Progresses in treating agitation: a major clinical challenge in Alzheimer’s disease

Panza, Francesco; Solfrizzi, Vincenzo; Seripa, Davide; Imbimbo, Bruno P.; Santamato, Andrea; Lozupone, Madia; Prete, Camilla; Greco, Antonio; Pilotto, Alberto; Logroscino, Giancarlo

doi:10.1517/14656566.2015.1092520

Cited by 46 publications

(25 citation statements)

References 57 publications

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“…TPH is encoded by two separate enzymes: TPH1 produces serotonin in the pineal gland and entero-chromaffin cells, while TPH2 produces serotonin in the Raphe nuclei of the brain stem and myenteric plexus. Interestingly, serotonin is phylogenetically the oldest neurotransmission system present involved in cognition and memory in both vertebrate and invertebrate species, and pathological alterations in 5-HT metabolism and/or down-regulation of serotonergic signaling have been associated with various pathophysiological conditions in the CNS including amyloidogenesis and SP formation, hyper-phosphorylation of tau and NFT formation, two classical aggregates that in part characterize AD brain neuropathology (McClam et al, 2015; Panza et al, 2015; Butzlaff and Ponimaskin, 2016; Wirth et al, 2016). Due to the extensive serotonergic denervation observed in AD and the important roles played by serotonin in both behavior and cognition, this neurotransmitter system has become a focus of dedicated research efforts to identify novel pathways in Aβ peptide or NFT assembly and/or aggregation (Butzlaff and Ponimaskin, 2016; Schneider et al, 2016; Wirth et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Genetics of Aggression in Alzheimer’s Disease (AD)

Lukiw

Rogaev

2017

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a terminal, age-related neurological syndrome exhibiting progressive cognitive and memory decline, however AD patients in addition exhibit ancillary neuropsychiatric symptoms (NPSs) and these include aggression. In this communication we provide recent evidence for the mis-regulation of a small family of genes expressed in the human hippocampus that appear to be significantly involved in expression patterns common to both AD and aggression. DNA array- and mRNA transcriptome-based gene expression analysis and candidate gene association and/or genome-wide association studies (CGAS, GWAS) of aggressive attributes in humans have revealed a surprisingly small subset of six brain genes that are also strongly associated with altered gene expression patterns in AD. These genes encoded on five different chromosomes (chr) include the androgen receptor (AR; chrXq12), brain-derived neurotrophic factor (BDNF; chr11p14.1), catechol-O-methyl transferase (COMT; chr22q11.21), neuronal specific nitric oxide synthase (NOS1; chr12q24.22), dopamine beta-hydroxylase (DBH chr9q34.2) and tryptophan hydroxylase (TPH1, chr11p15.1 and TPH2, chr12q21.1). Interestingly, (i) the expression of three of these six genes (COMT, DBH, NOS1) are highly variable; (ii) three of these six genes (COMT, DBH, TPH1) are involved in DA or serotonin metabolism, biosynthesis and/or neurotransmission; and (iii) five of these six genes (AR, BDNF, COMT, DBH, NOS1) have been implicated in the development, onset and/or propagation of schizophrenia. The magnitude of the expression of genes implicated in aggressive behavior appears to be more pronounced in the later stages of AD when compared to MCI. These recent genetic data further indicate that the extent of cognitive impairment may have some bearing on the degree of aggression which accompanies the AD phenotype.

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Section: Discussionmentioning

confidence: 99%

Genetics of Aggression in Alzheimer’s Disease (AD)

Lukiw

Rogaev

2017

Front. Aging Neurosci.

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“…22 Both patients were treated with citalopram in order to reduce the depressive symptoms. Recently completed randomized controlled trial 23 on novel or repositioned drugs (mibampator, dextromethorphan/quinidine, cannabinoids, and citalopram) showed some promise in treating agitation in Alzheimer's disease, but still with safety concerns.…”

Section: Discussionmentioning

confidence: 99%

Musical hallucinations in elderly patients with visuospatial impairment: two case reports

et al. 2017

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Musical hallucinations are an uncommon type of auditory hallucinations, they widely occur in elderly. Our group analyzed medical history, pharmacological therapy, neuropsychological pattern, audiometric testing, electroencephalogram, cerebral magnetic resonance and cerebral fludeoxyglucose-positron emission tomography (FDG-PET) of two patients. FDG-PET showed in both patients hypometabolism pronounced in posterior regions. In particular the medial-inferior temporal cortex and the occipital associative areas were affected. Moreover, neuropsychological pattern suggested a visuospatial-executive deficit, conformed to the occipital involvement. Our reported cases might suggest that musical hallucinations have been arisen from a combination of peripheral and central dysfunction. A further explanation might be that musical hallucinations result from multiple white matter lacunar lesions due to small vascular events. A question is whether musical hallucinations might be primarily associated with occipital areas hypometabolism and visuospatial alterations typically associated with Levy body dementia (LBD).

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“…The treatment of agitation has been identified as an unmet need in relation to adequate care provided for those suffering from cognitive impairments (Gitlin et al, 2012;Herrmann and Lanctot, 2007). When the agitation is severe the symptoms include disinhibition, irritability, aggression and aberrant motor activity, which affect the patient's quality of life and cause increased stress for the family and caregivers (Antonsdottir et al, 2015;Cummings et al, 2015;Panza et al, 2015;Kales et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Agitation related to dementia is frequently observed clinically (Cohen-Mansfield, 2013;Ballard et al, 2001;Lyketsos et al, 2000), and various pharmacological interventions have been employed to treat this. These treatments include the use of anxiolytic, antidepressant, antipsychotic and anticonvulsant drugs (Antonsdottir et al, 2015;Cummings et al, 2015;Panza et al, 2015;Soto et al, 2015;Kales et al, 2014;Salzman et al, 2008). The most contentious approach relates to the use of antipsychotic drugs , which have been reported to be of only modest value (Ballard et al, 2009;, and to produce adverse effects (Gitlin et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Overall, the currently available pharmacological treatments for agitation in dementia are of little value, and the adverse effects of antipsychotic drugs are of considerable concern (Sacchetti et al, 2012;Ma et al, 2014;Ballard, 2006;. Basically, there are no officially approved pharmacotherapies for agitation in dementia, and few if any safe and effective pharmacotherapies (Antonsdottir et al, 2015;Cummings et al, 2015;Panza et al, 2015;Soto et al, 2015;Kales et al, 2014;. Also, non-pharmaceutical approaches have been shown to be of very limited value (Ballard et al, 2016;Steinberg, 2016;Kales et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia

O’Hare

Page

Curran

et al. 2017

Behavioural Pharmacology

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Agitation associated with dementia is frequently reported clinically but has received little attention in preclinical models of dementia. The current study used a 7PA2 CM intracerebroventricular (ICV) injection model of Alzheimer's disease (AD) to assess acute memory impairment, and a bilateral intrahippocampal (IH) injection model of AD (aggregated Aβ1-42 injections) and a bilateral IH injection model of dementia with Lewy bodies (DLB; aggregated NAC61-95 injections) to assess chronic memory impairment in the rat. An alternating-lever cyclic-ratio schedule of operant responding was employed for data collection, where incorrect lever perseverations measured executive function (memory) and running response rates (RRR) measured behavioral output (agitation). The results indicate that bilateral IH injections of Aβ1-42 and bilateral IH injections of NAC61-95 decreased memory function and increased RRRs, whereas ICV injections of 7PA2 CM decreased memory function but did not increase RRRs. These findings show that using the aggregated peptide IH injection models of dementia to induce chronic neurotoxicity, memory decline was accompanied by elevated behavioral output. This demonstrates that IH peptide injection models of dementia provide a preclinical screen for pharmacological interventions used in the treatment of increased behavioral output (agitation), that also establish detrimental side effects on memory.

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Progresses in treating agitation: a major clinical challenge in Alzheimer’s disease

Cited by 46 publications

References 57 publications

Genetics of Aggression in Alzheimer’s Disease (AD)

Genetics of Aggression in Alzheimer’s Disease (AD)

Musical hallucinations in elderly patients with visuospatial impairment: two case reports

A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia

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