Neurobiological Correlates of Apathy in Alzheimer's Disease and Mild Cognitive Impairment: A Critical Review

Stella, Florindo; Radanovic, Márcia; Aprahamian, Ivan; Canineu, Paulo Renato; Andrade, Larissa Pires de; Forlenza, Orestes Vicente

doi:10.3233/jad-131385

Cited by 46 publications

(35 citation statements)

References 54 publications

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“…Considering the present results and the above evidence in bvFTD and in AD patients (Stella et al, 2013), it appears that the neural correlates of apathy may be shared across different dementias. Notably, also eating and appetite changes in dementia (i.e.…”

Section: Discussionsupporting

confidence: 72%

“…These structures are involved in motivation and decision-making (Kouneiher et al, 2009; Wallis, 2007) and, together with other frontal and subcortical structures (e.g. ACG, dorsolateral prefrontal cortices, caudate nucleus), were found hypometabolic in apathetic AD patients (Benoit et al, 2004; Stella et al, 2013). Specifically, the work by Benoit et al (2004) showed that the exact component of apathy that correlates with a reduced rCBF in medial frontal and medial orbitofrontal regions is lack of interest (Benoit et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease

Ballarini

Iaccarino

Magnani³

et al. 2016

Human Brain Mapping

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Neuropsychiatric symptoms (NPSs) often occur in early-age-of-onset Alzheimer’s disease (EOAD) and cluster into sub-syndromes (SSy). The aim of this study was to investigate the association between 18F-FDG-PET regional and connectivity-based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective and psychotic SSy). 85% of EOAD showed at least one NPS. Voxel-wise correlations between SSy scores and brain glucose metabolism (assessed with 18F-FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N=51) and Healthy Controls (N=57). The apathetic, hyperactivity and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision-making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease

Ballarini

Iaccarino

Magnani³

et al. 2016

Human Brain Mapping

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“…In addition, the combination treatment activated the anterior cingulate cortex, a region which has been demonstrated to have reduced metabolism in AD patients with apathy—the most common neuropsychiatric symptom and a symptom associated with worse prognosis for cognitive and functional progression (Marshall et al, 2007; Guimaraes et al, 2008; Stanton et al, 2013; Stella et al, 2014). By increasing activity in the entorhinal and anterior cingulate cortices, the combination treatment may enhance function of these brain regions affected during the course of AD pathology.…”

Section: Discussionmentioning

confidence: 99%

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

et al. 2017

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The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.

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“…There are no authoritative estimates available on the prevalence of apathy in general, but it has been estimated that ~10 million people in the US suffer from apathy (Chase, 2011; Clarke et al, 2011; van Dalen et al, 2013). Across various disorders, apathy is regarded as the strongest predictor of poor cognitive, functional, and occupational outcome, reduced medication compliance, increased caregiver burden, diminished quality of life, and general health (Levy et al, 1998; Stuss et al, 2000; van Reekum et al, 2005; Guimaraes et al, 2008; Dujardin et al, 2009; Ishii et al, 2009; Starkstein et al, 2009; Jorge et al, 2010; Benoit and Robert, 2011; Chase, 2011; Clarke et al, 2011; Kostic and Filippi, 2011; Hsieh et al, 2012; Caeiro et al, 2013; Moretti et al, 2013; Santangelo et al, 2013; van Dalen et al, 2013; Stella et al, 2014; Theleritis et al, 2014; Fervaha et al, 2015; McIntosh et al, 2015). …”

Section: What Do We Know About Apathy From Clinical Practice?mentioning

confidence: 99%

Neural Correlates for Apathy: Frontal-Prefrontal and Parietal Cortical- Subcortical Circuits

Moretti

Signori

2016

Front. Aging Neurosci.

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Apathy is an uncertain nosographical entity, which includes reduced motivation, abulia, decreased empathy, and lack of emotional involvement; it is an important and heavy-burden clinical condition which strongly impacts in everyday life events, affects the common daily living abilities, reduced the inner goal directed behavior, and gives the heaviest burden on caregivers. Is a quite common comorbidity of many neurological disease, However, there is no definite consensus on the role of apathy in clinical practice, no definite data on anatomical circuits involved in its development, and no definite instrument to detect it at bedside. As a general observation, the occurrence of apathy is connected to damage of prefrontal cortex (PFC) and basal ganglia; “emotional affective” apathy may be related to the orbitomedial PFC and ventral striatum; “cognitive apathy” may be associated with dysfunction of lateral PFC and dorsal caudate nuclei; deficit of “autoactivation” may be due to bilateral lesions of the internal portion of globus pallidus, bilateral paramedian thalamic lesions, or the dorsomedial portion of PFC. On the other hand, apathy severity has been connected to neurofibrillary tangles density in the anterior cingulate gyrus and to gray matter atrophy in the anterior cingulate (ACC) and in the left medial frontal cortex, confirmed by functional imaging studies. These neural networks are linked to projects, judjing and planning, execution and selection common actions, and through the basolateral amygdala and nucleus accumbens projects to the frontostriatal and to the dorsolateral prefrontal cortex. Therefore, an alteration of these circuitry caused a lack of insight, a reduction of decision-making strategies, and a reduced speedness in action decision, major responsible for apathy. Emergent role concerns also the parietal cortex, with its direct action motivation control. We will discuss the importance of these circuits in different pathologies, degenerative or vascular, acute or chronic.

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Neurobiological Correlates of Apathy in Alzheimer's Disease and Mild Cognitive Impairment: A Critical Review

Abstract: Abnormalities in frontal regions (associated with impairments in planning and decision making) and anterior cingulate (related to emotional blunting and loss of motivation) were the crucial structures associated with apathy in AD and MCI.

Cited by 46 publications

References 54 publications

Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease

Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

Neural Correlates for Apathy: Frontal-Prefrontal and Parietal Cortical- Subcortical Circuits

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