Reference | Treatment | Design | Sample | fMRI protocol/scan timing | Outcome measures | Clinical findings | Direction fMRI changes | Brain areas involved | Clinical-fMRI relationship |
---|---|---|---|---|---|---|---|---|---|
Bakker et al., 2015 [40] | Levetiracetam (different doses: 62.5 mg twice/day, 125 mg twice/day, and 250 mg twice/day) and placebo | RCT double-blind for patients and single-blind for HC | 17 HC 54 MCI | Three-choice recognition memory task Pre-/post-treatment | Task-related medial temporal, temporal-polar, and hippocampal functional activity changes; performance improvement at fMRI task and cognitive assessment | Improvement on recognition memory task in the group on low-dose treatment. No changes at the BSRT, Verbal Pair Associate test, or BVRT | Decreased | Post-treatment vs placebo: L CA3 and DG of hippocampus | Decreased activity; higher memory performance during task |
Increased | Post-treatment vs placebo:L entorhinal cortex | ||||||||
Bakker et al., 2012 [41] | Levetiracetam (125 mg twice/day) and placebo | RCT double-blind for patients and single-blind for HC | 17 HC 17 MCI | Three-choice recognition memory task Pre-/post-treatment | Task-related hippocampal functional activity changes; performance improvement at fMRI task and cognitive assessment | Improvement on recognition memory task. No changes at the BSRT, Verbal Pair Associate test, and BVRT | Decreased | Post-treatment vs placebo: L CA3 and DG of hippocampus | Decreased activity; higher memory performance during task |
Bentley et al., 2008 [26] | Physostigmine (infusion at a rate of 1 mg/1 h) and placebo (an equivalent volume of saline), in both groups 25 min prior to scan | NRCT double-blind | 17 HC 16 mild AD | Visuo-attentional task Post-treatment | Task-related parietal functional activity changes; performance improvement at fMRI task | Improvement on RT for the ‘deeper’ task in AD | Increased | Group X time, treated vs placebo: R precuneus and posterior parahippocampal cortex; R parietal and PFC | – |
Decreased | Group X time, treated vs placebo: R fusiform gyrus | ||||||||
Bentley et al., 2009 [27] | Physostigmine (infusion at a rate of 1 mg/1 h) and placebo (an equivalent volume of saline), in both groups 25 min prior to scan | NRCT double-blind | 18 HC 13 mild AD | Face-encoding task Post-treatment | Task-related fusiform functional activity changes and their relationship with performance improvement at fMRI task | Task-independent (‘shallow’ vs ‘deeper’) improvement in confident memory | Increased | Group X time, treated vs placebo: Bilateral fusiform cortex | Increased activity; higher face recognition post-scanning |
Blautzik et al., 2016 [55] | Galantamine (6-month treatment: 8 mg/day for the first month; 16 mg/day for the second month; 24 mg/day for the other months) or placebo, followed by 6 months galantamine (24 mg/day) – open label period | RCT double-blind and open-label | 11 HC 13 mild-moderate AD | RS fMRI At baseline At 6 months At 12 months | DMN functional connectivity changes; performance improvement at cognitive assessment | No changes at the CEREAD | Increased | Post-treatment vs HC (12-month follow-up):Posterior DMN (PCC, precuneus, L > R); Post-treatment vs placebo (12-month follow-up):Hippocampal sub-component (anterior division of hippocampus, R > L) | – |
Bokde et al., 2016 [47] | Rivastigmine (3-month treatment: 3 mg/day for the first month; 6 mg/day for the second month; 9 mg/day for the third month) or placebo, followed by 9 months rivastigmine (9 mg/day) – open label period | RCT double-blind and open-label | 12 MCI | Face- and location-matching task At baseline At 3 months At 6 months | Task-related whole-brain functional activity changes and performance improvement at cognitive assessment | After 3 and 6 months: lower performances at the verbal fluency; stable performances at the CERAD and at the task | Increased | Pre-/post-treatment (3-month follow-up): Face-matching task: bilateral lingual and fusiform gyrus, L angular gyrus and cerebellum. Location matching task: L inferior temporal gyrus, R precuneus, R angular and inferior frontal gyri | – |
Pre-/post-treatment (6-month follow-up): Location matching task: R inferior parietal and supramarginal gyrus, L precuneus and paracentral lobule, L medial frontal gyrus | |||||||||
Bokde et al., 2009 [32] | Galantamine (3-month treatment: 8 mg/day for the first month; 16 mg/day for the second month; 24 mg/day for the last month) | Case series | 5 mild AD | Face- and location-matching task Pre-/post-treatment | Task-related ventral and dorsal visual pathway changes; performance improvement at fMRI task and cognitive assessment | No changes at the task or at the CEREAD | Decreased | Pre-/post-treatment:Location-matching task: bilateral dorsal pathway (from occipital to parietal and frontal cortices) | – |
Dhanjal et al., 2013 [29] | Donepezil (6-week treatment: 5 mg/day for the first 2 weeks; 10 mg until the end of the study) | Case series | 9 mild AD | Auditory sentence encoding and retrieval with auditory working memory suppressors Pre-/post-treatment | Task-related primary auditory, ventro-lateral temporal, pars triangularis and angular gyri functional activity changes; performance improvement at fMRI task | Increased percentage of retrieved trials during task | Increased | Pre-/post-treatment: L anterior ventral temporal cortex and pars triangularis | – |
Dhanjal et al., 2014 [30] | Donepezil (6-week treatment: 5 mg/day for the first 2 weeks; 10 mg until the end of the study) | Cohort study | 18 HC 18 mild AD | Auditory sentence encoding and retrieval with auditory working memory suppressors Pre-/post-treatment | Task-related functional activity changes within the executive and salience networks; performance improvement at fMRI task | Increased percentage of retrieved trials during task | Increased | Pre-/post-treatment: Fronto-parietal executive network: L lateral posterior parietal cortex and lateral frontal cortex. Higher-order cortex: L parahippocampal gyrus and anterior ventral temporal cortex | – |
Goekoop et al., 2004 [39] | Galantamine (oral intake, single dose: 8 mg; and after prolonged exposure: 4 mg day 1, 8 mg next 4 days, 4 mg on day 6). Washout period: 2 days | Cross-over | 28 MCI | Episodic face-encoding and N-letter back task Pre-/post-treatment | Task-related whole-brain functional activity changes | N-letter back: task accuracy increased and latency decreased, mainly after single dose intake | Increased | Pre-/post-treatment (prolonged exposure): Face encoding: L middle frontal and occipital cortices, L posterior hippocampus and R anterior cingulate cortex. N-letter back: R precuneus and middle frontal cortex | – |
Goekoop et al., 2006 [31] | Galantamine (acute (8 mg) and prolonged 5 days exposure (4 mg the first day, 8 mg the following 4 days, 4 mg the last day)) | Cross-over | 18 mild AD 28 MCI | Face-recognition task Pre-/post-treatment | Task-related whole-brain functional activity changes | No changes at the task | Increased | Pre-/post-treatment (acute exposure): MCI: L PCC, anterior and temporal lobe, L superior parietal, R frontal lobe and cerebellum. AD: vermis of cerebellum, R inferior temporal and parahippocampal gyri | – |
Decreased | Pre-/post-treatment (prolonged exposure): MCI: bilateral superior frontal cortices, L PCC, R middle frontal gyrus. AD: R parahippocampal cortex | ||||||||
Goveas et al., 2011 [50] | Donepezil (3-month treatment: 5 mg/day for 4 weeks; 10 mg/day until the end of the study) | Cohort study | 14 HC 18 mild AD | RS fMRI, seed-based (hippocampus) connectivityPre-/post-treatment | Hippocampal functional connectivity changes; performance improvement at cognitive assessment | Improvement on ADAS-cog but not on MMSE | Increased | Pre-/post-treatment: Positively correlated hippocampal functional connectivity network: L middle frontal and precentral gyri, L parahippocampus, insula and thalamus, R PCC | Increased hippocampal connectivity strength in the L dorsolateral PFC and middle frontal gyrus; improvement on ADAS-cog |
Decreased | Pre-/post-treatment: Negatively correlated hippocampal functional connectivity network: L inferior parietal cortex/supramarginal gyrus, L posterior middle temporal gyrus, and R dorsolateral PFC | ||||||||
Griffanti et al., 2016 [52] | Donepezil (12-week treatment: 5 mg/day for the first 4 weeks, followed by 10 mg/day until the end of the study) | Case series | 18 mild-moderate AD | RS fMRIPre-/post-treatment | Relationship between whole-brain functional connectivity changes and performance improvement at cognitive assessment | Greater improvement on MMSE and MoCA in responders compared to nonresponders | Increased | Pre-/post-treatment: Orbitofrontal network: precuneus, PCC and R dorsolateral frontal cortex (responders > nonresponders) | Increased connectivity of anterior and posterior cingulate cortices, precuneus, and R dorsolateral frontal regions within the orbitofrontal network; improvement on MoCA |
Grön et al., 2006 [38] | Galantamine (4 mg twice a day for 7 days) | Case series | 10 MCI | Spatial navigation taskPre-/post-treatment | Task-related hippocampal functional activity changes and performance improvement at cognitive assessment | Improvement on verbal episodic memory but not at the task | Increased | Pre-/post-treatment: R middle occipital and temporal gyri, R PCC, R hippocampus and parahippocampal gyrus; L anterior hippocampus | – |
Haller et al., 2014 [45] | Caffeine (one capsule containing caffeine 200 mg or placebo) 30 min before testing | NRCT double-blind | 15 HC 13 MCI | 2-back (vs 0-back) working memory taskPre-/post-treatment | Task-related whole-brain functional activity changes | No effect on task RT neither on accuracy | Increased | Post-treatment vs placebo: Task-related: bilateral striatum, temporal and parietal cortices. TICA: L working memory network including PFC, supplementary motor area, ventral premotor and parietal cortices | – |
Kircher et al., 2005 [28] | Donepezil (10-week treatment: 5 mg/day for the first 4 weeks; 10 mg/day until the end of the study) | Cohort study | 10 HC 10 mild-moderate AD | Face memory encoding taskPre-/post-treatment | Task-related fusiform gyrus functional activity | Improvement on ADAS-cog total score and on the memory subscale. No changes at the task | Increased | Pre-/post-treatment/Post-treatment vs HC: R fusiform gyrus | – |
Li et al., 2012 [51] | Donepezil (12-week treatment: 5 mg/day for the first 4 weeks; 10 mg/day until the end of the study) | Case series | 12 mild AD | RS fMRI, seed based (MCC and PCC) connectivityPre-/post-treatment | MCC and PCC functional connectivity changes; cerebral blood flow changes; performance improvement at cognitive assessment | Improvement on ADAS-cog but not on MMSE, NPI, or IADL | Increased | Pre-/post-treatment: Middle cingulate and PCC network connectivity | Increased connectivity between the middle cingulate cortex and the ventral anterior cingulate cortex and PFC; and between the PCC and the ventral anterior cingulate cortex-changes in ADAS-cog |
Lorenzi et al., 2011 [56] | Memantine (6-month treatment: 5 mg/day, increasing by 5 mg/day to a final dose of 20 mg/day) or placebo | RCT double-blind | 15 moderate AD | RS fMRI Pre-/post-treatment | DMN functional connectivity changes; performance improvement at cognitive assessment | No changes at the cognitive assessment | Increased | Pre-/post-treatment/Group X time, treated vs placebo: R precuneus and calcarine gyrus within DMN | – |
McGeown et al., 2010 [36] | Donepezil (20-week treatment: 10 mg/day) | Cohort study | 9 HC 12 mild AD | Semantic association and N-back (1-back) task Pre-/post-treatment | Task-related whole-brain functional activity changes; performance improvement at fMRI task | No changes at the cognitive assessment (including ADAS-cog, NPI and ADL) or at the task | Decreased | Pre-/post-treatment: Semantic association: L superior parietal, middle temporal, medial and inferior frontal gyrus, and R superior temporal gyrus. Working memory: L caudate, L middle and superior temporal gyri, and R inferior frontal gyrus. Post-treatment vs HC: Semantic association: bilateral middle frontal gyrus, R superior occipital, cuneus and anterior cingulate cortex. Working memory: L thalamus, L parahippocampal gyrus, R inferior frontal gyrus | Increased activity in non-task relevant regions (such as bilateral inferior parietal lobe, PCC and precuneus); higher accuracy at the semantic association task |
McGeown et al., 2008 [34] | Rivastigmine (20-week treatment: 6 mg twice/day) | Cohort study | 9 HC 11 mild AD | Semantic association and N-back (1-back) task Pre-/post-treatment | Task-related whole-brain functional activity changes; performance improvement at cognitive assessment | Improvement on ADAS-cog. No further changes at the cognitive assessment or at the task | Increased | Pre-/post-treatment: Semantic association: bilateral middle frontal and paracentral gyri, parahippocampal and fusiform gyri. Working memory: R superior, middle, medial and inferior frontal gyrus, and R precentral gyrus. Post-treatment vs HC: Semantic association: R inferior frontal and L anterior cingulate cortex. Working memory: R middle frontal, postcentral and supramarginal gyri | – |
Decreased | Pre-/post-treatment: Working memory: L middle frontal, precentral and cingulate gyrus, L insula and thalamus. Post-treatment vs HC: Working memory: L PCC and angular gyrus | ||||||||
Miettinen et al., 2011 [24] | A single oral dose of rivastigmine (3 mg, acute); and 1.5 mg of rivastigmine twice a day for 4 weeks (chronic); a single oral dose of placebo | NRCT double-blind | 20 mild AD | Face recognition memory task Post-treatment | Task-related whole-brain functional activity changes and their relationship with baseline cognitive assessment | No changes at the task | Increased | Post-treatment vs placebo (acute): bilateral PFC, R middle and superior temporal gyrus. Post-treatment vs placebo (chronic): bilateral PFC, L middle temporal and anterior cingulate cortices, and L parietal gyrus | Increased PFC activity after chronic treatment; poorer MMSE at baseline |
Pa et al., 2013 [42] | Donepezil (3-month treatment: 5 mg/day for 1 month and 10 mg/day for 2 months) or placebo | RCT double-blind | 27 MCI | Face recognition task Pre-/post-treatment | Task-related prefrontal, parietal and hippocampal functional activity changes; performance improvement at cognitive assessment | Improvement on task RT and accuracy. No changes at the cognitive assessment | Increased | Group X time, treated vs placebo: L fusiform face area and its connectivity with R hippocampus and inferior frontal junction | Increased connectivity between L fusiform face and R hippocampus; reduced RT for face recognition in treated patients |
Petrella et al., 2009 [44] | Donepezil (12- or 24- week treatment: 5 mg/day for 42 days, followed by 10 mg/day until the end of the study) | RCT double-blind | 13 MCI | Novel face visual memory task Pre-/post-treatment | Task-related whole-brain functional activity changes; performance improvement at cognitive assessment | No improvement at the cognitive assessment or at the task | Increased | Post-treatment vs placebo: Bilateral dorsal e ventrolateral PFC. Group X time,treated vs placebo: L inferior frontal gyrus | – |
Risacher et al., 2013 [43] | Donepezil (3-month treatment: 5 mg/day for 4 weeks, 10 mg/day until the end of study) | NRCT open-label | 20 HC 18 MCI | Verbal episodic encoding task Pre-/post-treatment | Task-related whole-brain functional activity changes and their relationship with patient performances at cognitive assessment before and after treatment | Improvement on CVLT. Mild accuracy decline during task | Increased | Group X time/treated vs HC: R hippocampus and parahippocampal gyrus, R middle frontal gyrus. Increased deactivation of the medial parietal lobe | Changes on medial parietal lobe activity-changes in CVLT. Increased connectivity of the L frontal lobe and L caudate; improved task accuracy |
Rombouts et al., 2002 [25] | Single dose (3 mg) of rivastigmine, 3 h before the first vs the second scanning | NRCT single-blind | 11 mild AD | Face encoding and working memory task Pre-/post-treatment | Task-related whole-brain functional activity changes | No changes at the task | Increased | Post-treatment vs placebo: Face encoding: bilateral fusiform gyrus. Simple working memory: L middle and superior frontal gyrus. Increased working memory load: L middle frontal gyrus, R inferior and superior frontal gyrus. | – |
Decreased | Post-treatment vs placebo: Increased working memory load: R middle and superior frontal gyrus | ||||||||
Saykin et al., 2004 [46] | Donepezil (5 mg/day for 4 weeks; 10 mg/day for 5.67 ± 1.66 weeks on average) | NRCT open-label | 9 HC 9 MCI | Auditory N-back task Pre-/post-treatment | Task-related whole-brain functional activity changes; performance improvement at cognitive assessment and fMRI task | Improvement on accuracy during task and on TMT-B. Reduction of subjective cognitive concerns | Increased | Group X time, treated vs HC: L dorsolateral PFC and L superior frontal cortex | Increased activity of the L anterior prefrontal-improved task accuracy |
Shanks et al., 2007 [35] | Galantamine (20-week treatment: 16 mg twice/day) | Cohort study | 9 HC 9 mild AD | Semantic association and target detection task Pre-/post treatment | Task-related frontal and parieto-temporal functional activity changes | No improvement at the cognitive assessment or at the tasks. Increased awareness in patient self-assessment with respect to problems during daily activities | Increased | Pre-/post-treatment: Semantic association: L paracentral lobule, L caudate and R lingual gyrus. Target detection: bilateral postcentral, L inferior parietal lobule. Post-treatment vs HC: Semantic association: bilateral superior temporal gyri and insula, R medial frontal gyrus, L inferior frontal. Target detection: bilateral middle frontal, L superior temporal and precuneus | – |
Solé-Padullés et al., 2013 [49] | Donepezil (3-month treatment: 5 mg/day for 1 month and 10 mg/day for 2 months) or no treatment | RCT single-blind | 15 mild-moderate AD | RS fMRI andvisual scene encoding task Pre-/post-treatment | RS whole-brain functional connectivity and task-related activity changes; performance improvement at fMRI task | Improvement on semantic fluency. No further changes at the cognitive assessment or at the task | Increased | Post-treatment vs untreated: R parahippocampal gyrus within the DMN. No task-related changes were observed | – |
Thiyagesh et al., 2010 [33] | Donepezil (23-week treatment: 5 mg/day) | Cohort study | 11 HC 10 mild AD | Visuospatial tasks Pre-/Post-treatment | Task-related functional activity changes in brain regions subtending visuospatial abilities | Improvement on MMSE, ADAS-cog, and Present Functioning Questionnaire. No changes at the task | Increased | Pre-/post-treatment: L precuneus | Increased activity of the L precuneus-improvement atthe Present Functioning Questionnaire |
Venneri et al., 2009 [37] | AchEI treatment (20-week treatment: at the maximum guideline-recommended dosage) | Cohort study | 9 HC 26 mild AD | Semantic association and N-back (1-back) task Pre-/post-treatment | Task-related whole-brain functional activity changes and performance improvement at cognitive assessment in responders compared with nonresponders | Improvement of the responders on ADAS-cog. No further changes at the cognitive assessment or at the task | Increased | Pre-/post-treatment/Group X time, responders vs nonresponders: Semantic association: bilateral inferior and medial frontal gyri, L precentral and postcentral gyri, L insula, middle temporal and inferior parietal gyri and anterior cingulate cortex; R inferior temporal gyrus, precuneus and caudate. Working memory: R precentral, precuneus, inferior parietal and thalamus, L inferior and superior frontal gyrus | Increased activity of the L frontal cortex during the semantic association task; poorer performance at the baseline semantic fluency |
Wang et al., 2014 [54] | Stable dose of AchEIs (donepezil, rivastigmine, or galantamine) for at least 15 days and for almost 18 months | Case-control | 25 mild treated AD 19 mild untreated AD | RS fMRI Post-treatment | Functional connectivity changes and interaction with the APOE genotype | – | Increased | Pre-/post-treatment/ApoEε4 treated vs ApoEε4 untreated: Greater composite scores in dorsal attention, control and salience networks | – |
Zaidel et al., 2012 [53] | Donepezil (8-week treatment: 5 mg/day for 28 days; 10 mg/day until the end of the study) | Case series | 11 mild AD | RS fMRI, L hemisphere seed-based connectivity Pre-/post-treatment | RS functional changes in the interhemispheric connectivity | – | Increased | Pre-/post-treatment: L-R dorsolateral PFC | – |
Zhang et al., 2016 [57] | Bushen capsule (24-month treatment: 4 capsules 3 times a day) or placebo | RCT double-blind | 60 MCI | RS fMRI At baseline At 12 months At 24 months | DMN functional connectivity and performance improvement at cognitive assessment, and their relationship | Improvement on MMSE, RAVLT, and digit span | Increased | Group X time, treated vs placebo:R precuneus within the DMN | No relationship was observed between connectivity and cognitive changes |
Zhang et al., 2014 [48] | CCRC (3-month treatment: 3 capsules per day) or placebo | RCT double-blind | 39 MCI | N-back (0-1-and 2 back) working-memory task Pre-/Post-treatment | Task-related whole-brain functional activity changes; performance improvement at cognitive assessment | Improvement on MMSE and digit span. No further changes on other cognitive scores or on task | Increased | Group X time, treated vs placebo and vs HC: Increased negative activation of L PCC and R fusiform gyrus | Increased negative activity in L PCC; changes on MMSE and digit span scores |