The neurochemistry of agitation in Alzheimer’s disease: a systematic review

Liu, Kathy; Stringer, Aisling; Reeves, Suzanne; Howard, Robert

doi:10.1016/j.arr.2018.03.003

Cited by 32 publications

(43 citation statements)

References 101 publications

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“…Behavioral measures also changed during the pre‐MCI period despite the absence of any clinically identified behavioral problems, although the confidence intervals were wide in all cases. The source of these behavioral changes is not certain, but the median raphe and locus ceruleus are sites of early pathology, and the neurochemistry of agitation in AD dementia reflects an alteration of multiple monoaminergic neurochemical projection systems . Additionally, in patients experiencing visual hallucinations in the setting of dementia with Lewy bodies, as well as Parkinson's disease, cortical GABA‐ergic interneuron signaling is impaired in the absence of visual cortex synucleinopathy.…”

Section: Discussionmentioning

confidence: 99%

“…The source of these behavioral changes is not certain, but the median raphe 34 and locus ceruleus 35 are sites of early pathology, and the neurochemistry of agitation in AD dementia reflects an alteration of multiple monoaminergic neurochemical projection systems. 36 Additionally, in patients experiencing visual hallucinations in the setting of dementia with Lewy bodies, 37 as well as Parkinson's disease, 38 cortical GABAergic interneuron signaling is impaired in the absence of visual cortex synucleinopathy. Regarding depression, for which we found three of four tests declining more rapidly in MCI converters relative to nonconverters postinflection, we have previously shown in a normal aging cohort that there was no differential acceleration in depression scores among e4 carriers.…”

Section: F I G U R Ementioning

confidence: 99%

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Neuropsychological decline up to 20 years before incident mild cognitive impairment

Caselli

Langlais

Dueck

et al. 2020

Alzheimer's & Dementia

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Introduction Some Alzheimer's disease biomarker studies found amyloid changes 20 years or more in advance of expected symptoms, while cognitive changes lagged for more than a decade, but this apparent lag might reflect the sensitivities of the biomarker and cognitive assays used. How far in advance of incident amnestic mild cognitive impairment (MCI) does cognition begin to decline? Methods Longitudinal neuropsychological study of an apolipoprotein E e4 enriched cohort of cognitively normal individuals at entry. Linear mixed models for MCI converters (n = 65) and nonconverters (n = 719) fitted for each neuropsychological measure; annual changes compared between groups before and after linear model intersections (inflection points). Results 34 of 35 cognitive measures and 9 of 18 behavioral measures declined faster post‐inflection in the MCI converters; the earliest cognitive inflection point was nearly 20 years in advance of MCI diagnosis. Discussion The preclinical duration of cognitive and behavioral changes approaches the earliest reported biomarker changes.

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Section: Discussionmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

Neuropsychological decline up to 20 years before incident mild cognitive impairment

Caselli

Langlais

Dueck

et al. 2020

Alzheimer's & Dementia

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“…Evidence suggests that, rather than being at opposite ends of a behavioral spectrum, agitation and apathy share common neuroanatomical features involving overlapping structures (frontal, anterior cingulate, orbitofrontal cortices, amygdala and insula) [7,[24][25][26] and may copresent within a "dysexecutive syndrome" [27,28]. Agitation in AD has been associated with dysfunction in multiple neurotransmitter networks, especially the noradrenergic and serotonergic systems [6], and the same neurotransmitter systems have been implicated in apathy in other neurodegenerative disorders such as frontotemporal lobar degeneration [29] and Parkinson's disease [30,31]. There is also evidence that dysregulated dopamine signalling in the mesocorticolimbic network contributes to both apathy (via impaired motivation) [32], and delusion formation (via abnormal salience attribution to sensory stimuli) [33,34].…”

Section: Discussionmentioning

confidence: 99%

“…Agitation significantly reduces quality of life and precipitates earlier institutionalization [4], but in terms of treatment, the best evidence is for short-term use of antipsychotic drugs, which have only modest efficacy and potential harmful side-effects. As agitation in dementia may have many different etiologies [5], including AD-related brain changes [6,7], there is a clear need to better understand what may influence individuals' risk of developing agitation in order to develop better targeted prevention and treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

The Relationship Between Anxiety and Incident Agitation in Alzheimer’s Disease

Liu

Costello

Reeves

et al. 2020

JAD

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Background: Agitation in Alzheimer’s disease (AD) has been hypothesized to be an expression of anxiety, but whether anxiety early in the course of dementia could be a risk factor for developing later agitation is unknown. Objective: We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to examine the longitudinal relationship between anxiety and incident agitation in individuals with a diagnosis of AD at baseline or during follow-up. Methods: Longitudinal neuropsychiatric symptom data from AD individuals who were agitation-free at study baseline (N = 272) were analyzed using mixed effects regression models to test the longitudinal relationship between baseline and incident anxiety with incident agitation. Results: Anxiety at baseline was not associated with subsequent agitation, but there was a positive linear relationship between incident anxiety and agitation over the study duration. Baseline apathy and delusions were consistently associated with subsequent agitation and greater disease severity and illness duration also appeared to be risk factors for agitation. Conclusion: Our findings support the concept that anxiety and agitation are likely to be distinct rather than equivalent constructs in mild-moderate AD. Future longitudinal cohort studies are needed to replicate these findings and further characterize potential risk factors for agitation, such as apathy and delusions.

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“…Agitation in dementia has been associated with frontal lobe dysfunction [52] and brain regions involved in subjective emotional experiences [53]. It has been hypothesised that agitation could arise from overestimating or misinterpreting potential threats [54], whereby those threats could for example be pain or changes in the environment. It is however also conceivable that, as possibly in the agitation and psychosis group, those overinterpreted threats are psychotic or quasi psychotic experiences.…”

Section: Mortalitymentioning

confidence: 99%

Antipsychotic use in dementia: the relationship between neuropsychiatric symptom profiles and adverse outcomes

et al. 2020

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Antipsychotic treatments are associated with safety concerns in people with dementia. The authors aimed to investigate whether risk of adverse outcomes related to antipsychotic prescribing differed according to major neuropsychiatric syndromes-specifically psychosis, agitation, or a combination. A cohort of 10,106 patients with a diagnosis of dementia was assembled from a large dementia care database in South East London. Neuropsychiatric symptoms closest to first dementia diagnosis were determined according to the Health of the Nation Outcome Scales' mental and behavioural problem scores and the sample was divided into four groups: 'agitation and psychosis', 'agitation, but no psychosis', 'psychosis, but no agitation', and 'neither psychosis nor agitation'. Antipsychotic prescription in a one-year window around first dementia diagnosis was ascertained as exposure variable through natural language processing from free text. Cox regression models were used to analyse associations of antipsychotic prescription with all-cause and stroke-specific mortality, emergency hospitalisation and hospitalised stroke adjusting for sixteen potential confounders including demographics, cognition, functioning, as well as physical and mental health. Only in the group 'psychosis, but no agitation' (n = 579), 30% of whom were prescribed an antipsychotic, a significant antipsychotic-associated increased risk of hospitalised stroke was present after adjustment (adjusted hazard ratio (HR) 2.16; 95% confidence interval (CI) 1.09-4.25). An increased antipsychotic-related all-cause (adjusted HR 1.14; 95% CI 1.04-1.24) and stroke-specific mortality risk (adjusted HR 1.28; 95% CI 1.01-1.63) was detected in the whole sample, but no interaction between the strata and antipsychotic-related mortality. In conclusion, the adverse effects of antipsychotics in dementia are complex. Stroke risk may be highest when used in patients presenting with psychosis without agitation, indicating the need for novel interventions for this group.

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The neurochemistry of agitation in Alzheimer’s disease: a systematic review

Cited by 32 publications

References 101 publications

Neuropsychological decline up to 20 years before incident mild cognitive impairment

Neuropsychological decline up to 20 years before incident mild cognitive impairment

The Relationship Between Anxiety and Incident Agitation in Alzheimer’s Disease

Antipsychotic use in dementia: the relationship between neuropsychiatric symptom profiles and adverse outcomes

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