How promising are the latest monoclonal antibodies targeting amyloid-ß for the treatment of early Alzheimer's disease?

INTRODUCTION: Monoclonal antibodies targeting amyloid-ß are the first disease-modifying treatments for Alzheimer disease to have received FDA-approval. There are three different drugs approved or pending FDA-approval: aducanumab, lecanemab, and donanemab. These three drugs are each in different stages of regulatory approval by the FDA. AREAS COVERED: We discuss the development of these drugs, the data regarding their clinical efficacy, their dosing regimens, and side effects. In addition, we examine pragmatic issues with their potential implementation as common treatments to slow the rate of decline in Alzheimer disease, and what unanswered questions remain regarding this new class of drugs. EXPERT OPINION: We conclude that these new monoclonal antibodies that target amyloid-ß represent a genuine advance in the treatment of Alzheimer disease. However, questions remain regarding their clinical significance. Additionally, it is presently unclear which patients would most benefit from these expensive drugs given the risk of side effects and the logistical difficulties concerning administration and the determination of eligibility.

Reduction and prevention of agitation in persons with neurocognitive disorders: an international psychogeriatric association consensus algorithm.

OBJECTIVES: To develop an agitation reduction and prevention algorithm is intended to guide implementation of the definition of agitation developed by the International Psychogeriatric Association (IPA). DESIGN: Review of literature on treatment guidelines and recommended algorithms; algorithm development through reiterative integration of research information and expert opinion. SETTING: IPA Agitation Workgroup. PARTICIPANTS: IPA panel of international experts on agitation. INTERVENTION: Integration of available information into a comprehensive algorithm. MEASUREMENTS: None. RESULTS: The IPA Agitation Work Group recommends the Investigate, Plan, and Act (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and acting with an emphasis on shared decision-making; the success of the plan is evaluated and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Psychosocial interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal/circadian agitation; mild-moderate agitation or agitation with prominent mood features; moderate-severe agitation; and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a variety of venues-home, nursing home, emergency department, hospice-and adjustments to the therapeutic approach are presented. CONCLUSIONS: The IPA definition of agitation is operationalized into an agitation management algorithm that emphasizes the integration of psychosocial and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision-making.

Agitation in cognitive disorders: Progress in the International Psychogeriatric Association consensus clinical and research definition.

BACKGROUND: The International Psychogeriatric Association (IPA) published a provisional consensus definition of agitation in cognitive disorders in 2015. As proposed by the original work group, we summarize the use and validation of criteria in order to remove "provisional" from the definition. METHODS: This report summarizes information from the academic literature, research resources, clinical guidelines, expert surveys, and patient and family advocates on the experience of use of the IPA definition. The information was reviewed by a working group of topic experts to create a finalized definition. RESULTS: We present a final definition which closely resembles the provisional definition with modifications to address special circumstances. We also summarize the development of tools for diagnosis and assessment of agitation and propose strategies for dissemination and integration into precision diagnosis and agitation interventions. CONCLUSION: The IPA definition of agitation captures a common and important entity that is recognized by many stakeholders. Dissemination of the definition will permit broader detection and can advance research and best practices for care of patients with agitation.

Mood Disorders and Anxiety in Parkinson's Disease: Current Concepts.

Mood disorders and anxiety significantly impact the prognosis and disease course of Parkinson's disease. Non-motor symptoms of Parkinson's disease such as apathy, anhedonia, and fatigue overlap with diagnostic criteria for anxiety and depression, thus making accurate diagnosis of mood disorders in Parkinson's disease patients difficult. Furthermore, treatment options for mood disorders can produce motor complications leading to poor adherence and impaired quality of life in Parkinson's disease patients. This review aims to clarify the current state of diagnostic and treatment options pertaining to anxiety and mood disorders in Parkinson's disease. It explores both the pharmacologic and non-pharmacologic treatment modalities for various mood disorders in comorbid Parkinson's disease with a brief discussion of the future outlook of the field given the current state of the literature.

The Role of The Gut Microbiome in Parkinson's Disease.

The gut microbiota is known to play a role in various disease states through inflammatory, immune and endocrinologic response. Parkinson's Disease is of particular interest as gastrointestinal involvement is one of the earlier features seen in this disease. This paper examines the relationship between gut microbiota and Parkinson's Disease, which has a growing body of literature. Inflammation caused by gut dysbiosis is thought to increase a-synuclein aggregation and worsen motor and neurologic symptoms of Parkinson's disease. We discuss potential treatment and supplementation to modify the microbiota. Some of these treatments require further research before recommendations can be made, such as cord blood transplant, antibiotic use, immunomodulation and fecal microbiota transplant. Other interventions, such as increasing dietary fiber, polyphenol and fermented food intake, can be made with few risks and may have some benefit for symptom relief and speed of disease progression.

Psychosis in Parkinson's Disease: Current Treatment Options and Impact on Patients and Caregivers.

Parkinson's disease (PD) is the second most common neurodegenerative disease seen in older adults after Alzheimer's disease, with increasing prevalence worldwide. Parkinson's disease psychosis (PDP) is a common, non-motor feature of PD, which increases caregiver stress and is a risk-factor for nursing home placement. In this paper we review PDP epidemiology, features, diagnosis, and treatment. PDP most often presents with sequential development of minor and then increasingly complex visual hallucinations mediated by dopaminergic-serotonergic interactions activating the mesolimbic pathway, with contributions from other structures and neurotransmitters. Appropriate evaluation of differential diagnoses for psychosis is vital before diagnosing PDP. Initial treatment should involve non-pharmacologic approaches. If these are unsuccessful and PDP symptoms significantly impact the patient's and or their caregivers' quality of life and functions, then pharmacotherapy is indicated. Pimavanserin is a recently FDA-approved pharmacologic treatment for PDP with a better profile of balanced effectiveness and safety compared to previous use of atypical antipsychotics. Early diagnosis and safer, more effective treatments for PDP should help reduce caregiver burden and enable caregivers to continue to provide care at home versus institutionalization.

Doll therapy in dementia: Facts and controversies.

BACKGROUND: The management of major neurocognitive disorder (MNCD), formerly known as dementia, is of increasing concern as the elderly population continues to grow. Doll therapy (DT) is a controversial method observed in clinical practice that has both promising benefits and potential ethical concerns. To date, little research has been done on this therapy. METHODS: A PubMed search was performed using the keywords "dementia," "elderly," "dolls," "doll therapy," and "Alzheimer's disease." A list of pertinent articles was assembled, with irrelevant articles excluded. References from these articles were also reviewed and additional articles were included in the final list. RESULTS: Research on the utility of DT for patients with MNCD is limited. Current literature suggests that DT may be beneficial in decreasing the use of pharmacologic interventions and alleviating symptoms such as agitation and anxiety. However, most studies consisted of small, unrepresentative sample populations. CONCLUSIONS: Preliminary studies favor DT as an effective management strategy for behavioral symptoms of MNCD. However, the few existing randomized controlled trials are limited in size and demographics. Further research involving larger, more diverse study samples with more male patients is needed. Additionally, the exact parameters to guide this therapy have not been established and require investigative study.

Impact of agitation in long-term care residents with dementia in the United States.

OBJECTIVES: To describe characteristics and compare clinical outcomes including falls, fractures, infections, and neuropsychiatric symptoms (NPS) among long-term care residents with dementia with and without agitation. METHODS: A cross-sectional secondary analysis of administrative healthcare data was conducted whereby residents with dementia residing in a long-term care facility for ≥12 months were identified from the AnalytiCare LLC database (10/2010-06/2014) and were classified into mutually exclusive cohorts (Agitation Cohort or No-Agitation Cohort) based on available agitation-related symptoms. Entropy balancing was used to balance demographic and clinical characteristics between the two cohorts. The impact of agitation on clinical outcomes was compared between balanced cohorts using weighted logistic regression models. RESULTS: The study included 6,265 long-term care residents with dementia among whom, 3,313 were included in the Agitation Cohort and 2,952 in the No-Agitation Cohort. Prior to balancing, residents in the Agitation Cohort had greater dementia-related cognitive impairment and clinical manifestations compared to the No-Agitation Cohort. After balancing, residents with and without agitation, respectively, received a median of five and four distinct types of medications (including antipsychotics). Further, compared to residents without agitation, those with agitation were significantly more likely to have a recorded fall (OR = 1.58), fracture (OR = 1.29), infection (OR = 1.18), and other NPS (OR = 2.11). CONCLUSIONS: Agitation in long-term care residents with dementia was associated with numerically higher medication use and an increased likelihood of experiencing falls, fractures, infections, and additional NPS compared to residents without agitation, highlighting the unmet need for effective management of agitation symptoms in this population.

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials.

OBJECTIVE: To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD). DESIGN: Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258). SETTING: Study 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries. PARTICIPANTS: Patients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. INTERVENTION: Study 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5-2 mg/day or placebo (1:1) for 12 weeks. MEASUREMENTS: Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29-203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression - Severity of illness (CGI-S) as related to agitation. Safety was also assessed. RESULTS: In Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, -3.77; confidence limits, -7.38, -0.17; t(316) = -2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; -3.40, 3.86; t(314) = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5-2 mg/day did not achieve statistical superiority over placebo (-2.34; -5.49, 0.82; t(230) = -1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (-5.06; -8.99, -1.13; t(144) = -2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (-0.16; -0.39, 0.06; t(337) = -1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5-2 mg/day in Study 2 (-0.31; -0.55, -0.06; t(222) = -2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5-2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity. CONCLUSIONS: Brexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.

Criteria for Psychosis in Major and Mild Neurocognitive Disorders: International Psychogeriatric Association (IPA) Consensus Clinical and Research Definition.

Psychosis is common among individuals with neurocognitive disorders, is difficult to manage, and causes considerable burden and stress to patients and caregivers. Developing effective treatments is a substantial unmet medical need but research has been slowed by the need for updated consensus diagnostic criteria. To address this need, the International Psychogeriatrics Association initiated a process to develop criteria for clinical use, research, and treatment development efforts. The process included clinical, regulatory, and industry stakeholders as well as input from a global network of experts in geriatric psychiatry responding to two surveys (N = 336). Results from the consensus process confirmed that clinicians wanted elaboration of aspects of the definition proposed by Jeste and Finkel in 2000 to ensure that the criteria are applied appropriately. Based on discussions, the survey, and emerging research, criteria were revised to apply to psychosis occurring with all major and mild neurocognitive disorders. Other important changes include providing examples of hallucinations and delusions and clarifying time course, impact, and exclusionary criteria. This definition of psychosis in major and mild neurocognitive disorders can be used to advance many types of research including development of much needed pharmacologic and nonpharmacologic interventions for psychosis in patients with neurocognitive disorders.

Rational deprescribing in the elderly.

BACKGROUND: Polypharmacy, defined as being prescribed 5 or more medications, has been shown to be associated with a decline in mental and physical functioning in elderly patients. Despite this, elderly patients are currently being prescribed a median of 7 medications, which often causes more harm than benefit, and emphasizes the importance of deprescribing. METHODS: Five classes of potentially inappropriate medications for the elderly population, especially for the aging brain, are discussed, including anticholinergics, benzodiazepines, antipsychotics, opioids, and proton pump inhibitors. Recommendations regarding these medications were collected from the 2015 Beer's Criteria, the Screening Tool of Older Person's Prescriptions (STOPP) criteria, the Screening Tool to Alert doctors to the Right Treatment (START) criteria, and the Fit fOR The Aged (FORTA) list. The PubMed database was also searched for the most recent evidence regarding prescription patterns, adverse effects, and recommendations regarding discontinuation of these medications in older adults. RESULTS: Anticholinergics, benzodiazepines, antipsychotics, and opioids were all found to have significant adverse effects in the elderly population. All of the discussed medication classes have been shown to be successfully deprescribable. CONCLUSIONS: Polypharmacy increases the risk of adverse drug reactions and hospitalizations in geriatric patients. Rational deprescribing of anticholinergics, benzodiazepines, antipsychotics, opioids, and proton pump inhibitors in selected patients may be a good first step to reducing this risk.

The cholinergic system in the pathophysiology and treatment of Alzheimer's disease.

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-ß proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

Memantine ER Maintains Patient Response in Moderate to Severe Alzheimer's Disease: Post Hoc Analyses From a Randomized, Controlled, Clinical Trial of Patients Treated With Cholinesterase Inhibitors.

Memantine extended release (ER) significantly outperformed placebo on co-primary endpoints of Clinician's Interview-based Impression of Change Plus Caregiver Input (CIBIC-Plus) and baseline to endpoint changes on the Severe Impairment Battery (SIB) in a 24-week, randomized trial (NCT00322153) in patients with moderate to severe Alzheimer's disease taking a cholinesterase inhibitor (ChEI). A post hoc analysis compared patients receiving memantine ER/ChEI to placebo/ChEI for time to onset of response and if the response was maintained (achieving improvement at weeks 8, 12, or 18 and maintaining through endpoint/week 24) on the SIB, the Neuropsychiatric Inventory (NPI), CIBIC-Plus, and Activities of Daily Living (ADL) using Fisher exact test. A second post hoc analysis compared percentages of patients for all possible combinations of 2 to 4 assessments with either no decline or clinically notable response using Wald χ. Significantly greater percentages of memantine ER/ChEI patients achieved an early response that was maintained on SIB, NPI, and CIBIC-Plus (P<0.05) versus placebo/ChEI. Significantly greater percentages of memantine ER/ChEI-treated patients achieved and maintained a clinically notable response on ADL/NPI, SIB/ADL/NPI, and SIB/ADL/CIBIC-Plus, compared with placebo/ChEI (P<0.05). Memantine ER results in early, maintained improvement in patients with moderate to severe Alzheimer's disease concurrently taking ChEIs, compared with cholinesterase treatment alone.

Empathy changes in neurocognitive disorders: A review.

BACKGROUND: Empathy can be broadly defined as the ability to understand what others feel (cognitive empathy) and feel what others feel (affective empathy). The capacity to empathize may be impaired in certain major neurocognitive disorders (MNCDs), affecting not only the patient, but also the caregivers. METHODS: PubMed and Google Scholar databases were searched for studies investigating empathy changes, using an objective scale, in patients with MNCDs. RESULTS: The Interpersonal Reactivity Index was most commonly used to evaluate empathy in this population. Impairments in cognitive but not affective empathy were found in patients with Alzheimer's disease (AD), and may be attributable to overall cognitive decline. Patients with frontotemporal dementia (FTD) have demonstrated severe deficits in empathy, correlating with greater caregiver burden. Empathy changes in patients with dementia with Lewy bodies, vascular dementia, and Parkinson's disease dementia have not yet been studied. Intranasal oxytocin has emerged as a promising therapeutic approach for empathy loss, but it has not been explored yet in patients with MNCDs. CONCLUSIONS: Caregivers need to be educated about empathy loss, which is an important part of the disease process in AD and FTD. Future research should further assess empathy changes in other MNCDs, as well as explore novel treatment options in this field.

Emerging chemical therapies targeting 5-hydroxytryptamine in the treatment of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a major neuropsychiatric disorder affecting more than 5 million Americans over age 65. By the year 2050, AD is expected to affect over 30 million. Characterized by neuronal cell death accompanied by the accumulation of neurofibrillary tangles and neuritic plaques, AD results in devastating clinical symptomatology with a lasting psychosocial and financial impact. Studies have shown that the current treatments for AD, cholinesterase inhibitors (ChEI's) and NMDA receptor antagonists, have limited efficacy. The 5-HT-6 receptor antagonists Idalopirdine and Intepirdine have shown the most progress in current clinical trials and warrant consideration as emerging treatments for AD. Areas covered: This review discusses 5-HT6 antagonists currently in clinical trials as potential treatments for AD symptomatology and how 5-HT6 physiology may play a positive role in alleviating AD symptom pathophysiology. A literature search using PubMed was conducted using the terms Idalopirdine, Intepirdine, 5-HT-6 antagonist, and AD as keywords. Clinicaltrials.gov and Alzforum were also used to obtain information on clinical trials. Expert opinion: If current Phase-3 trials are positive, 5-HT6 antagonists such as Idalopirdine and Intepirdine may be considered as supplementary treatments to ChEI's and NMDA receptor antagonists for the symptomatic treatment of AD.

Renal concerns relative to the use of lithium in geriatric bipolar disorder patients.

BACKGROUND: Lithium is a first-line treatment for bipolar disorder in geriatric patients; however, it has long been associated with potentially significant renal consequences, including chronic kidney disease (CKD). METHODS: We reviewed the available evidence to characterize the effects of lithium on renal function, provide a consensus on periodic monitoring, and propose criteria for transitioning an older patient with bipolar disorder and renal issues to an alternate medication. RESULTS: Although the evidence on lithium use, duration, and dosage on progression of CKD and end-stage renal disease in geriatric patients is mixed, there is solid evidence that patients receiving lithium generally have a reduced glomerular filtration rate compared with controls. The current guidelines for monitoring lithium use in geriatric patients are nearly sufficient, but adherence in clinical practice frequently falls short. Alternative medications for bipolar disorder in geriatric patients are generally considered safe and effective, but do not have the strength of evidence that exists in the general adult population. CONCLUSIONS: Currently, there is no compelling evidence that lithium should be avoided in geriatric patients; however, prudent monitoring strategies are recommended, with a strong consideration of transitioning geriatric patients with poor tolerance to an alternative medication.

Ideomotor limb apraxia as a staging tool in individuals with Alzheimer's disease (ILIAD).

BACKGROUND: Ideomotor apraxia (IMA) is known to affect individuals with Alzheimer's disease (AD). Combined with impaired cognitive function, IMA can support evidence of probable AD. However, apraxia is a condition that is difficult to diagnose. The Postural Knowledge Test (PKT), developed by Mozaz et al, was designed to easily identify limb apraxia in multiple sclerosis yet demonstrated potential utility for AD. ILIAD is a pilot study to investigate correlation between the PKT and Mini-Mental State Examination (MMSE). METHODS: Participants with mild, moderate, and severe AD were administered the MMSE by 1 examiner, followed by the PKT by a second blinded examiner. RESULTS: Seventy-seven participants with mild (25), moderate (26), and severe AD (26) met study criteria. Correlation was demonstrated between the MMSE and PKT at 0.835 among all AD groups. Correlation between MMSE and PKT-1 (transitive) and PKT-2 (intransitive) separately was 0.819 and 0.793. CONCLUSIONS: There is significant correlation between the MMSE (memory loss) and PKT (IMA). This suggests the PKT may be used in conjunction with the MMSE to aid in staging AD and to monitor disease severity. Correlation between the MMSE and separate PKT tests suggests that administration of only 1 test may be necessary clinically, saving valuable time.

Development of a brief validated geriatric depression screening tool: the SLU "AM SAD".

OBJECTIVES: Combining five commonly observed symptoms of late-life depression to develop a short depression screening tool with similar sensitivity and specificity as the conventional, more time-consuming tools. METHODS: We developed the St. Louis University AM SAD (Appetite, Mood, Sleep, Activity, and thoughts of Death) questionnaire. The frequency of each symptom in the prior 2 weeks is quantified as 0, 1, or 2. Patients 65 years or older from our clinics were administered the AM SAD, the Geriatric Depression Scale (GDS-15), the Montgomery-Asberg Depression Rating Scale (MADRS), and the St. Louis University Mental Status Exam (SLUMS). RESULTS: 100 patients were selected. AM SAD correlation with GDS was 0.72 and MADRS 0.80. AM SAD yielded a sensitivity and specificity of 79% and 62% against diagnosis of depression; of 88% and 62% with GDS-15; and 92% and 71% with MADRS. CONCLUSIONS: The AM SAD can be reliably used as a short depression screening tool in patients with a SLUMS score of 20 or higher.