Neurobiology of neuropsychiatric symptoms in Alzheimer's disease: A critical review with a focus on neuroimaging

Abstract

The objective of this critical review of the literature was to reveal the neural circuits involved in the occurrence of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) patients through the association of these symptoms with neuroimaging findings. The search for articles was performed on PUBMED from January 2000 to May 2013, using the key words: Dementia AND BPSD; Dementia AND Neuropsychiatric Symptoms; and Dementia AND Psychosis, Delusions, Hallucinations, Agitation, Depression, Anxiety, Apathy, Euphoria, Disinhibition, Irritability, Aberrant Motor Behavior, Sleep or Eating Disorders. Forty-six articles were reviewed and important contributions, especially regarding the psychopathological concepts discussed, were also considered even if not included in this time period. The available evidence suggests the three most relevant neurobiological models for neuropsychiatric symptoms in Alzheimer's disease are the frontal-subcortical circuits, the cortico-cortical networks, and the monoaminergic system. We discussed the association of the individual symptoms or syndromes with these models.

Association of Alzheimer's genetic loci with mild behavioral impairment

“…NME8 has been previously associated with nonneurological related diseases (Liu et al, ), and recently with cognitive decline, elevated CSF tau, and hippocampal atrophy (Liu et al, ). The pathophysiology of apathy in AD is characterized by dysfunctions in the prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, amygdala, and basal ganglia, particularly in regard to cortico‐subcortical circuits involving dopaminergic and cholinergic pathways (Nowrangi, Lyketsos, & Rosenberg, ; Tascone & Bottino, ). As with NME8 , the function of ZCWPW1 is unknown, though the index SNP was shown to have functional evidence as an expression quantitative trait locus for PILRB , which is expressed in microglia and is involved in the regulation of immune response (Karch, Ezerskiy, Bertelsen, & Goate, ).…”

“…As with NME8 , the function of ZCWPW1 is unknown, though the index SNP was shown to have functional evidence as an expression quantitative trait locus for PILRB , which is expressed in microglia and is involved in the regulation of immune response (Karch, Ezerskiy, Bertelsen, & Goate, ). The neurobiological correlates of disinhibition in AD include orbitofrontal–subcortical circuit dysfunction that impairs social cognitive abilities and loss of control over reactions (Tascone & Bottino, ; Wijngaarden et al, ). Because of the scarcity of studies investigating the role of NME8 and ZCWPW1, the possible underlying mechanisms for their associations with the MBI domains are not known.…”

Alzheimer’s Genetic Risk Score linked to Incident Mild Behavioral Impairment

“…The pathophysiology of apathy in AD is characterised by dysfunctions in the prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, amygdala and basal ganglia, particularly in regard to cortico-subcortical circuits involving dopaminergic and cholinergic pathways 51,52 . As with NME8, the function of ZCWPW1 is unknown, though the index SNP was shown to have functional evidence as an expression quantitative trait locus for PILRB, which is expressed in microglia and is involved in the regulation of immune response 53 .…”

“…As with NME8, the function of ZCWPW1 is unknown, though the index SNP was shown to have functional evidence as an expression quantitative trait locus for PILRB, which is expressed in microglia and is involved in the regulation of immune response 53 . The neurobiological correlates of disinhibition in AD include Orbitofrontal-subcortical circuit dysfunction, that impairs social cognitive abilities and loss of control over reactions 52,54 . Due to the scarcity of studies investigating the role of NME8 and ZCWPW1, the possible underlying mechanisms for their associations with the MBI domains are not known.…”

Neuropsychiatric symptom profiles of community‐dwelling persons living with dementia: Factor structures revisited

“…NPS may be the direct result of the degradation in neurocircuitry associated with dementia, [22][23][24] which would warrant consideration of pharmacologic interventions for certain behaviors. 25,26 This neurodegeneration, in turn, impairs various cognitive domains such as executive functioning and memory/new learning and also decreases the ability of the PLWD to interpret environmental stimuli (eg, physical, social, or other), which may increase stress.…”