Table 4.
Detailed brain changes correlates of neuropsychiatric symptoms in AD
| NPS items | Neuroimaging markers | Author, year | Subject (Number) | Diagnostic criteria | Scale | Structures associated | References no. |
|---|---|---|---|---|---|---|---|
| Apathy | Atrophy | Apostolova, 2007 | AD (N = 35) | NINCDS-ADRDA | NPI | Bilateral anterior cingulate and left medial frontal cortex | [45] |
| Bruen, 2008 | Mild AD (N = 31) | NINCDS-ADRDA | NPI | Anterior cingulate and frontal cortex bilaterally, the head of the left caudate nucleus and in bilateral putamen | [46] | ||
| Cortical thinning | Donovan, 2014 | HC (N = 229), MCI (N = 395), AD (N = 188) | NINCDS-ADRDA | NPI | Inferior temporal region | [47] | |
| Apostolova, 2007 | AD (N = 35) | NINCDS-ADRDA | NPI | Left cingulate | [45] | ||
| Tunnard, 2011 | AD (N = 111) | NINCDS-ADRDA and DSM- IV criteria | NPI | Left caudal anterior cingulate cortex and left lateral orbitofrontal cortex, as well as left superior and ventrolateral frontal regions | [48] | ||
| FA | Tighe, 2012 | MCI (N = 22), mild AD (N = 23) | NINCDS-ADRDA, CDR | NPI | Anterior cingulum | [49] | |
| Kim, 2011 | Very mild or mild probable AD (N = 51) | NINCDS-ADRDA | NPI | Left anterior cingulum | [50] | ||
| Ota, 2012 | AD (N = 21) | NINCDS-ADRDA | Apathy Scale | Right anterior cingulate, right thalamus, and bilateral parietal regions | [51] | ||
| Aβ | Mori, 2014 | Aβ-positive AD (N = 28) | NINCDS-ADRDA | NPI | Bilateral frontal and right anterior cingulate | [52] | |
| Hypometabolism | Marshall, 2007 | AD (N = 41) | NINCDS-ADRDA | NPI | Bilateral anterior cingulate region extending inferiorly to the medial orbitofrontal region and the bilateral medial thalamus | [53] | |
| Holthoff, 2005 | AD (N = 53) | NINCDS-ADRDA | NPI | Left orbitofrontal regions | [54] | ||
| Neurofibrillary tangle | Marshall, 2006 | AD (N = 29) | CERAD | NPI | Anterior cingulate | [55] | |
| Tekin, 2001 | AD (N = 31) | CERAD | NPI | Left anterior cingulate | [56] | ||
| Depression | Atrophy | Son, 2013 | AD (N = 49) | DSM IV-TR criteria | GDS | Left inferior temporal gyrus | [40] |
| Zahodne, 2013 | MCI (N = 334) | Petersen criteria | NPI | Anterior cingulate cortex | [57] | ||
| Morra, 2009 | AD (N = 100), MCI (N = 200), HC (N = 100) | NINCDS-ADRDA, CDR | GDS | Right hippocampal | [58] | ||
| Cortical thickness | Lebedev, 2014 | Mild AD/LBD (N = 71) | NINCDS-ADRDA | MADRS | Prefrontal and temporal areas | [59] | |
| Zahodne, 2013 | MCI (N = 334) | Petersen criteria | NPI | Entorhinal cortex | [57] | ||
| Lebedeva, 2014 | AD (N = 189) | NINCDS-ADRDA, DSM-IV/ICD-10 | CSDD, GDS | Left parietal and temporal brain regions, including supramarginal, superior and inferior temporal and fusiform gyri, right posterior cingulate and precuneus | [60] | ||
| Gray matter hypodensities | Brommelhoff, 2011 | AD (N = 192) | NINCDS-ADRDA | History of depression | Caudate nucleus and lentiform nucleus | [61] | |
| White matter atrophy | Lee, 2012 | MCI (N = 243) | Petersen | NPI | Frontal, parietal, and temporal | [62] | |
| Aβ | Chung, 2015 | aMCI (N = 78) | Petersen | GDS/NPI | bilateral frontal cortex | [63] | |
| Hypometabolism | Lee, 2017 | MCI (N = 36) | Petersen | HRSD | Right superior frontal gyrus | [64] | |
| Hirono, 1998 | AD (N = 53) | DSM-IV, NINCDS-ADRDA | NPI | Bilateral superior frontal and left anterior cingulate cortices | [65] | ||
| Holthoff, 2005 | AD (N = 53) | NINCDS-ADRDA | NPI | Dorsolateral prefrontal regions. | [54] | ||
| Anxiety | Atrophy | Poulin, 2011 | Very mild and mild AD (N1 = 90; N2 = 174) | NINCDS-ADRDA | NPI | Amygdala | [66] |
| Mah, 2015 | aMCI (N = 376) | Petersen | NPI | Entorhinal cortical | [67] | ||
| Tagai, 2014 | Mild AD (N = 26) | NINCDS-ADRDA | Behave-AD | Right precuneus and inferior parietal lobule | [68] | ||
| Nour, 2020 | AD (N = 35) | NINCDS-ADRDA | NPI | left parahippocampal, posterior cingulate gyrus, left insula and bilateral putamen | [69] | ||
| White matter hyperintensities | Berlow, 2010 | AD (N = 37) | NINCDS-ADRDA | NPI | – | [70] | |
| Bensamoun, 2016 | HC (N = 230), MCI (N = 308), AD (N = 119) | NINCDS-ADRDA | NPI | All diagnostic groups: frontal, cingulate, and global cerebral; MCI subgroup: frontal and global cerebral | [71] | ||
| Hyperperfusion | Tagai, 2014 | Mild AD (N = 26) | NINCDS-ADRDA | Behave-AD | Bilateral anterior cingulate cortices | [68] | |
| Hashimoto, 2006 | AD (N = 41) | NINCDS-ADRDA | NPI | Bilateral entorhinal cortex. Anterior parahippocampal gyrus, left anterior superior temporal gyrus and insula | [72] | ||
| Delusion | Atrophy | Serra, 2010 | AD (N = 27), aMCI (N = 19), HC (N = 23) | NINCDS-ADRDA | NPI | Right hippocampus | [73] |
| Geroldi, 2002 | Mild AD (N = 41) | Standardized clinical, neuropsychological, and instrumental evaluation | NPI | Left frontal and right temporal lobe | [74] | ||
| Geroldi, 2000 | AD (N = 41) | Standardized clinical, neuropsychological, and instrumental evaluation | NPI | Right medial temporal lobe | [75] | ||
| Cortical thickness | Whitehead, 2012 | AD (N = 113) | NINCDS-ADRDA, DSM-IV | NPI | Left medial orbitofrontal and left superior temporal region | [76] | |
| FA | Nakaaki, 2013 | AD (N = 25) | NINCDS-ADRDA | NPI | Left parieto-occipital region, body of the corpus callosum, superior temporal gyrus | [77] | |
| WMH | Anor, 2017 | AD/VaD (N = 180) | NIA-AA | NPI | Right frontal | [78] | |
| White matter changes | Lee, 2006 | AD (N = 55) | NINCDS-ADRDA | BRSD | Bilateral frontal, parieto-occipital and left basal gangli | [79] | |
| Hypermetabolism | Mentis, 1995 | AD (N = 24), HC (N = 17) | NINCDS-ADRDA | Sustained reduplicative delusions of misidentification | Sensory association cortices (superior temporal and inferior parietal) | [80] | |
| Hirono, 1998 | AD (N = 65) | NINCDS-ADRDA, DSM-IV | Behave-AD /NPI | Left inferior temporal gyrus | [81] | ||
| Hypometabolism | Mentis, 1995 | AD (N = 24), HC (N = 17) | NINCDS-ADRDA | Sustained reduplicative delusions of misidentification | Paralimbic (orbitofrontal and cingulate areas bilaterally) and left medial temporal areas | [80] | |
| Sultzer, 2003 | AD (N = 25) | NINCDS-ADRDA, NIA-AA | Neurobehavioral Rating Scale | Prefrontal and anterior cingulate regions | [82] | ||
| Sultzer, 2014 | AD (N = 88) | NINCDS-ADRDA, NIA-AA | NPI | Right lateral frontal cortex, orbitofrontal cortex, and bilateral temporal cortex | [34] | ||
| Hirono, 1998 | AD (N = 65) | NINCDS-ADRDA, DSM-IV | Behave-AD /NPI | Left medial occipital region | [81] | ||
| Mega, 2000 | AD (N = 20) | NINCDS-ADRDA | NPI | Right and left dorsolateral frontal, left anterior cingulate, and left ventral striatal regions along with the left pulvinar and dorsolateral parietal cortex | [83] | ||
| Hallucination | Atrophy | Blanc, 2014 | AD (N = 78) | NINCDS-ADRDA | NPI | Anterior part of the right insula, left superior frontal gyrus and lingual gyri | [84] |
| Holroyd, 2000 | AD (N = 14) | NINCDS-ADRDA | Subjects/caregiver reported | Occipital lobe | [85] | ||
| Cortical thickness | Donovan, 2014 | HC (N = 229), MCI (N = 395), AD (N = 188) | NINCDS-ADRDA | NPI | Supramarginal | [47] | |
| White matter lesions | Lin, 2006 | AD (N = 10) | NINCDS-ADRDA | Subjects/caregiver reported | Occipital lobe | [86] | |
| Hypometabolism | Blanc, 2014 | AD (N = 78) | NINCDS-ADRDA | NPI | Right ventral and dorsolateral prefrontal area | [84] | |
| Hypoperfusion | Kotrla, 1995 | AD (N = 46) | HRSD, DSM-III-R, Behave-AD | HRSD, DSM-III-R, Behave-AD | Parietal lobe | [87] | |
| Hypoperfusion | Mega, 2000 | AD (N = 20) | NINCDS-ADRDA | NPI | Right and left dorsolateral frontal, left anterior cingulate, and left ventral striatal regions along with the left pulvinar and dorsolateral parietal cortex | [83] | |
| Atrophy | Bruen, 2008 | Mild AD (N = 31) | NINCDS-ADRDA | NPI | Left insula, and in anterior cingulate cortex bilaterally | [46] | |
| Trzepacz, 2013 | AD/MCI (N = 462) | NINCDS-ADRDA | NPI | Frontal, insular, amygdala, cingulate, and hippocampal regions | [88] | ||
| Hsu, 2015 | AD (N = 129), MCI (N = 31) | NIA-AA | NPI | Posterior cingulate and parieto-occipital sulcus and sulci of the parietal lobes and precuneus | [89] | ||
| FA | Tighe, 2012 | MCI (N = 22), mild AD (N = 23) | NINCDS-ADRDA, CDR | NPI | Anterior cingulum | [49] | |
| Increased functional connectivity | Balthazar, 2014 | Mild to moderate AD (N = 20) | NINCDS-ADRDA | NPI | Anterior cingulate cortex and right insula areas | [90] | |
| Neurofibrillary tangles | Tekin, 2001 | AD (N = 31) | CERAD | NPI | Left orbitofrontal cortex and left anterior cingulate | [56] | |
| Hypometabolism | Weissberger, 2017 | AD (N = 88) | NINCDS-ADRDA, NIA-AA | NPI | Right temporal, middle, and superior gyri, Right calcarine cortex, Right lingual gyrus, Right fusiform gyrus, Right cuneus, Bilateral cingulate, middle, and posterior | [91] | |
| Irritability | Atrophy | Poulin, 2011 | Very mild and mild AD (N1 = 90; N2 = 174) | NINCDS-ADRDA | NPI | Amygdala | [66] |
| FA | Tighe, 2012 | MCI (N = 22), mild AD (N = 23) | NINCDS-ADRDA, CDR | NPI | Anterior cingulum | [49] | |
| Increased functional connectivity | Balthazar, 2014 | Mild to moderate AD (N = 20) | NINCDS-ADRDA | NPI | Anterior cingulate cortex and right insula areas | [90] | |
| Aβ | Bensamoun, 2016 | HC (N = 230), MCI (N = 308), AD (N = 119) | NINCDS-ADRDA | NPI | All diagnostic groups: frontal, cingulate, parietal and global cerebral; AD:parietal | [71] | |
| Hypometabolism | Weissberger, 2017 | AD (N = 88) | NINCDS-ADRDA, NIA-AA | NPI | Right temporal, middle, and superior gyri, Right insula, Right precentral and postcentral gyri, Right frontal, middle, and inferior | [91] | |
| Aberrant Motor Behavior | Atrophy | Poulin, 2011 | Very mild and mild AD (N1 = 90; N2 = 174) | NINCDS-ADRDA | NPI | Amygdala | [66] |
| Increased functional connectivity | Balthazar, 2014 | Mild to moderate AD (N = 20) | NINCDS-ADRDA | NPI | Anterior cingulate cortex and right insula areas | [90] | |
| Hypometabolism | Meguro, 1997 | Moderately severe AD (N = 10) | NINCDS-ADRDA | Subjects/caregiver reported | Striatum and the frontal and temporal lobes | [92] | |
| Hypermetabolism | Reilly, 2011 | AD (N = 135) | DSM-IV | NPI | Orbitofrontal cortex | [93] | |
| Neurofibrillary tangles | Tekin, 2001 | AD (N = 31) | CERAD | NPI | Left orbitofrontal cortex | [56] | |
| Euphoria | Increased functional connectivity | Balthazar, 2014 | Mild to moderate AD (N = 20) | NINCDS-ADRDA | NPI | Anterior cingulate cortex and right insula areas | [90] |
| Disinhibition | Atrophy | Serra, 2010 | AD (N = 27) | NINCDS-ADRDA | NPI | Bilateral cingulate and right middle frontal gyri | [73] |
| Increased functional connectivity | Balthazar, 2014 | Mild to moderate AD (N = 20) | NINCDS-ADRDA | NPI | Anterior cingulate cortex and right insula areas | [90] | |
| Sleep disturbance | FA | Tighe, 2012 | MCI (N = 22), mild AD (N = 23) | NINCDS-ADRDA, CDR | NPI | Anterior cingulum | [49] |
| Hypometabolism | Liguori, 2017 | AD (N = 18) | NIA-AA | Polysomnography | Hypothalamic | [94] | |
| Hyperperfusion | Ismail, 2009 | AD (N = 55) | NINCDS-ADRDA | NPI, CSDD | Right middle frontal gyrus | [95] | |
| Appetite disturbance | Atrophy | Grundman, 1996 | AD (N = 58), HC (N = 16) | NINCDS-ADRDA | Body mass index | Mesial temporal cortex | [96] |
| Hypometabolism | Hu, 2002 | AD (N = 27) | NINCDS-ADRDA | Body mass index | Anterior cingulate cortex | [97] | |
| Hypoperfusion | Ismail, 2008 | AD (N = 66) | NINCDS-ADRDA | NPI | left anterior cingulate and left orbitofrontal cortices | [98] |
Abbreviations: AD Alzheimer’s disease, aMCI amnestic mild cognitive impairment, LBD Lewy body dementia, VaD vascular dementia, HC healthy controls, NPS neuropsychiatric symptom, WMH white matter hyperintensities, GDS Geriatric Depression Scale, MADRS Montgomery-Asberg Depression Rating Scale, HRSD Hamilton Rating Scale for Depression, Behave-AD Behavioral Pathology in Alzheimer’s Disease Scale, CDR Clinical Dementia Rating, DSM-IV Diagnostic and Statistical Manual of Mental Disorders, forth version, ICD-10 International Statistical Classification of Disease, tenth version, NIA-AA National Institute on Aging-Alzheimer’s Association workgroups, CERAD Consortium to Establish a Registry for AD