Table 3.
Neuroimaging studies of apathy in Alzheimer’s disease (AD).
| Authors & year | Imaging modality | Apathy scale | Study sample | Study findings |
|---|---|---|---|---|
| Craig et al., [96] | 99m Tc-HMPAO SPECT | NPI | Probable AD (n = 31) | Apathy was associated with more severe hypoperfusion in the prefrontal and anterior temporal cortex |
| Ott et al., [97] | 99m Tc-HMPAO SPECT | AES | Possible AD (n = 40) | Lower right temporoparietal perfusion was correlated with apathy |
| Benoit et al., 1999 [98] | 99m Tc-ECD SPECT | NPI | AD (n = 20) | Hypoperfusion of the anterior cingulate cortex (ACC) |
| Benoit et al., 2002 [98] | 99m Tc-ECD SPECT (SPM99) | NPI |
Apathetic AD (n = 15), non-apathetic AD (n = 15), healthy controls-HC (n = 11) |
Decreased perfusion of left ACC, right inferior and medial gyrus frontalis, left orbitofrontal cortex (OFC) and right gyrus lingualis was found in the apathetic subgroup compared with the non-apathetic AD subgroup |
| Benoit et al., [81] | 99m Tc-ECD SPECT | Apathy Inventory | AD (n = 30) | Apathy was associated with lower brain perfusion in bilateral superior OFC, and to a lesser extent in left middle frontal gyrus (BA10). Lack of initiative score was correlated with hypoperfusion in right ACC. Lack of interest score correlated with hypoperfusion in right middle OFC. Emotional blunting score correlated with hypoperfusion in left superior dorsolateral prefrontal cortex (dlPFC) |
| Tanaka et al., [99] | SPECT | NPI |
Mild to moderate AD (n = 70) treated with donepezil for 12 weeks |
Donepezil responder (n = 21), non-responder (n = 42), worsened (n = 7). Apathy and depression in AD patients involved distinct functional circuits. Dysphoria, anxiety and apathy significantly improved among the responder group. CBF in the premotor and parietotemporal cortices was higher in the responder group than in the worsened group. |
| Robert et al., [82] | SPECT | Apathy Inventory | AD (n = 30) | Lack of initiative and lack of interest were associated with hypoperfusion in right ACC |
| Lanctôt et al., [100] | SPECT and sMRI | NPI |
Apathetic AD (n = 23) non- apathetic AD (n = 23) healthy controls (n = 23) |
The AD patients with lack of initiative and interest showed a significantly lower perfusion in the ACC than the AD patients without lack of initiative and interest. |
| Kang et al., [101] | 99m Tc-HMPAO SPECT | NPI | AD (n = 81) | Apathetic non-depressed patients had lower regional perfusion in the right amygdala, temporal, posterior cingulate (PCC), right superior frontal, postcentral, and left superior temporal gyri than non-apathetic patients. Apathy and depression in AD patients involved distinct functional circuits. |
| Oka et al., [102] | 99m Tc-HMPAO SPECT | NPI-Q and Dysexecutive Questionnaire score (DEX) | AD (n = 27) | Lower baseline regional cerebral blood flow in several frontal areas, including the dlPFC and ventrolateral prefrontal cortex (vlPFC), the ACC, and the OFC predicted greater reductions in the score for apathy and DEX after patients switched from donepezil to galantamine therapy |
| Mega et al., [103] | [18F]FDG-PET | NPI |
Mild to moderate AD (n = 19) galantamine treatment |
Right ACC glucose metabolism increase significantly correlated with improvement in depression, and right ventral putamen metabolic increase correlated with improvement in apathy |
| Holthoff et al., [104] | [18F]FDG-PET | NPI |
AD with apathy (n = 17), AD without apathy (n = 36) |
Hypometabolism of left OFC in the apathetic AD group relative to the non-apathetic group |
| Marshall et al., [105] | [18F]FDG-PET | Scale for the Assessment of Negative Symptoms in AD (SANS-AD) |
AD with apathy (n = 14), AD without apathy n = 27) |
Reduced glucose metabolism in ACC, medial orbitofrontal (mPFC) region and bilateral medial thalamus were found in the apathetic group |
| Schroeter et al., [106] | [18F]FDG-PET | NPI | 54 subjects mainly with early AD, frontotemporal lobar degeneration, and subjective cognitive impairment | Apathy was associated with hypometabolism in the ventral tegmental area (VTA), a component of the motivational dopaminergic network |
| Gatchel, et al. [107] |
[18F]FDG-PET ROI analysis |
NPI-Q |
CN (n = 104) amnestic MCI (n = 203) mild AD (n = 95) ADNI data |
Cross-sectionally, the PCC hypometabolism was correlated with higher apathy scores. In longitudinal analysis, baseline PCC hypometabolism was associated with higher apathy over time and baseline supramarginal gyrus hypometabolism was positively associated with rate of change in apathy over time |
| Delrieu et al. [108] |
MRI (volume) [18F]FDG-PET |
NPI |
MCI with apathy (n = 11), MCI without apathy (n = 54) |
Decreased metabolism of PCC |
| Ballarini et al. [109] |
[18F]FDG-PET Voxel-wise interregional correlation analysis |
Neuropsychiatric symptoms (NPSs) sub-syndromes (SSy) |
early-age-of-onset AD (n = 51), among which 27 had NPSs data, HC (n = 57) |
The apathetic subsydrome score was negatively correlated with metabolism in the bilateral OFC and dlPFC |
| Marshall et al. [78] |
PIB-PET (amyloid) FDG-PET (glucose uptake) ACC, OFC, precuneus, SMA |
AES | MCI (N = 24) | No association between apathy and regional FDG metabolism, but a significant association between increased apathy and greater cortical PiB retention independent of age |
| Mori et al. [77] | PIB PET (amyloid) ROI analysis | NPI |
AD with PIB + (n = 28) |
Apathy severity was associated with greater PIB retention in bilateral frontal and right ACC. Presence of apathy was associated with greater PIB retention in bilateral frontal cortex |
| Kitamura et al. [79] |
(11)C-PBB3-PET for tau (11)C-PIB-PET for Aβ sMRI dMRI |
Apathy Scale (AS) |
AD with high AS (n = 10) AD with low AS (n = 7) |
Elevated (11)C-PBB3 SUVR in OFC, decreased OFC thickness and decreased FA in the uncinate fasciculus (UNC) correlated with AS. Path analysis indicated that increased (11)C-PBB3 SUVR in OFC affects apathy directly and through reduction of OFC thickness and subsequent decrease in fractional anisotropy of UNC. |
| Johansson et al. [110] |
(18)F-flutemetamol-PET sMRI, FreeSurfer T2 FLAIR for white matter lesions (WML), LST toolbox |
AES |
CN (n = 104), MCI (n = 53) followed for up to 4 years |
Apathy and anxiety were shown related to Aβ deposition and predicted cognitive decline. Apathy level, but not anxiety, was associated with atrophy in the ACC, PCC, lateral temporal, and parietal cortex, as well as white matter lesion volume |
| Sun et al. [111] |
Aβ PET, ROI - medial orbitofrontal cortex (mOFC) and the pars orbitalis cortex (POFC). |
NPI | non-demented apathy(+) n = 114, among which 78 with Aβ PET, non-demented apathy (-) n = 943, among which 569 with Aβ PET, 5–6 year follow-up (ADNI data) | Individuals with apathy, higher CSF Aβ42 level, or frontal lobe Aβ deposition had an increased risk of cognitive decline compared with those without apathy. Subjects with higher frontal Aβ deposition had a higher risk for apathy conversion to cognitive decline |
| Lavretsky et al., [112] | sMRI | Psychiatric Evaluation section of the Minimum Uniform Dataset (MUDS) of the California Alzheimer’s Disease Centers Program | 270 community-dwelling elderly cognitively intact (38%), cognitively impaired (27%), demented (35%) | Apathy was associated with higher total volume of lacunes in the white matter |
| Bruen et al., [113] | sMRI (voxel-based morphometry,VBM) | NPI | Mild AD (n = 31) | Apathy was associated with gray matter density loss in the ACC and frontal cortex bilaterally, the head of the left caudate nucleus, and bilateral putamen |
| Tunnard et al., [114] | sMRI | NPI | Mild to moderate AD (n = 111) | Apathetic patients had significantly greater cortical thinning in left caudal ACC, left lateral OFC, and left superior and vlPFC regions compared with those without apathy |
| Kim et al., [115] |
sMRI dMRI |
NPI | Very mild or mild probable AD (n = 51) | Apathy group showed significantly lower fractional anisotropy (FA) values than apathy-free group in the left anterior cingulum (A-C). Left A-C FA values were negatively correlated with apathy severity |
| Ota et al., [116] |
sMRI dMRI |
Apathy Scale | Probable AD (n = 21) | Apathy was associated with lower white matter integrity index (FA) in the ACC and medial thalamus. |
| Tighe et al., [117] |
sMRI dMRI |
NPI |
MCI (n = 22), AD (n = 23) |
Participants with the lowest anterior cingulum (A-C) fractional anisotropy tertile were more likely to exhibit irritability, agitation, dysphoria, apathy, and nighttime behavioral disturbances compared to those in the highest tertile. However, only irritability remained significant after adjusting for MMSE. |
| Stanton et al. [118] | sMRI, VBM | Apathy defined by Robert criteria |
AD (n = 17), progressive supranuclear palsy (n = 17) |
Apathy was associated with atrophy of the vmPFC, OFC, and left insula in both AD and PSP. Reduced initiative associated with atrophy of the ACC and vlPFC. Emotional blunting was assocated with atrophy of the left insula. |
| Donovan et al. [119] |
sMRI, (cortical thickness) CSF Aβ1–42 |
NPI-Q change over time |
CN (n = 229) MCI (n = 395) AD (n = 88) |
Reduced baseline inferior temporal cortical thickness was predictive of increasing apathy over time, and reduced supramarginal cortical thickness was predictive of increasing hallucinations over time |
| Moon et al. [120] | sMRI | NPI-Apathy | AD (N = 40) | Apathy and irritability associated with decreased volume of bilateral ACC and right posterior insula |
| Guercio et al. [121] | sMRI (cortical thickness) | AES-C |
MCI (n = 47), HC (n = 19) |
Lower inferior temporal cortical thickness was predictive of greater apathy. Greater ACC cortical thickness was also predictive of greater apathy |
| Zahodne, et al. [89] | sMRI | NPI | MCI (n = 334) | Depression was associated with reduced cortical thickness in the entorhinal cortex at baseline and accelerated atrophy in the ACC. Apathy did not correlate with atrophy |
| Huey et al. [122] |
sMRI FreeSurfer whole-brain ROI volumes VBM |
NPI | mild AD (n = 57) | Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC); PCC and adjacent lateral cortex; and the bank of the superior temporal sulcus. |
| Kumfor et al. [123] | sMRI | NPI-Q | AD (n = 53) | Affective apathy was associated with the vPFC, behavioral apathy with the basal ganglia, and cognitive apathy with the dmPFC. Finally, affective and behavioral apathy significantly predicted carer burden |
| Garcia-Alberca, et al. [124] |
sMRI & FLAIR Scheltens visual rating scale |
NPI | Probable AD (n = 46) | Increased total medial temporal atrophy (MTA) was significantly associated with apathy. WMH measures did not significantly predict any BPSD item |
| Wei et al. [85] | sMRI | Dimensional Apathy Scale (DAS) |
AD-early (n = 10), AD-late (n = 10), Behavioral variant-FTD (bvFTD)-early (n = 22), bvFTD-late (n = 22) HC (n = 28) |
In the early stage of the disease (< 5 years since onset), emotional apathy was greater in bvFTD than AD. In contrast, in the late stage (> 5 years since onset), executive apathy was greater in AD than bvFTD, although apathy was elevated across all dimensions compared to controls. |
| Chan et al., [125] |
sMRI FreeSurfer ROI analysis |
NPI |
Cognitive impairment (CI) With Apathy (n = 96), CI Without Apathy (n = 311) |
Cortical GM was thinner in the right mOFC and left rACC and thicker in the left MTC in CI participants with apathy relative to CI participants without apathy. |
| Nour et al. [126] } |
sMRI FreeSurfer ROI analysis (ADNI data) |
NPI |
HC (n = 35), AD with anxiety (n = 27), AD with depression (n = 19), AD with apathy (n = 24) |
The left insula had a strong negative association with Clinical Dementia Rate Sum of Boxes and AD Assessment Scale-cognitive subscale-13 items in anxiety and apathy groups. The difference in GM density in the left insula and hippocampus plays a crucial role in depression, anxiety, and apathy |
| Chaudhary, et al. [127] | sMRI |
Meta-analysis control (n = 59), AD (n = 167), Validation MCI/AD (n = 19), HC (n = 25) |
Label-based review showed atrophy in the ACC, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) in AD patients with apathy. Right putamen and MTG showed gray matter volume was in negative correlation with AES, behavioral, and emotional scores, and right IFG with emotional score. Putamen, MTG and IFG atrophy in AD-associated apathy, potentially independent of CI and depression | |
| Johansson, et al. [128] |
sMRI, T2FLAIR CSF amyloid-beta [Aβ]42/Aβ40 ratio, plasma phosphorylated tau |
AES | Cognitively unimpaired older adults (n = 356) followed up for 8 years | Aβ pathology at baseline was associated with increasing levels of apathy longitudinally. More rapid decline of cognition over time was related to increasing levels of apathy |
| Moon et al. [93] |
FLAIR for WMH Hypertension and cardiovascular events, Diabetes mellitus and hyperlipidemia |
NPI | AD (n = 162) | Hypertension was correlated with the severity of apathy. The remaining vascular factors were not significant. Presence of hypertension and asymptomatic stroke are related with the severity of apathy and depression in Alzheimer’s dementia. |
| Sarabia-Cobo et al. [94] | WMH |
AD (n = 109 MCI (n = 59) |
The older group with AD had a higher prevalence of leukoaraiosis and apathy, with significant differences compared to the MCI group | |
| Torso et al. [129] |
sMRI FLAIR for WML voxel-lesion-symptom mapping (VLSM) |
NPI |
Amnestic MCI (n = 31, 32% at 2-year follow-up, HC (n = 29) |
VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD. |
| Misquitta, et al. [92] |
sMRI FLAIR for WMH |
NPS |
AD (n = 121), MCI (n = 315), HC (n = 225) |
The focal grey matter atrophy and WMH volume both contributed significantly to NPS subsyndromes in MCI and AD subjects, and WMH burden played a greater role. |
| Hahn, et al. [130] | sMRI, TBSS | NPI and IA |
Apathetic AD (n = 30), Non-apathetic AD (n = 30) |
The apathy group had significantly reduced FA values in the genu of the corpus callosum compared to the non-apathy group. The severity of apathy was negatively correlated with FA values of the left anterior and posterior cingulum, right superior longitudinal fasciculus, splenium, body and genu of the corpus callosum and bilateral uncinate fasciculus in the apathy group |
| Tokuchi, et al. [131] |
sMRI FLAIR for WML |
NPI |
subcortical ischemic vascular disease (SIVD, n = 24) AD (n = 32) |
MD value within the right superior longitudinal fasciculus and CDR predicted the apathy domain. Distinct patterns of regression models between SIVD and AD including the left superior longitudinal fasciculus to the hyperactivity domain, the left uncinate fasciculus/forceps major to the psychosis domain, and the right superior longitudinal fasciculus to the apathy domain. |
| Setiadi, et al. [132] | dMRI (DTI) | AES-C |
aMCI (n = 29), HC (n = 20) |
In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus |
| Balthazar, et al. [133] |
rsfMRI networks: default-mode (DMN) salience (SN) frontoparietal control (FPCN), attention (AN) |
NPI |
mild to moderate AD (n = 20), HC (n = 17) |
There was a significant association between greater affective factor symptoms and reduced FPCN connectivity. There was no association between the hyperactivity factor and any of the networks. There was an association between greater apathy and reduced FPCN connectivity |
| Jones, et al. [134]} |
rsfMRI networks: default-mode (DMN) salience (SN) frontoparietal control (FPCN), attention (AN) |
NPI |
Apathetic AD (n = 35), non-apathetic AD (n = 35) |
Apathetic patients had reduced connectivity between the left insula and right superior parietal cortex. Apathetic patients also had increased connectivity between the right dlPFC seed and the right superior parietal cortex. |
| Tumati, et al. [135] |
rsfMRI functional connectome graph theory |
NPS-A factor analysis on NPS: Affective factor Hyperactivity factor |
Apathy AD (n = 21), non-apathy non-NPS AD (n = 28) non-apathy with other NPS AD (n = 38) |
Apathy was associated with increased participation coefficient in the frontoparietal and cingulo-opercular template-based networks. AD patients showed higher modularity compared to controls at the whole brain level and higher participation coefficient in the ventral attention network. Loss of segregation in the frontoparietal and cingulo-opercular network, which are involved in the control of goal-directed behavior, was associated with apathy in MCI/AD |
| Amanzio, et al., [136] |
tfMRI go/no-go task |
Awareness of Deficit Questionnaire-Dementia scale. |
Unaware AD (n = 14), Aware AD (n = 15) |
Unaware patients showed reduced activation in the right post-central gyrus, the associative cortical areas such as the right parieto-temporal-occipital junction and the left temporal gyrus, the striatum, and the cerebellum. |
| Aguera-Ortiz, et al. [137] | sMRI,dMRI, T2 FLAIR | Apathy in Dementia-Nursing Home Version Scale | Moderate to severe nursing home AD (n = 37) | Bilateral damage to the corpus callosum and internal capsule was associated with apathy severity. A smaller and more anteriorly located region of the right internal capsule and corpus callosum was associated with higher emotional blunting |
| Raimo, et al. [138] |
meta-analysis PET, SPECT, MRI |
Apathy |
PD 15 studies; AD 15 studies; FDG-PET 14 studies; FTD 13 studies; [11c]PET 2 studies, SPECT 6 studies. fMRI 4 studies |
Overall analysis showed that apathy is associated with hypometabolism and a decreased gray matter volume in the left IFG. an altered brain perfusion and decreased gray matter volume in ACC (BA 24, 32) in AD, decreased gray matter volume in IFG (BA 44, 45) and parietal cortex (BA 40) in FTD patients. |
| Alexopoulos, et. al, [88] |
fMRI ROI-to-ROI FC Nacc and ACC as ROIs |
AES |
HC (n = 10), LLD with apathy (n = 7), LLD without apathy (n = 9) |
Apathetic depressed patients had lower FC of the NAcc with emotion/reward related regions (amygdala, caudate, putamen, globus pallidus) and thalamus, lower FC of dACC with dorsal executive related regions (the superior, middle, and inferior frontal gyruses, right superior parietal and VLPFC), increased FC of the NAcc with dorsomedial PFC (dACC and dmPFC), and higher FC within salience network (dACC-insula) and FC of the dACC with OFC and dlPFC. |
| Yuen, et al., [139] |
rsfMRI ROI-to-voxel FC right anterior insula, rAI as ROIs |
AES |
HC (n = 10), LLD with apathy (n = 7) LLD without apathy (n = 9) |
LLD with apathy had lower FC within salience network (rAI-dACC) and higher rAI-dlPFC and rAI-PCC FC. |
| Oberlin, et al., [140] |
rsfMRI, dMRI ROI-to-Voxel functional connectivity and structrual connectivity |
AES |
LLD with apathy (n = 20) LLD without apathy (n = 20) Among the 40 LLD, 12-week nonrandomized single-group trial of escitalopram, 27 remitted |
Relative to nonapathetic depression, those depression with apathy had lower FC of SN seeds with the dlPFC, premotor cortex, mid CC, and paracentral lobule and greater FC of SN with the lateral temporal cortex and temporal pole. Compared with depression without apathy, those with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus. |
| Onoda, et al., [90] |
rsfMRI, graph theory |
Apathy Scale (AS) Self-rating Depression Scale (SDS) |
middle-aged and older adults (n = 392). mild depression (n = 79) apathy (n = 66) both depression & apathy (n = 33) |
ACC showed lower nodal efficiency, local efficiency, and betweenness centrality in apathy, whereas in depression, it showed higher nodal efficiency and betweenness centrality. The ACC constitutes “salience network (SN), which detects salient experiences. These results indicate that apathy is characterized by decreased salience-related processing in ACC, whereas depression is characterized by increased salience-related processing. |
ADNI Alzheimer’s Disease Neuroimaging Initiative, AES Apathy Evaluation Scale, CBF cerebral blood flow, CN cognitively normal, FDG-PET fluorodeoxyglucose-positron emission tomography, HC healthy control, MCI mild cognitive impairment, NPI Neuropsychiatric Inventory, NPS neuropsychiatric symptoms, PIB Pittsburgh compound B, rsfMRI resting-state functional MRI, SPECT single photon emission computed tomography.