Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits?
Open accessAbstract
Neuropsychiatric symptoms (NPS) are very common in Alzheimer’s disease (AD), particularly agitation, apathy, depression, and delusions. Brain networks or circuits underlying these symptoms are just starting to be understood, and there is a growing imaging and neurochemical evidence base for understanding potential mechanisms for NPS. We offer a synthetic review of the recent literature and offer hypotheses for potential networks/circuits underlying these NPS, particularly agitation, apathy, and delusions. Agitation in AD appears to be associated with deficits in structure and function of frontal cortex, anterior cingulate cortex, posterior cingulate cortex, amygdala, and hippocampus, and may be associated with mechanisms underlying misinterpretation of threats and affective regulation. Apathy in AD is associated with frontal cortex, anterior cingulate cortex, posterior cingulate cortex, as well as orbitofrontal cortex, and inferior temporal cortex, and may be associated with mechanisms underlying avoidance behaviors.
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Written from the paper’s full text.
TL;DR
This synthetic review proposes that neuropsychiatric symptoms in Alzheimer’s disease (AD), especially agitation and apathy, arise from dysfunction in distributed brain networks/circuits rather than single regions. It links agitation to frontal/cingulate/amygdala/insular circuits and apathy to frontal/cingulate/orbitofrontal/insular/inferior temporal circuits, while noting insufficient evidence for depression and psychosis hypotheses.
Key findings
- Agitation in AD was consistently associated with volume loss in frontal cortex, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), insula, amygdala, and hippocampus; autopsy studies concurred on decreased cholinergic markers, particularly in frontal and temporal cortex, and decreased serotonin/metabolites, with higher tau/phospho-tau and decreased PB2A enzymatic activity in frontal cortex.
- Apathy in AD was associated with ACC damage (reduced gray matter volume, cortical thinning, decreased perfusion, decreased white matter integrity, and increased amyloid burden in right ACC), PCC hypometabolism, frontal volume loss/cortical thinning, greater bilateral frontal amyloid burden, reduced orbitofrontal metabolism, decreased insula volume, and decreased inferior temporal cortical thickness; one CSF study of 32 AD subjects found apathy severity associated with higher CSF tau and phospho-tau but not Aβ1–42.
- Delusions in AD were associated with decreased gray matter volume, perfusion, or metabolism in frontal cortex and ACC, with varied localization to orbitofrontal, dorsolateral, or inferior frontal cortex, plus insula involvement; one raclopride PET study found increased D2/D3 receptor density. Delusions had a 5-year period prevalence of >50% in the longitudinal Cache County study.
- Depression in AD had very few imaging data: in 334 subjects with MCI, NPI-Q Depression was associated with reduced entorhinal cortical thickness at baseline and accelerated ACC atrophy; in 202 MCI and 85 AD subjects, it was associated with decreased left middle frontal gray matter volume; lower CSF taurine was associated with depression and overall NPS in 202 AD subjects. The paper concludes there is insufficient evidence to generate hypotheses for depression.
Methods
- Synthetic, not systematic, review of recent literature (last 10 years with selected older studies), focused on AD and excluding other dementias, emphasizing replicated findings where available.
- Reviewed neuroimaging (MRI, DTI, SPECT perfusion, amyloid PET, resting-state fMRI) and neurochemical/autopsy/CSF studies relevant to agitation, apathy, delusions, and depression in AD.
- Main analysis is narrative synthesis and hypothesis generation about brain networks/circuits; no primary data collection or meta-analysis.
Limitations
- Paper-stated: the literature is sparse, making direct comparisons challenging; phenotyping is varied with different NPS definitions and little consideration of symptom overlap; there is no consensus on dimensional vs. categorical definitions; imaging analysis methods vary (ROI vs. VBM); laterality findings are contradictory; some studies are likely underpowered; and there is insufficient evidence for depression or psychosis to develop cogent hypotheses.
- Evident from the text: most evidence is associative rather than causal; agitation had no neurochemical imaging studies; apathy had only one neurochemical CSF study; delusion studies often did not dissociate delusions from agitation; and the review offers hypotheses rather than confirmatory tests.
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Claims the paper makes
0 of 65 cited sources checked · 0 supported · 0 flagged
- Findingcitation
Apathy in Alzheimer's disease is associated with decreased bilateral putamen dopamine transporter density.
“Of the two reports involving neurochemical imaging, one reported decreased bilateral putamen dopamine transporter density (David et al., 2008) while the other reported no association with D2/D3 dopamine receptor density (Reeves et al., 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites David et al., 2008 source
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- Findingcitation
Agitation in Alzheimer's disease is associated with hypoperfusion in left anteriotemporal, right parietal, and bilateral dorsofrontal cortex.
“The sole SPECT perfusion study (Hirono et al., 2000) linked agitation with hypoperfusion in left anteriotemporal, right parietal, and bilateral dorsofrontal cortex.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hirono et al., 2000 source
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- Findingcitation
Agitation in Alzheimer's disease is associated with volume loss in frontal cortex, anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and hippocampus.
“Agitation was consistently associated with volume loss in several specific brain areas including frontal cortex (Hu et al., 2015; Trzepacz et al., 2013b), anterior cingulate cortex (ACC) (Bruen et al., 2008; Trzepacz et al., 2013b), posterior cingulate cortex (PCC) (Hu et al., 2015; Trzepacz et al., 2013b), insula (Bruen et al., 2008; Hu et al., 2015; Trzepacz et al., 2013b), amygdala (Trzepacz et”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Hu et al., 2015
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- cites Trzepacz et al., 2013b
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- cites Bruen et al., 2008 source
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- Findingcitation
Agitation in Alzheimer's disease is associated with deficits in structure and function of frontal cortex, anterior cingulate cortex, posterior cingulate cortex, amygdala, and hippocampus.
“Agitation in AD appears to be associated with deficits in structure and function of frontal cortex, anterior cingulate cortex, posterior cingulate cortex, amygdala, and hippocampus, and may be associated with mechanisms underlying misinterpretation of threats and affective regulation.”
- Also stated in: § 2. Results · plain
“Agitation was consistently associated with volume loss in several specific brain areas including frontal cortex (Hu et al., 2015; Trzepacz et al., 2013b), anterior cingulate cortex (ACC) (Bruen et al., 2008; Trzepacz et al., 2013b), posterior cingulate cortex (PCC) (Hu et al., 2015; Trzepacz et al., 2013b), insula (Bruen et al., 2008; Hu et al., 2015; Trzepacz et al., 2013b), amygdala (Trzepacz et”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Hu et al., 2015
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- cites Trzepacz et al., 2013b
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- cites Bruen et al., 2008 source
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- Also stated in: § 2. Results · plain
- Findingcitation
Apathy in Alzheimer's disease is associated with increased amyloid burden in right anterior cingulate cortex.
“Similarly apathy is associated with decreased perfusion in ACC (Benoit et al., 2004; Lanctôt et al., 2007; Robert et al., 2006), decreased ACC white matter integrity by DTI (Hahn et al., 2013; Kim et al., 2011; Ota et al., 2012) and increased amyloid burden in right ACC (Mori et al., 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mori et al., 2014 source
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- Findingcitation
Apathy in Alzheimer's disease is associated with decreased insula volume.
“Two studies report an association of apathy with decreased insula volume (Moon et al., 2014; Stanton et al., 2013) although they disagree on whether this is bilateral or unilateral.”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingcitation
Apathy in Alzheimer's disease is associated with volume loss and/or cortical thinning in frontal cortex.
“There are also links between apathy and volume loss and/or cortical thinning in frontal cortex (Apostolova et al., 2007; Bruen et al., 2008; Stanton et al., 2013; Tunnard et al., 2011), though there is no strict concordance on the specific regions of frontal cortex which include medial, lateral, and orbital regions.”
Quote in the paperSubstantial claim0 of 3 sources checked - Findingcitation
Apathy in Alzheimer's disease is associated with decreased perfusion in anterior cingulate cortex.
“Similarly apathy is associated with decreased perfusion in ACC (Benoit et al., 2004; Lanctôt et al., 2007; Robert et al., 2006), decreased ACC white matter integrity by DTI (Hahn et al., 2013; Kim et al., 2011; Ota et al., 2012) and increased amyloid burden in right ACC (Mori et al., 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked - Findingcitation
Apathy in Alzheimer's disease is associated with volume loss in anterior cingulate cortex, including reduced gray matter volume and cortical thinning.
“Structural imaging studies report volume loss in ACC, including reduced gray matter volume (Apostolova et al., 2007; Bruen et al., 2008; Stanton et al., 2013) and cortical thinning (Tunnard et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Findingnone given
Apathy in Alzheimer's disease is associated with frontal cortex, anterior cingulate cortex, posterior cingulate cortex, orbitofrontal cortex, and inferior temporal cortex.
“Apathy in AD is associated with frontal cortex, anterior cingulate cortex, posterior cingulate cortex, as well as orbitofrontal cortex, and inferior temporal cortex, and may be associated with mechanisms underlying avoidance behaviors.”
Quote in the paperNot a substantial claim - Findingcitation
Apathy in Alzheimer's disease is associated with decreased posterior cingulate cortex metabolism.
“Apathy is also associated with decreased PCC metabolism (Delrieu et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Delrieu et al., 2015 source
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- Findingcitation
Apathy in Alzheimer's disease is associated with decreased anterior cingulate cortex white matter integrity by diffusion tensor imaging.
“Similarly apathy is associated with decreased perfusion in ACC (Benoit et al., 2004; Lanctôt et al., 2007; Robert et al., 2006), decreased ACC white matter integrity by DTI (Hahn et al., 2013; Kim et al., 2011; Ota et al., 2012) and increased amyloid burden in right ACC (Mori et al., 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked - Findingcitation
Apathy in Alzheimer's disease is associated with decreased inferior temporal cortical thickness.
“Two studies note an association of apathy with decreased inferior temporal cortical (ITC) thickness (Donovan et al., 2014; Guercio et al., 2015).”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingcitation
Delusions in Alzheimer's disease are associated with increased D2/D3 receptor density.
“One neurochemical study with raclopride PET imaging found an association between delusions and increased D2/D3 receptor density (Reeves et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Reeves et al., 2009 source
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- Findingnone given
Apathy in Alzheimer's disease is associated with dysfunction in several structures overlapping with agitation (frontal cortex, ACC, orbitofrontal cortex and insula) as well as amygdala and, to a limited extent, striatum.
“We note that apathy in AD is associated with dysfunction in several structures overlapping with agitation (frontal cortex, ACC, orbitofrontal cortex and insula) as well as amygdala and (to a limited extent) striatum (Fig. 2).”
Quote in the paperSubstantial claim - Findingcitation
Reduced initiative in Alzheimer's disease is associated with volume loss in anterior cingulate cortex.
“Two studies have endeavored to map specific subdomains of apathy (i.e., reduced initiative, emotional blunting, or lack of initiative) to neuroimaging findings in specific brain regions (Benoit et al., 2004; Stanton et al., 2013), with the only notable finding being that reduced initiative was associated with volume loss in ACC.”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingnone given
Several dysfunctional areas were identified in delusional, but not agitated, Alzheimer's disease patients: parahippocampal gyrus, inferior frontal pole, right superior frontal cortex, putamen, left superior temporal, and claustrum.
“We did identify several dysfunctional areas in delusional, but not agitated AD patients, including the parahippocampal gyrus, inferior frontal pole, right superior frontal cortex, putamen, left superior temporal, and claustrum.”
Quote in the paperSubstantial claim - Findingcitation
Apathy in Alzheimer's disease is not associated with D2/D3 dopamine receptor density.
“Of the two reports involving neurochemical imaging, one reported decreased bilateral putamen dopamine transporter density (David et al., 2008) while the other reported no association with D2/D3 dopamine receptor density (Reeves et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Reeves et al., 2009 source
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- Findingnone given
Agitated Alzheimer's disease patients appear to have dysfunction in frontal cortex, anterior cingulate cortex, orbitofrontal cortex, amygdala, and insula.
“Agitated AD patients appear to have dysfunction in frontal cortex, ACC, orbitofrontal cortex, amygdala, and insula.”
Quote in the paperNot a substantial claim - Findingreasoning
Apathetic Alzheimer's disease patients tend to isolate and avoid social interaction.
“apathetic AD patients tend to isolate and avoid social interaction”
Quote in the paperNot a substantial claim - Findingcitation
Delusions in Alzheimer's disease are associated with decreased gray matter volume, perfusion or metabolism in frontal cortex and anterior cingulate cortex.
“Delusions were associated with decreased gray matter (GM) volume, perfusion or metabolism in frontal cortex and ACC (Bruen et al., 2008; Koppel et al., 2014; Mega et al., 2000; Nakaaki et al., 2013; Rafii et al., 2011; Sultzer et al., 2003; Whitehead et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked - Findingcitation
Apathy in Alzheimer's disease is associated with reduced connectivity in left-sided circuits, predominantly involving limbic striatal and frontal territories.
“A study of resting-state connectivity using functional MRI (fMRI) reported an association of apathy with reduced connectivity in left-sided circuits, predominantly involving limbic striatal and frontal territories (Baggio et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Baggio et al., 2015 source
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- Interpretationreasoning
The anatomy of neurochemical changes associated with agitation in Alzheimer's disease fits partially with the functional and structural imaging evidence.
“Thus the anatomy of neurochemical changes associated with agitation in AD fits partially with the functional and structural imaging evidence.”
Quote in the paperSubstantial claim - Interpretationreasoning
Agitation in Alzheimer's disease is linked to core aspects of Alzheimer's disease pathology.
“This further links agitation to core aspects of AD pathology.”
Quote in the paperSubstantial claim - Interpretationnone given
Apathy in Alzheimer's disease may be associated with mechanisms underlying avoidance behaviors.
“Apathy in AD is associated with frontal cortex, anterior cingulate cortex, posterior cingulate cortex, as well as orbitofrontal cortex, and inferior temporal cortex, and may be associated with mechanisms underlying avoidance behaviors.”
Quote in the paperNot a substantial claim - Interpretationcitation
Agitation in Alzheimer's disease is associated with core Alzheimer's disease disease progression.
“First, there are structural and functional deficits in a number of brain regions that are also implicated in the distribution of core AD pathology including PCC and hippocampus (Mattsson et al., 2014), suggesting an association between the core processes of AD disease progression and agitation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mattsson et al., 2014 source
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- Interpretationreasoning
Agitation in Alzheimer's disease may be associated with mechanisms underlying misinterpretation of threats and affective regulation.
“Agitation in AD appears to be associated with deficits in structure and function of frontal cortex, anterior cingulate cortex, posterior cingulate cortex, amygdala, and hippocampus, and may be associated with mechanisms underlying misinterpretation of threats and affective regulation.”
Quote in the paperSubstantial claim - Premisecitation
Neuropsychiatric symptoms are caused by dysfunction in specific networks.
“There is increasing evidence that NPS are caused by dysfunction in specific networks (Dichter et al., 2014; Greicius, 2008; Grupe and Nitschke, 2013; Hamon and Blier, 2013; Menon, 2011; Price and Drevets, 2010; Price and Drevets, 2012; Tromp et al., 2012; Uhlhaas, 2013), with overlap between proposed networks and conditions.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisenone given
There is one report of delusions in Alzheimer's disease being associated with increased dopamine receptor density.
“There is one report of delusions in AD being associated with increase dopamine receptor density”
Quote in the paperNot a substantial claim - Interpretationreasoning
Agitation may be an example of removing inhibitory input that ordinarily serves to control behavior to the cortical circuits associated with agitation.
“Thus agitation may be an example of removing inhibitory input that ordinarily serves to control behavior to the cortical circuits associated with agitation.”
Quote in the paperSubstantial claim - Interpretationreasoning
The brain areas affected in agitation in Alzheimer's disease are largely localized to the salience network.
“The brain areas affected in agitation in AD are largely localized to SN (Fig. 1).”
Quote in the paperSubstantial claim - Interpretationreasoning
There is insufficient evidence for generating hypotheses about depression in Alzheimer's disease.
“While these four papers are intriguing there is insufficient evidence for generating hypotheses at this time.”
Quote in the paperSubstantial claim - Interpretationreasoning
In apathy, the relevant circuits underlie behavioral and cognitive avoidance.
“For apathy, these circuits underlie behavioral and cognitive avoidance.”
Quote in the paperSubstantial claim - Premisecitation
The structures dysfunctional in apathy overlap with circuits that subsume behavioral and cognitive avoidance.
“In Grupe et al.’s schematic, this overlaps with circuits that subsume behavioral and cognitive avoidance (Grupe and Nitschke, 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Grupe and Nitschke, 2013 source
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- Premisecitation
The method of drug discovery by re-purposing FDA drugs is inherently limited especially in terms of interpreting null results.
“While this method of drug discovery has the attractive feature of studying drugs with generally well-characterized safety profiles, it is inherently limited especially in terms of interpreting null results (Rosenberg et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rosenberg et al., 2010 source
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- Interpretationreasoning
Apathy is associated with the core neurodegenerative processes of Alzheimer's disease.
“suggesting as before an association between apathy and the core neurodegenerative processes of AD”
Quote in the paperSubstantial claim - Interpretationreasoning
There is much overlap between the imaging findings in delusional and agitated Alzheimer's disease patients.
“there is understandably much overlap between the imaging findings in these areas”
Quote in the paperSubstantial claim - Premisenone given
There is overlap between symptoms of neuropsychiatric illnesses.
“It is increasingly evident that there is overlap between symptoms of neuropsychiatric illnesses”
Quote in the paperNot a substantial claim - Interpretationreasoning
Agitation in Alzheimer's disease is an emotionally hyperreactive state largely based on misinterpretation of threats ultimately rooted in cognitive deficits.
“Seen this way, agitation is an emotionally hyperreactive state largely based on misinterpretation of threats ultimately rooted in cognitive deficits.”
Quote in the paperSubstantial claim - Interpretationreasoning
Phenotyping is varied between studies, which likely accounts for much of the heterogeneity in results.
“First, phenotyping is quite varied between studies, which likely accounts for much of the heterogeneity in results.”
Quote in the paperSubstantial claim - Premisenone given
Most studies of delusions in Alzheimer's disease did not exclude agitation.
“Since most of the studies of delusions in AD did not exclude agitation”
Quote in the paperNot a substantial claim - Premisecitation
There was no association between dopamine D2/D3 receptor density and apathy in Alzheimer's disease.
“there was no association between dopamine D2/ D3 receptor density and apathy in AD (Reeves et al., 2009)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Reeves et al., 2009 source
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- Interpretationown data
It is not clear how the identified delusion-related regions might fit together as a brain network.
“Based on current evidence it is not clear how these regions might fit together as a brain network.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Damage to agitation circuits might cause a patient who forgot a routine event to conclude that it was an unexpected threat leading to overreaction and agitation.
“Damage to these agitation circuits might cause a patient who forgot a routine event (resulting from damage to memory circuits) to conclude that it was an unexpected threat leading to overreaction and agitation.”
Quote in the paperSubstantial claim - Interpretationreasoning
Decreased serotoninergic and acetylcholinergic neurotransmission implies less inhibition of cortex.
“decreased serotoninergic and acetylcholinergic neurotransmission would imply less inhibition of cortex”
Quote in the paperSubstantial claim - Interpretationreasoning
Alterations in brain circuitry most likely mediate the association of brain neurodegenerative pathology with behavior and emotion.
“Rather alterations in brain circuitry most likely mediate the association of brain neurodegenerative pathology with behavior and emotion.”
Quote in the paperSubstantial claim - Interpretationreasoning
Apathy in Alzheimer's disease is associated with core Alzheimer's disease neurodegenerative processes.
“Since tau and phospho-tau are considered to be markers of downstream neurodegeneration in AD (Jack et al., 2013), this suggests that apathy is associated with core AD neurodegenerative processes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jack et al., 2013 source
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- Premisenone given
CSF tau was associated with apathy in Alzheimer's disease.
“CSF tau was associated with apathy in AD”
Quote in the paperNot a substantial claim - Premisecitation
The SSRI citalopram, noted for its anxiolytic effects, has been recently reported to be an effective treatment for agitation in Alzheimer's disease.
“the SSRI citalopram, noted for its anxiolytic effects, has been recently reported to be an effective treatment for agitation in AD (Porsteinsson et al., 2014)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Porsteinsson et al., 2014 source
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- Premisecitation
To date, successful medication trials have been re-purposing FDA drugs approved for similar or dissimilar indications.
“To date, successful medication trials have been re-purposing FDA drugs approved for similar (Porsteinsson et al., 2014) or dissimilar (Rosenberg et al., 2013) indications.”
Quote in the paperNot a substantial claim0 of 2 sources checked
- May combine two claims. 21
- Classified as probably not a substantial claim. 15
May combine two claims.
FindingcitationOveractivity and/or aggressiveness in Alzheimer's disease are associated with decreased cholinergic markers, particularly in frontal and temporal cortex, and with decreased serotonin and serotonin metabolites.
“All three studies concur: overactivity and/or aggressiveness were associated with decreased cholinergic markers, particularly in frontal and temporal cortex, and with decreased serotonin and serotonin metabolites.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
FindingcitationAgitation in Alzheimer's disease is associated with higher levels of tau and phosphorylated tau, and with decreased PP2A enzymatic activity in frontal cortex.
“Two studies concur that agitation was associated with higher levels of tau and phosphorylated tau (phospho-tau), association with decreased PB2A enzymatic activity (PB2A is a tau phosphatase) in frontal cortex.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationApathy in Alzheimer's disease is associated with damage to anterior cingulate cortex, as evidenced by decreased structural integrity or perfusion of anterior cingulate cortex, and with increased amyloid burden globally, especially in anterior cingulate cortex.
“First and foremost, apathy in AD is associated with damage to the ACC as evidenced by decreased structural integrity or perfusion of the ACC, as well as with increased amyloid burden globally (Marshall et al., 2013) especially in ACC.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Marshall et al., 2013 source
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May combine two claims.
FindingcitationApathy in Alzheimer's disease is associated with greater amyloid burden in bilateral frontal cortex, reduced orbitofrontal metabolism on the left or right, and reduced connectivity in left-sided functional connectivity with frontal cortex.
“Apathy is further associated with greater amyloid burden in bilateral frontal cortex (Mori et al., 2014), reduced orbitofrontal metabolism on the left (Holthoff et al., 2005) or right (Lanctôt et al., 2007), and reduced connectivity in left-sided functional connectivity with frontal cortex (Baggio et al., 2015).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
FindingcitationNPI Irritability, but not Agitation/Aggression, is associated with lower fractional anisotropy in anterior cingulate cortex in Alzheimer's disease.
“In a study using DTI Tighe et al. (2012) reported that NPI Irritability (but not Agitation/Aggression) was associated with lower fractional anisotropy (FA) (suggesting decreased WM integrity) in ACC.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tighe et al., 2012 source
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May combine two claims.
FindingcitationApathy severity in Alzheimer's disease is associated with higher levels of cerebrospinal fluid tau and phospho-tau but not cerebrospinal fluid Aβ1-42.
“Apathy severity was associated with higher levels of CSF tau and phospho-tau but not CSF Aβ1–42.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Skogseth et al., 2008 source
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Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationLower cerebrospinal fluid taurine in Alzheimer's disease is associated with depression and overall neuropsychiatric symptoms.
“The sole CSF study examined monoaminergic neurotransmitters, metabolites, and amino acids in 202 AD subjects reporting that lower CSF taurine was associated not only with depression, but also with overall NPS (Vermeiren et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vermeiren et al., 2013 source
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May combine two claims.
FindingcitationDelusions in Alzheimer's disease are associated with decreased perfusion in right anterior insula and decreased gray matter volume in left insula.
“Delusions were also associated with decreased perfusion in right anterior insula (Matsuoka et al., 2010) and decreased GM volume in left insula (Nakaaki et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Matsuoka et al., 2010 source
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- cites Nakaaki et al., 2013
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FindingcitationDepression in Alzheimer's disease is associated with decreased gray matter volumes in left middle frontal cortex.
“Hu et al. (2015) reported on a similar ADNI cohort of 202 subjects with MCI and 85 with AD, and found that NPI-Q Depression was associated with decreased GM volumes in left middle frontal cortex.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hu et al., 2015
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May combine two claims.
FindingreasoningAgitated Alzheimer's disease patients appear to overestimate and overreact to threats and be unable to modulate strong emotional responses.
“agitated AD patients indeed appear to overestimate and overreact to threats and be unable to modulate strong emotional responses”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
FindingcitationDepression in Alzheimer's disease is associated with reduced entorhinal cortical thickness at baseline and with accelerated atrophy in anterior cingulate cortex.
“They found Depression to be associated with reduced entorhinal cortical thickness at baseline and with accelerated atrophy in ACC.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zahodne et al., 2013 source
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InterpretationreasoningAgitation in Alzheimer's disease arises out of deficits in regulating emotional responses and/or attentional resources, and may involve deficits in problem-solving.
“These suggest that agitation in AD arises out of deficits in regulating emotional responses and/or attentional resources, and may involve deficits in problem-solving.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S1 (asserted), S4 (based).
InterpretationreasoningThe brain regions associated with neuropsychiatric symptoms in Alzheimer's disease are functionally linked as brain networks or circuits.
“As several spatially disparate regions are associated with NPS, we hypothesize that these are in fact linked functionally as brain “networks” or “circuits,” terms that we use interchangeably.”
- Also stated in: § 1. Background · hedged
“While most of the evidence is associative at this point, the idea that regions associated with NPS are part of functional networks (circuits) is our central hypothesis.”
Quote in the paperNot a substantial claim- Also stated in: § 1. Background · hedged
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenVariability of brain network disruption by the Alzheimer's disease brain disease accounts for variability in neuropsychiatric symptom phenotypes.
“Applying a similar approach to understanding NPS, we propose that variability of brain network disruption by the AD brain disease accounts for variability in NPS phenotypes.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningAgitation in Alzheimer's disease may constitute two different mechanisms, one due to deficits in affective regulation and the other due to deficits in executive function.
“These may constitute two different mechanisms for agitation in AD, one due to deficits in affective regulation (emotional responses) and the other due to deficits in executive function (problem-solving).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
InterpretationreasoningIncreased salience network connectivity in agitated Alzheimer's disease patients may reflect compensatory changes in network connectivity that account for reduction of default mode network connectivity.
“The only published study on this reports increased SN connectivity in agitated AD patients, perhaps reflecting compensatory changes in network connectivity that account for reduction of DMN connectivity.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThere is evidence for the efficacy of dopaminergic agents for apathy in Alzheimer's disease.
“there is evidence for the e3cacy of dopaminergic agents for apathy in AD (Rosenberg et al., 2013)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rosenberg et al., 2013 source
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May combine two claims.
Interpretationnone givenCurrent evidence does not clarify the temporal order of neurochemical changes versus circuit disruptions; one may precede the other or they may be simultaneous.
“However, the current evidence does not clarify the temporal order of neurochemical changes vs. circuit disruptions, one may precede the other or they may be simultaneous processes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
Interpretationnone givenWe are only beginning to understand how the associated regions are connected at the white matter level.
“we are only beginning to understand how these are in fact “connected” at the white matter level”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S1 (asserted).
InterpretationreasoningAgitation in Alzheimer's disease may be due to alterations in the balance of the default mode network and salience network.
“Since there are similarities between agitated AD patients and bvFTD in that both may be disinhibited and demonstrate poor social judgment, one might hypothesize that agitation in AD is due to alterations in the balance of DMN and SN.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenThere is insufficient evidence for depression or psychosis to develop cogent hypotheses.
“There is insufficient evidence for depression or psychosis to develop cogent hypotheses.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningDamage to agitation circuits might cause a patient with agnosia to react to a family member as a stranger and become agitated.
“Similarly, damage to agitation circuits might cause a patient with agnosia to react to a family member as a stranger and become agitated.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationCircuits underlying neuropsychiatric disorders give rise to neuropsychiatric symptoms either by intrinsic circuit dysfunction or by loss or aberrant regulation of circuits from ascending monoamine systems.
“We have previously proposed that circuits underlying neuropsychiatric disorders give rise to NPS either by intrinsic circuit dysfunction or by loss or aberrant regulation of circuits from ascending monoamine systems (Lyketsos et al., 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lyketsos et al., 2004 source
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Probably not a substantial claim: may not pass S2 (checkable), S4 (based).
Interpretationnone givenWe have good data to suggest regions and structures that may be associated with a behavior or symptom.
“While we have good data to suggest regions and structures that may be associated with a behavior or symptom”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenDopaminergic neurotransmission is thought to underlie many goal-directed behaviors including addiction.
“Although dopaminergic neurotransmission is thought to underlie many goal-directed behaviors including addiction”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThalamocortical circuits, and most circuits connecting deep brain structures to cortex, are inhibitory.
“thalamocortical circuits (and indeed most circuits connecting deep brain structures to cortex) are inhibitory (Nowrangi et al., 2014)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nowrangi et al., 2014 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningDelusions in Alzheimer's disease are associated with core Alzheimer's disease neurodegenerative processes, especially with deficits in salience and the ability to focus brain resources to cope with emotionally charged states.
“As well, they suggest that delusions are associated with core AD neurodegenerative processes along, especially with deficits in salience and the ability to focus brain resources to cope with emotionally charged states.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationSpecific circuit alterations underlie the link of Alzheimer's disease pathology with neuropsychiatric symptoms, with these associations being particularly compelling for agitation and apathy in specific circuits.
“Our review of the data on the biology of NPS in AD suggests specific circuit alterations underlying the link of AD pathology with NPS, with these associations being particularly compelling for agitation and apathy in specific circuits (Fig. 1 and Fig. 2) given intriguing overlap with relevant brain circuits (Grupe and Nitschke, 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Grupe and Nitschke, 2013 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningIn agitation, the relevant circuits underlie inflated estimations of threat cost or probability, as well as maladaptive control of responses.
“In the case of agitation, these circuits underlie inflated estimations of threat cost or probability, as well as maladaptive control of responses.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningOne cannot map neuropsychiatric symptoms to deficits in single brain regions or to global neurochemical changes in the brain.
“It is similarly evident that one cannot map NPS to deficits in single brain regions or to global neurochemical changes in the brain.”
Quote in the paperSubstantial claimMay combine two claims.
Premisenone givenAgitation in Alzheimer's disease is associated with elevated tau and decreased acetylcholine and serotonin neurotransmission.
“The neurochemical data on agitation in AD suggest it is associated with elevated tau and decreased acetylcholine and serotonin neurotransmission (all associated with the core neurodegenerative processes of AD).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn Alzheimer's disease, default mode network connectivity is decreased and salience network connectivity is increased, while in behavioral variant frontotemporal dementia the opposite is true.
“Zhou et al. (2010) pointed out that in AD, DMN connectivity is decreased and SN is increased, while in bvFTD the opposite is true.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhou et al., 2010 source
Not checked in the free run.
May combine two claims.
InterpretationcitationAgitation in Alzheimer's disease involves miscalculation of the magnitude of potential threats, accompanied by increased threat attention and vigilance, and/or heightened reactivity to threat uncertainty.
“Thus, agitation in AD involves miscalculation of the magnitude of potential threats, accompanied by increased threat attention and vigilance, and/or heightened reactivity to threat uncertainty (Grupe and Nitschke, 2013) (see their fig. 1a, 1b, and 1f).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Grupe and Nitschke, 2013 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationreasoningLack of interest, lack of initiative, and emotional blunting could be construed as manifestations of avoidance, as the patient seeks to avoid anxiety-provoking situations and thoughts.
“Certainly lack of interest, lack of initiative, and emotional blunting could be construed as manifestations of avoidance, as the patient seeks to avoid anxiety-provoking situations and thoughts.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Understanding the etiopathogenesis of neuropsychiatric symptoms in Alzheimer's disease, particularly their links to the Alzheimer's disease brain disease, will help address the paucity of therapeutic options.
“One of the reasons for the relative paucity of therapeutic options is the limited understanding of the etiopathogenesis of NPS in AD, in particular their links to the AD brain disease.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The presence of psychiatric symptoms in patients with Alzheimer's disease is associated with alterations of brain circuitry.
“A number of studies has shown that the presence of psychiatric symptoms in patients with AD is associated with alterations of brain circuitry (37–39).”
From The impact of COVID-19 infection and enforced prolonged social isolation on neuropsychiatric symptoms in older adults with and without dementia: A review (2020) · cites this paper as [39]
The citation lists haven’t been fetched yet
References 102 · Cited by 302
- Authors
- Rosenberg, P. B., Nowrangi, M. A., & Lyketsos, C. G.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Rosenberg, Paul B.
- Venue
- Molecular Aspects of Medicine
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 43-44
- Pages
- 25-37
- ISSN
- 0098-2997 (ISSN-L)
- PMC
- PMC4600424
- OpenAlex
- W638243159
- Semantic Scholar
- 9e1d2830d7995fb37636a6ab706a0ee413534c2b
- Cited by
- 302
- References
- 102
- Citations by year
- 2026: 25 · 2025: 22 · 2024: 32 · 2023: 29 · 2022: 51 · 2021: 38 · 2020: 28 · 2019: 24 · 2018: 19 · 2017: 19 · 2016: 13 · 2015: 2
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Aspects of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG039384, P50AG005146)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- neuropsychiatric symptoms, Alzheimer's disease, agitation, apathy, delusions, depression, brain circuits, artificial neural networks, frontal cortex, anterior cingulate cortex, posterior cingulate cortex, amygdala, hippocampus, emotion regulation, avoidance behavior
- MeSH terms
- Alzheimer Disease, Amygdala, Brain, Delusions, Depression, Gyrus Cinguli, Humans, Neuroimaging
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