Antipsychotics in Alzheimer's disease: A critical analysis

Abstract The estimated worldwide prevalence of dementia among adults older than 60 years of age was 3.9% in 2005. About 90% of demented patients will develop neuropsychiatric symptoms (NS) such as delirium, delusion, aggressiveness and agitation. The treatment of NS involves non-pharmacologic strategies (with varying degrees of success according to the scientific literature) and pharmacologic treatment (PT). The present review of literature examined the current role of AP in the management of NS in dementia. Methods: A thematic review of medical literature was carried out. Results: 313 articles were found, 39 of which were selected for critical analysis. Until 2005, the best evidence for PT had supported the use of selective serotonin re-uptake inhibitors (SSRIs), anticholinesterases, memantine and antipsychotics (AP). In 2005, the U.S. Food and Drug Administration (FDA) disapproved the use of atypical APs to treat neuropsychiatric symptoms in individuals with dementia (the same occurred with the typical APs in 2008). After this, at least two important randomized placebo-controlled multicenter trials were published examining the effectiveness of atypical APs in Alzheimer's disease (CATIE-AD) and the effects of interrupting AP treatment (DART-AD). Conclusions: Based on the current evidence available, APs still have a place in treatment of the more serious psychotic symptoms, after the failure of non-pharmacological treatment and of an initial approach with selective inhibitors of serotonin uptake, anticholinesterases and memantine.

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The individual course of neuropsychiatric symptoms in people with Alzheimer's and Lewy body dementia: 12-year longitudinal cohort study

The British Journal of Psychiatry ◽

10.1192/bjp.2019.195 ◽

2019 ◽

Vol 216 (1) ◽

pp. 43-48 ◽

Cited By ~ 9

Author(s):

Audun Osland Vik-Mo ◽

Lasse Melvaer Giil ◽

Miguel Germán Borda ◽

Clive Ballard ◽

Dag Aarsland

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuropsychiatric Symptoms ◽

Personalised Medicine ◽

Lewy Bodies ◽

Lewy Body Dementia ◽

Psychotic Symptoms ◽

Primary Inclusion ◽

The Individual

IntroductionUnderstanding the natural course of neuropsychiatric symptoms (NPS) in dementia is important for planning patient care and trial design, but few studies have described the long-term course of NPS in individuals.MethodPrimary inclusion of 223 patients with suspected mild dementia from general practice were followed by annual assessment, including the Neuropsychiatric Inventory (NPI), for up to 12 years. Total and item NPI scores were classified as stable, relapsing, single episodic or not present based on 4.96 (s.d. 2.3) observations (98% completeness of longitudinal data) for 113 patients with Alzheimer's disease and 84 patients with LBD (68 dementia with Lewy bodies and 16 Parkinson's disease dementia).ResultsWe found that 80% had stable NPI total ≥1, 50% had stable modest NPI total ≥12 and 25% had stable NPI total ≥24 scores. Very severe NPS (≥48) were mostly single episodes, but 8% of patients with Alzheimer's disease had stable severe NPS. Patients with Alzheimer's disease and the highest 20% NPI total scores had a more stable or relapsing course of four key symptoms: aberrant motor behaviour, aggression/agitation, delusions and irritability (odds ratio 55, P < 0.001). This was not seen in LBD. Finally, 57% of patients with Alzheimer's disease and 84% of patients with LBD had reoccurring psychotic symptoms.ConclusionsWe observed a highly individual course of NPS, with most presenting as a single episode or relapsing; a stable course was less common, especially in LBD. These findings demonstrate the importance of an individualised approach (i.e. personalised medicine) in dementia care.

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The Role of the Innate Immune System in Alzheimer’s Disease and Frontotemporal Lobar Degeneration: An Eye on Microglia

Clinical and Developmental Immunology ◽

10.1155/2013/939786 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 20

Author(s):

Elisa Ridolfi ◽

Cinzia Barone ◽

Elio Scarpini ◽

Daniela Galimberti

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontotemporal Lobar Degeneration ◽

Environmental Changes ◽

Current Evidence ◽

Neuronal Function ◽

Immune Effector ◽

Effector Cells ◽

The Central Nervous System

In the last few years, genetic and biomolecular mechanisms at the basis of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) have been unraveled. A key role is played by microglia, which represent the immune effector cells in the central nervous system (CNS). They are extremely sensitive to the environmental changes in the brain and are activated in response to several pathologic events within the CNS, including altered neuronal function, infection, injury, and inflammation. While short-term microglial activity has generally a neuroprotective role, chronic activation has been implicated in the pathogenesis of neurodegenerative disorders, including AD and FTLD. In this framework, the purpose of this review is to give an overview of clinical features, genetics, and novel discoveries on biomolecular pathogenic mechanisms at the basis of these two neurodegenerative diseases and to outline current evidence regarding the role played by activated microglia in their pathogenesis.

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Frequency and subgroups of neuropsychiatric symptoms in mild cognitive impairment and different stages of dementia in Alzheimer's disease

International Psychogeriatrics ◽

10.1017/s1041610217001879 ◽

2017 ◽

Vol 30 (1) ◽

pp. 103-113 ◽

Cited By ~ 20

Author(s):

N. Siafarikas ◽

G. Selbaek ◽

T. Fladby ◽

J. Šaltytė Benth ◽

E. Auning ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Factor Analysis ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Neuropsychiatric Symptoms ◽

Small Sample ◽

Psychotic Symptoms ◽

Cross Sectional

ABSTRACTBackground:Neuropsychiatric symptoms (NPS), such as depression, apathy, agitation, and psychotic symptoms are common in mild cognitive impairment (MCI) and dementia in Alzheimer's disease (AD). Subgroups of NPS have been reported. Yet the relationship of NPS and their subgroups to different stages of cognitive impairment is unclear. Most previous studies are based on small sample sizes and show conflicting results. We sought to examine the frequency of NPS and their subgroups in MCI and different stages of dementia in AD.Methods:This was a cross-sectional study using data from a Norwegian national registry of memory clinics. From a total sample of 4,571 patients, we included those with MCI or AD (MCI 817, mild AD 883, moderate–severe AD 441). To compare variables across groups ANOVA or χ2-test was applied. We used factor analysis of Neuropsychiatric Inventory Questionnaire (NPI-Q) items to identify subgroups of NPS.Results:The frequency of any NPS was 87.2% (AD 91.2%, MCI 79.5%; p < 0.001) and increased with increasing severity of cognitive decline. The most frequent NPS in MCI was depression. Apathy was the most frequent NPS in AD across different stages of severity. The factor analysis identified three subgroups in MCI and mild AD, and a fourth one in moderate–severe AD. We labelled the subgroups “depression,” “agitation,” “psychosis,” and “elation.”Conclusions:The frequency of NPS is high in MCI and AD and increases with the severity of cognitive decline. The subgroups of NPS were relatively consistent from MCI to moderate-severe AD. The subgroup elation appeared only in moderate-severe AD.

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Neuropsychiatric symptoms and executive function impairments in Alzheimer’s disease and vascular dementia: The role of subcortical circuits

Dementia & Neuropsychologia ◽

10.1590/1980-57642018dn13-030005 ◽

2019 ◽

Vol 13 (3) ◽

pp. 293-298 ◽

Cited By ~ 2

Author(s):

Chan Tiel ◽

Felipe Kenji Sudo ◽

Ana Beatriz Calmon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Executive Function ◽

Vascular Dementia ◽

Neuropsychiatric Symptoms ◽

Vascular Lesions ◽

Cognitive Test ◽

Pathophysiological Mechanism ◽

Clinical Dementia Rating

ABSTRACT Neuropsychiatric symptoms (NPS) in dementia are prevalent, under-recognized and little studied regarding their pathophysiological aspects. The pathophysiological mechanism, as well as the possible role of vascular lesions in the genesis of these symptoms, are still matters of debate. Objective: to describe and compare the prevalence and severity of NPS in subjects with Alzheimer's disease (AD) and vascular dementia (VaD). Methods: a cross-sectional study involving 82 outpatients, divided into two groups (AD × VaD), was conducted. Patients were submitted to the Cambridge Cognitive Test (CAMCOG), the Clock Drawing Test (CLOX 1 and 2), the Neuropsychiatric Inventory (NPI) and the Clinical Dementia Rating (CDR) scale. Neuroimaging was scored using the de Leon and Fazekas scales. Results: 90.8% of the patients had at least one neuropsychiatric symptom. There were statistical differences on the CLOX test and in the apathy symptoms between AD and VaD groups. Apathy and disinhibition proved more prevalent in patients with higher vascular load. Conclusion: apathy and impaired executive function may reflect vascular damage in subcortical circuits in dementia patients.

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Determinants of quality of life in Alzheimer's disease: perspective of patients, informal caregivers, and professional caregivers

International Psychogeriatrics ◽

10.1017/s1041610212001081 ◽

2012 ◽

Vol 24 (11) ◽

pp. 1805-1815 ◽

Cited By ~ 43

Author(s):

Maria Gómez-Gallego ◽

Jesus Gómez-Amor ◽

Juan Gómez-García

Keyword(s):

Quality Of Life ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Medical Condition ◽

Neuropsychiatric Symptoms ◽

Chronic Medical Condition ◽

Psychotic Symptoms ◽

Sources Of Information ◽

Healthcare Staff

AbstractBackground: Alzheimer's disease (AD) is a chronic medical condition with symptoms that compromise patients’ quality of life (QoL). The identification of the factor predicting QoL in AD is essential to develop more effective interventions. Recent research suggests that these factors could be different for the distinct informants. This study explores the QoL predictors considering three different sources of information: patients, caregivers, and healthcare staff.Methods: In this cross-sectional study, a sample of 102 patients, their primary caregivers, and 15 members of the healthcare staff evaluated patients’ QoL (QoL-AD Scale). Patients’ and caregivers’ demographic and clinical data (cognitive function, neuropsychiatric symptoms, depression, and caregivers’ burden) were considered as QoL predictors.Results: In multivariate-adjusted linear regression analyses, we observed that patients’ ratings were mainly affected by their mood whereas caregivers’ ratings were also negatively influenced by patients’ irritability and burden. According to staff ratings, both psychotic symptoms and neuroleptics were associated with lower QoL.Conclusions: Our findings suggest that depression is the main variable related to patients’ QoL and that more careful management of neuropsychiatric disorders is necessary. Both proxies’ ratings are not equivalent to patients’ reports in terms of predictors but they are complementary. Thus, a thorough QoL assessment should consider separately the perspective of the different informants.

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The contribution of astrocytes to Alzheimer's disease

Biochemical Society Transactions ◽

10.1042/bst20140171 ◽

2014 ◽

Vol 42 (5) ◽

pp. 1316-1320 ◽

Cited By ~ 22

Author(s):

Amy M. Birch

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Current Evidence ◽

Amyloid Β Peptide ◽

Substantial Evidence ◽

Supporting Cells ◽

Pathological Conditions ◽

The Brain

Astrocytes were historically classified as supporting cells; however, it is becoming increasingly clear that they actively contribute to neuronal functioning under normal and pathological conditions. As interest in the contribution of neuroinflammation to Alzheimer's disease (AD) progression has grown, manipulating glial cells has become an attractive target for future therapies. Astrocytes have largely been under-represented in studies that assess the role of glia in these processes, despite substantial evidence of astrogliosis in AD. The actual role of astrocytes in AD remains elusive, as they seem to adopt different functions dependent on disease progression and the extent of accompanying parenchymal inflammation. Astrocytes may contribute to the clearance of amyloid β-peptide (Aβ) and restrict the spread of inflammation in the brain. Conversely, they may contribute to neurodegeneration in AD by releasing neurotoxins and neglecting crucial metabolic roles. The present review summarizes current evidence on the multi-faceted functions of astrocytes in AD, highlighting the significant scope available for future therapeutic targets.

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Epigenetics of Alzheimer’s Disease

Biomolecules ◽

10.3390/biom11020195 ◽

2021 ◽

Vol 11 (2) ◽

pp. 195

Author(s):

Matea Nikolac Perkovic ◽

Alja Videtic Paska ◽

Marcela Konjevod ◽

Katarina Kouter ◽

Dubravka Svob Strac ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Posttranslational Modifications ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Current Evidence ◽

Mtdna Copy Number ◽

Rna Regulation ◽

The Central Nervous System

There are currently no validated biomarkers which can be used to accurately diagnose Alzheimer’s disease (AD) or to distinguish it from other dementia-causing neuropathologies. Moreover, to date, only symptomatic treatments exist for this progressive neurodegenerative disorder. In the search for new, more reliable biomarkers and potential therapeutic options, epigenetic modifications have emerged as important players in the pathogenesis of AD. The aim of the article was to provide a brief overview of the current knowledge regarding the role of epigenetics (including mitoepigenetics) in AD, and the possibility of applying these advances for future AD therapy. Extensive research has suggested an important role of DNA methylation and hydroxymethylation, histone posttranslational modifications, and non-coding RNA regulation (with the emphasis on microRNAs) in the course and development of AD. Recent studies also indicated mitochondrial DNA (mtDNA) as an interesting biomarker of AD, since dysfunctions in the mitochondria and lower mtDNA copy number have been associated with AD pathophysiology. The current evidence suggests that epigenetic changes can be successfully detected, not only in the central nervous system, but also in the cerebrospinal fluid and on the periphery, contributing further to their potential as both biomarkers and therapeutic targets in AD.

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Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Cells ◽

10.3390/cells9020311 ◽

2020 ◽

Vol 9 (2) ◽

pp. 311 ◽

Cited By ~ 4

Author(s):

Sandeep Malampati ◽

Ju-Xian Song ◽

Benjamin Chun-Kit Tong ◽

Anusha Nalluri ◽

Chuan-Bin Yang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Small Molecules ◽

Neuropsychiatric Symptoms ◽

Misfolded Protein ◽

Older Individuals ◽

Progressive Dementia ◽

The Brain

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases in older individuals with specific neuropsychiatric symptoms. It is a proteinopathy, pathologically characterized by the presence of misfolded protein (Aβ and Tau) aggregates in the brain, causing progressive dementia. Increasing studies have provided evidence that the defect in protein-degrading systems, especially the autophagy-lysosome pathway (ALP), plays an important role in the pathogenesis of AD. Recent studies have demonstrated that AD-associated protein aggregates can be selectively recognized by some receptors and then be degraded by ALP, a process termed aggrephagy. In this study, we reviewed the role of aggrephagy in AD development and discussed the strategy of promoting aggrephagy using small molecules for the treatment of AD.

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Does Intraneuronal Accumulation of Carboxyl-terminal Fragments of the Amyloid Precursor Protein Trigger Early Neurotoxicity in Alzheimer’s Disease?

Current Alzheimer Research ◽

10.2174/1567205016666190325092841 ◽

2019 ◽

Vol 16 (5) ◽

pp. 453-457 ◽

Cited By ~ 16

Author(s):

I. Lauritzen ◽

R. Pardossi-Piquard ◽

A. Bourgeois ◽

A. Bécot ◽

F. Checler

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Amyloid Β ◽

Brain Network ◽

Current Evidence ◽

Behavioral Alterations ◽

Disease Etiology ◽

Intracellular Organelles

Background: Alzheimer’s disease (AD) is associated with extracellular accumulation and aggregation of amyloid β (Aβ) peptides ultimately seeding in senile plaques. Recent data show that their direct precursor C99 (βCTF) also accumulates in AD-affected brain as well as in AD-like mouse models. C99 is consistently detected much earlier than Aβ, suggesting that this metabolite could be an early contributor to AD pathology. C99 accumulates principally within endolysosomal and autophagic structures and its accumulation was described as both a consequence and one of the causes of endolysosomalautophagic pathology, the occurrence of which has been documented as an early defect in AD. C99 was also accompanied by C99-derived C83 (αCTF) accumulation occurring within the same intracellular organelles. Both these CTFs were found to dimerize leading to the generation of higher molecular weight CTFs, which were immunohistochemically characterized in situ by means of aggregate-specific antibodies. Discussion: Here, we discuss studies demonstrating a direct link between the accumulation of C99 and C99-derived APP-CTFs and early neurotoxicity. We discuss the role of C99 in endosomal-lysosomalautophagic dysfunction, neuroinflammation, early brain network alterations and synaptic dysfunction as well as in memory-related behavioral alterations, in triple transgenic mice as well as in newly developed AD animal models. Conclusion: This review summarizes current evidence suggesting a potential role of the β -secretasederived APP C-terminal fragment C99 in Alzheimer’s disease etiology

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The Neuroinflammasome in Alzheimer’s Disease and Cerebral Stroke

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000516074 ◽

2021 ◽

pp. 159-167

Author(s):

Jong-hoon Lee ◽

Chul Joong Lee ◽

Jungwuk Park ◽

So Jeong Lee ◽

Su-hee Choi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Neuropsychiatric Symptoms ◽

Clinical Staging ◽

Cerebral Stroke ◽

Study Cohort ◽

Diaminodiphenyl Sulfone

Aim/Background: This review investigated a patient with Alzheimer’s disease (AD) treated with 4,4’-diaminodiphenyl sulfone (DDS) as a neuroinflammasome competitor. Methods: We monitored AD’s progression through numeric clinical staging (NCS) with a new biomarker. NCS was determined by the presence of AD symptoms and neuropsychiatric (NP) symptoms caused by anti-AD (AAD) drugs (D) as a biomarker. We also monitored the function of DDS for stroke in a no-intake emergency state. Results: By introducing (D), AD’s progression was monitored through NCS staging. AAD side effects and neuropsychiatric symptoms were identified. DDS was stopped in patients with stroke with NCS 6 caused by AAD, and it rapidly proceeded to cerebral infarct. Conclusions: AAD can occasionally exacerbate AD and stroke. DDS can alleviate mild cognitive impairment (MCI), early AD and stroke. We clinically confirmed the role of DDS as a neuroinflammasome competitor after stroke. DDS preserved neuronal survival within 24–55 h in the Seoul Study cohort.

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