptide fibrils, and is accompanied by extensive loss of neurons in the brains of affected individuals. Although the pathophysiologic mechanism is not fully established, inflammation appears to be involved. Neuroinflammation has been known to play a critical role in the pathogenesis of chronic neurodegenerative disease in general, and in AD in particular. Numerous studies show the presence of a number of markers of inflammation in the AD brain: elevated inflammatory cytokines and chemokines, and accumulation of activated microglia in the damaged regions. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs suppresses the progression of AD and delays its onset, suggesting that there is a close correlation between neuroinflammation and AD pathogenesis. The aim of this review is (1) to assess the association between neuroinflammation and AD through discussion of a variety of experimental and clinical studies on AD and (2) to review treatment strategies designed to treat or prevent AD.     

Real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer’s disease: the EMBRACE study

Abstract

Objective:

To assess the real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer’s disease (AD) in Canada.     

Drinking water temperature affects cognitive function and progression of Alzheimer’s disease in a mouse model

Lifestyle factors may affect mental health and play a critical role in the development of neurodegenerative diseases including Alzheimer’s disease(AD).However,whether the temperatures of daily beverages have any impact on cognitive function and AD development has never been studied.In this study,we investigated the effects of daily drinking water temperatures on cognitive function and AD development and progression in mice and the underlying mechanisms.Cognitive function of mice was assessed using passive avoidance test,open field test,and Morris water maze.Wild-type Kunming mice receiving intragastric water(IW,10 mL/kg,2 times/day)at 0℃ for consecutive 15 days displayed significant cognitive defects accompanied by significant decrease in gain of body weight,gastric emptying rate,pepsin activity,and an increase in the energy charge in the cortex when compared with mice receiving the same amount of IW at 25℃(a temperature mimicking most common drinking habits in human),suggesting the altered neuroenergetics may cause cognitive decline.Similarly,in the transgenic APPwse/PS1De9 familial AD mice and their age-and gender-matched wild-type C57BL/6 mice,receiving IW at 0℃,but not at 25℃,for 35 days caused a significant time-dependent decrease in body weight and cognitive function,accompanied by a decreased expression of PI3K,Akt,the glutamate/GABA ratio,as well as neuropathy with significant amyloid lesion in the cortex and hippocampus.All of these changes were significantly aggravated in the APPwse/PS1De9 mice than in the control C57BL/6 mice.These data demonstrate that daily beverage at 0℃ may alter brain insulin-mediated neuroenergetics,glutamate/GABA ratio,cause cognitive decline and neuropathy,and promote AD progression.     

Leiden mutation in patients with Crohn’s disease

Background. Inherited resistance to activated protein C is a common risk factor of venous thrombosis. In a majority of patients the defect is caused by single-point mutation in the gene for factor V. This mutated form of factor Va is more stable against proteolytic attack by activated protein C. The prevalence of this inherited defect in the European population is at least 5%. The risk of thrombosis is increased in the case of heterozygosity 5- to 10-fold, in homozygous subjects 50- to 100-fold, but even homozygous individuals will not necessarily suffer from thrombosis. The aim of our study was to determine whether the presence of Leiden mutation might play a role in the pathophysiology and clinical manifestation of Crohn’s disease. Materials and methods. Thirty-four patients with Crohn’s disease (mean age 34 years, range 21–72 years) were studied. None of them had a history of thrombotic episodes. We examined the case history for risk factors: use of oral contraceptive, steroids, cigarette smoking. Levels of fibrinogen, APTT, lupus anticoagulant and levels of IgG and IgM class anticardiolipin (ACL) antibodies were determined. The Leiden mutation was detected by PCR method (Denninger et al., 1995). Results. Fibrinogen was elevated in five cases, lupus anticoagulant in one case, but none of the patients had ACL antibodies in the serum. Molecular analyses showed heterozygosity for the Leiden factor V gene mutation in the case of 30 patients (25%). Conclusion. Thromboembolic events frequently complicate the clinical course of patients with Crohn’s disease; however, we do not have enough knowledge about its role in manifestation of the disease. These results suggested the high frequency of Leiden mutation among our patients and suggest a new genetic background of Crohn’s disease.     

Impact of medication therapy management in patients with Parkinson’s disease

Background Since the new German Apothekenbetriebsordnung was released, medication therapy management (MTM) has increased in importance. MTM is intended to improve the quality of life of patients. Objectives The aim of this study was to improve the quality of life of patients with Parkinson’s disease through an MTM by a community pharmacist. Setting The patients were recruited in cooperation with the Deutsche Parkinson Vereinigung e.V. (dPV) in Germany. Methods All patients were evaluated at baseline (t0) and after a follow-up of 4 months (t1). During the intervention period, the pharmacists implemented an MTM with standardized pharmaceutical care. Main outcome measure The effects of the interventions were measured by the Unified Parkinson Disease Rating Scale (UPDRS) and the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS). Results In this study, 90 patients with Parkinson’s disease were included. The most common intervention was to find a therapy for untreated comorbidities. The UPDRS or MDS-UPDRS improved significantly after the intervention period by a median change rate of 1 (p < 0.05) or rather 2 (p < 0.05) compared to the baseline. Conclusion The study shows that the quality of life in Parkinson’s disease patients improved significantly through MTM.     

Ongoing trials in Alzheimer’s disease

Researchers have sought to understand the underlying pathophysiology of Alzheimer’s disease (AD) ever since Dr A Alzheimer first described the condition in 1907. Unfortunately however, until recently, they have done so with limited success. This lack of clarity has deterred advancements in therapeutic drug research beyond all but the purely symptomatic treatment relief currently available. However, through spatio-temporal analysis of the two types of cerebral lesions that characterise the disorder (senile plaques and neurofibrillary tangles) and the compilation of genetic data concerning familial AD, there now exists the foundation for a more comprehensive understanding of the disease. Although symptomatic cholinergic strategies have beneficial effects, their benefits are modest and current research has turned to the development of other promising strategies, including oestrogen replacement, anti-inflammatory agents, free radical scavengers, anti-oxidants and monoamine oxidase-B (MAO-B) inhibitors. Many of these strategies may have some merit, however further analysis and structured research are necessary before a definitive decision can be made about their efficacy and possible role in AD therapy. Strategies that are directed at halting the underlying biochemical changes in AD are nearing clinical testing and offer the promise for meaningful therapeutic outcomes.     

Advancements in the treatment of agitation in Alzheimer’s disease

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks well-established long-term interventions that are both effective and safe. While non-pharmacological interventions are the suggested first-line treatment, it isn’t effective in managing symptoms for every patient. In such cases, clinicians turn to the use of pharmacological interventions. Traditionally, these interventions consist of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine and antidepressants, where the efficacy doesn’t necessarily outweigh the associated risks.

Areas covered: Gains made in understanding the neurobiological mechanisms underlying agitation have fueled several recent clinical trials. A comprehensive literature search for published articles evaluating pharmacologic interventions for agitation in AD was done. A review of some of these clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, dronabinol and citalopram show promise in treating agitation.

Expert opinion: Neurobiological findings and enhanced trial designs have re-ignited the area of pharmacological treatment of NPS. Although further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to finding effective treatments for NPS such as agitation in patients with dementia is well underway.     

The role of inflammatory processes in Alzheimer’s disease

It has become increasingly clear that inflammatory processes play a significant role in the pathophysiology of Alzheimer's disease (AD). Neuroinflammation is characterized by the activation of astrocytes and microglia and the release of proinflammatory cytokines and chemokines. Vascular inflammation, mediated largely by the products of endothelial activation, is accompanied by the production and the release of a host of inflammatory factors which contribute to vascular, immune, and neuronal dysfunction. The complex interaction of these processes is still only imperfectly understood, yet as the mechanisms continue to be elucidated, targets for intervention are revealed. Although many of the studies to date on therapeutic or preventative strategies for AD have been narrowly focused on single target therapies, there is accumulating evidence to suggest that the most successful treatment strategy will likely incorporate a sequential, multifactorial approach, addressing direct neuronal support, general cardiovascular health, and interruption of deleterious inflammatory pathways.     

COX-2 and Alzheimer’s disease: potential roles in inflammation and neurodegeneration

Epidemiological and clinical data suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are beneficial in the treatment and prevention of Alzheimer’s disease (AD). NSAIDs act by inhibiting cyclooxygenase, an enzyme that occurs in constitutive and inducible isoforms, known respectively as COX-1 and COX-2. Recognition that COX-2 plays a key role in inflammation led to the hypothesis that COX-2 might represent the primary target for NSAIDs in AD, consistent with inflammatory processes occurring in AD brain. This review highlights recently gathered evidence leading to a more complex view of the role of COX-2 in AD, including evidence that COX-2 directly contributes to neuronal vulnerability. Consideration of these roles is critical for the rational implementation of NSAID therapy in AD.     

Discontinuation of ropinirole and pramipexole in patients with Parkinson’s disease: clinical practice versus clinical trials

Objective  To compare characteristics and incidence of discontinuation of Parkinson’s disease (PD) patients starting ropinirole or pramipexole in clinical practice with data from randomised controlled clinical trials (RCTs). Methods  Included in the retrospective clinical-practice cohort were first-time users of ropinirole or pramipexole diagnosed with PD before 2005. Baseline characteristics and incidence of discontinuation were compared between the clinical-practice cohort and RCTs. Treatment discontinuation was defined as more than 180 days between two refills of ropinirole or pramipexole. The incidence of discontinuation in RCTs was based on the reported rate of discontinuation for any cause. Results  Included were 45 patients who started with ropinirole and 59 patients who started with pramipexole. Treatment was discontinued within 3 years in 51% (ropinirole) and 60% (pramipexole) of the patients. Ten RCTs with ropinirole and 12 with pramipexole were identified. Baseline characteristics did not differ between the clinical-practice cohort and RCTs. RCTs reported discontinuation rates comparable with those at the same timepoint in the clinical practice until 1 year of follow-up. Conclusion  This study shows that the overall incidence of discontinuation of ropinirole and pramipexole between the patients in our clinical-practice cohort and patients in the RCTs was comparable for the short term. However for the long term, discontinuation in practice is possibly higher.     

Efficacy of memantine hydrochloride once-daily in Alzheimer’s disease

Introduction: In people with moderate-to-severe dementia in Alzheimer’s disease (AD) memantine provides some clinical benefits. It is commonly administered twice daily at a maximum dose of 20 mg. To improve medication adherence, convenience of use and to enable a higher daily dose, a 28 mg, extended-release formulation of memantine has been developed.

Areas covered: We review the results of a Phase III randomized and controlled trial of memantine extended release as an add-on treatment and compared the findings with a similarly designed previous trial evaluating the immediate release (IR) form.

Expert opinion: Memantine extended release produced minor benefits on cognitive ability, including verbal fluency, behavioral problems and global clinical assessment. There was no difference between the treatment groups on activities of daily living. The observed effects were not larger than those of the IR formulation tested in a similar setting. The lack of impact on activities of daily living suggests that the small improvements in cognition and behavior did not translate into clinically important changes. In conclusion, there is no convincing evidence that the novel once-daily formulation of memantine represents a significant progress in the clinical management of AD that would justify additional treatment costs.     

Future directions in the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) remains the most common of the neurodegenerative disorders. In the elderly, it represents the most frequently occurring form of dementia, especially if considered alongside concomitant cerebrovascular disease. Current treatment involves the use of acetylcholinesterase inhibitors, which have shown symptomatic benefits in the recognised domains of cognition, function and behaviour. While they may have intrinsic disease-modifying activity, this is yet to be proven, and strategies to alter the fundamental neuropathological changes in AD continue to be sought. Much of the evidence suggests that the accumulation of amyloid-β may play a pivotal role, therefore the bulk of current research is focused on possible intervention along the amyloid pathways. However, the abnormal phosphorylation of tau is also a reasonable target and as the molecular basis of AD is better delineated, more targeted treatment approaches are being proposed. This paper reports on the current data that is setting the future directions for research into AD.     

Allen’s test in patients with peripheral artery disease

Introduction

Transradial (TR) approach for coronary and peripheral angiography has become a popular technique. The Allen’s test (AT) could be used to determine the presence of collateral flow in the hand. Recently, angiographic background of modified AT was evaluated, but patients with peripherial arterial disease (PAD) were excluded in these studies. Therefore, the present study was designed to assess reliability of AT in patients with symptomatic PAD.

Methods

The present study comprised 92 symptomatic patients with PAD (Rutherford class 2–6). Perfusion of the hand was assessed with AT before outpatient peripheral angiography.

Results

Significant RA stenosis (n=6, 12.5%) and UA stenosis (n=26, 54.2%) were found in 30 patients with positive AT (62.5%). In patients with negative AT, only UA showed significant stenoses (n=6, 13.6%). Thirty-eight patients with positive AT had anatomic abnormality in the forearm arteries or in the palmar arch (79.2%). Anatomic abnormality in the forearm arteries or in the palmar arch could be detected in 15 cases with negative AT (34.1%, p<0.0001). Conclusions. In the presence of an abnormal AT and concommitant PAD, the use of RA for peripheral or coronary catheterization and angioplasty is not recommended.     

Loss of serotonin 5-HT<Subscript>2A</Subscript> receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease

Rationale Previous studies have demonstrated reductions of serotonin 5-HT_2A receptors in the neocortex of Alzheimers disease (AD) patients. However, it is unclear whether such losses play a role in the cognitive decline of AD.Objectives To correlate neocortical 5-HT_2A receptor alterations with cognitive decline in AD.Methods Postmortem frontal and temporal cortical 5-HT_2A receptors were measured by [³H]ketanserin binding in aged controls as well as in a cohort of AD patients who had been longitudinally assessed for cognitive decline and behavioral symptoms.Results 5-HT_2A receptor densities in both regions were reduced in severely demented AD patients compared to age-matched controls. In the temporal cortex, this reduction also correlated with the rate of decline of Mini-Mental State Examination (MMSE) scores. The association between 5-HT_2A receptor loss and cognitive decline was independent of the effects of choline acetyltransferase (ChAT) activity and presence of behavioral symptoms.Conclusions Our data suggest that loss of neocortical 5-HT_2A receptors may predict for faster cognitive decline in AD, and point to serotomimetics as potentially useful adjuvants to cholinergic replacement therapies.     

The role of mitochondrial defects and oxidative stress in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a complex, progressive, and irreversible neurodegenerative disorder. Recent reports suggest that it affects more than 36 million people worldwide and accounts 60–80% of all cases of dementia. It is characterised by aberrations of multiple interactive systems and pathways, which ultimately lead to memory loss and cognitive dysfunction. The exact mechanisms and initial triggering factors that underpin the known pathological defects in AD remain to be fully elucidated. In addition, an effective treatment strategy to reduce the progression of AD is yet to be achieved. In the light of above-mentioned facts, our article deals with the exploration of the mitochondrial defect and oxidative stress leading to this devastating disease. In this communication, we have highlighted specific mitochondrial and antioxidant-directed approach to ameliorate and manage AD. Nonetheless, new approaches should also be investigated that could tackle various molecular events involved in AD pathogenicity.