Neuroimaging facilitates the assessment of complementary medicines (CMs) by providing a noninvasive insight into their mechanisms of action in the human brain. This is important for identifying the potential treatment options for target disease cohorts with complex pathophysiologies. The aim of this systematic review was to evaluate study characteristics, intervention efficacy, and the structural and functional neuroimaging methods used in research assessing nutritional and herbal medicines for mild cognitive impairment (MCI) and dementia. Six databases were searched for articles reporting on CMs, dementia, and neuroimaging methods. Data were extracted from 21/2,742 eligible full text articles and risk of bias was assessed. Nine studies examined people with Alzheimer’s disease, 7 MCI, 4 vascular dementia, and 1 all-cause dementia. Ten studies tested herbal medicines, 8 vitamins and supplements, and 3 nootropics. Ten studies used electroencephalography (EEG), 5 structural magnetic resonance imaging (MRI), 2 functional MRI (fMRI), 3 cerebral blood flow (CBF), 1 single photon emission tomography (SPECT), and 1 positron emission tomography (PET). Four studies had a low risk of bias, with the majority consistently demonstrating inadequate reporting on randomisation, allocation concealment, blinding, and power calculations. A narrative synthesis approach was assumed due to heterogeneity in study methods, interventions, target cohorts, and quality. Eleven key recommendations are suggested to advance future work in this area.
Dementia is a syndrome comprising over 100 diseases and is characterised by a decline in cognition that interferes with function and independence [
In the absence of effective pharmaceutical options for dementia, complementary medicines (CMs) have been thoroughly explored. Randomised-controlled trials (RCTs) have been conducted on a range of CMs for dementia, cognitive decline, and mild cognitive impairment (MCI), with many studies currently ongoing. This research has largely focused on nutritional and herbal medicine interventions (e.g., resveratrol, anthocyanins, fish oil, vitamins B and E,
Neuroimaging techniques can provide an objective, precise, and noninvasive measure of neuronal function and are particularly useful in the assessment of complementary therapies for dementia. Popular functional techniques applied in CM research include electroencephalography (EEG), functional magnetic resonance imaging (fMRI), positron emission tomography (PET), magnetoencephalography (MEG), single photon emission computed tomography (SPECT), and functional near-infrared spectroscopy (fNIRS). Structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can also be used to assess changes in morphology following longer interventions. As detailed in Table
Neuroimaging technique, description, example quantification methods (by no means exhaustive), advantages, limitations, and relevance in CM studies on people with dementia.
Neuroimaging technique | Description | Quantification | Advantages | Limitations | Relevance in CM dementia research |
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EEG | Quantifies the electrical activity of the brain generated by electrical field potentials from excitatory and inhibitory neuronal activity. | Resting state EEG spectral activity (delta, theta, alpha, beta, gamma): power analyses and scalp-based functional connectivity measures (coherence, phase-lag). | Very high temporal resolution, relatively inexpensive, noninvasive, portable options available. | Poor spatial resolution due to volume conduction | Captures subtle changes in cognitive and/or sensory function. |
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fMRI | Measures changes in brain blood flow caused by neuronal activity. | Resting state: Region of interest functional connectivity approach. | Good spatial resolution, particularly with high resolution scanners (e.g., 7 T). | Poor temporal resolution: the BOLD response lags by 1-2 s behind the actual neuronal activity. Claustrophobia and high-pitched noises can make scanning uncomfortable for participants. | Captures changes in cognitive and/or sensory function that can have their source localised in the brain. |
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SPECT | Quantifies changes in brain blood flow and metabolism. Nuclear gamma camera captures a gamma-emitting tracer being absorbed by brain tissue at the same rate as blood flow. | Regional CBF. | Relatively cheap compared to other functional imaging methods (e.g., PET, fMRI). | Administration of radioactive isotope (usually injection) and exposure to gamma radiation. | Useful in assessing interventions for dementia as SPECT can differentiate dementia pathologies (e.g., vascular dementia versus Alzheimer’s disease). |
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PET | Typically assesses regional brain glucose metabolism by detecting gamma rays emitted by a positron-emitting tracer. | Regional CBF. | Different novel isotopes allow distinction between Alzheimer’s pathology and other dementias (PiB-PET). | Administration of radioactive isotope. | Different isotopes allow for tagging of different biochemical processes (e.g., FDG-PET for glucose uptake, or PiB-PET for amyloid imaging). |
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MEG | Measures magnetic fields generated by the electrical activity of the brain. | Similar to EEG, resting state measures (delta, theta, alpha, beta, gamma band power) and event-related measures are available. | Very high temporal resolution, and better spatial resolution (i.e., more accurate) compared to EEG. | Detects only tangential components of current source, so primarily sensitive to activity within sulci. | Captures subtle changes in cognitive and/or sensory function. |
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fNIRS | fNIRS captures changes in blood flow by detecting haemoglobin concentrations through the transmission and absorption of NIR light. | A range of measures are used, DOT or NIRI being popular forms of fNIR. | Noninvasive and portable. | Limitations when trying to measure activity in subcortical tissue. | CM intervention-associated changes in CBF can be ascertained. |
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MRI | Structural MRI images the anatomy of the brain using magnetic fields, radio waves, and field gradients. | Most frequently used measures are voxel-based morphometry and ROI analyses. | Good spatial resolution, particularly with high resolution scanners (e.g., 7 T). | No functional information available. | Volumetric changes in brain regions (or whole brain) can be investigated. |
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DTI | Measures diffusion of water in order to provide information on tissue microstructures so that white matter pathways within and between brain regions can be explored. | Tractography and tensor estimation. | Exploration of brain networks is becoming increasingly popular within the field. | No functional information available. | White matter integrity and structural network connectivity can be explored. |
Neuroimaging, in particular functional neuroimaging, can be utilised in dementia CM research as a sensitive measure of neurocognition, with the capacity to record changes that cannot otherwise be detected by standard pen-and-paper neuropsychological tests. This is useful given the small effect sizes often reported in CM research, particularly acute studies, and that any proposed intervention for cognitive decline is effectively fighting an uphill battle against neurodegenerative pathophysiology. Furthermore, some techniques can be used to explore the mechanisms of action of a therapy, which is particularly useful in psychopharmacological studies (e.g., nutritional and herbal medicines).
The aim of this systematic review was three-fold: (1) provide a comparison and critical evaluation of the characteristics of studies assessing nutritional and herbal medicines for MCI and dementia; (2) evaluate their use of structural and functional neuroimaging methods; (3) summarise intervention efficacy. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [
Several initial scoping reviews were conducted to determine the eligibility criteria and review scope. Eligibility criteria were determined in line with the PICO principles for systematic reviews [
Peer-reviewed studies were included if they reported a herbal or nutritional intervention for MCI or dementia and either structural or functional neuroimaging as an outcome measure. It should be noted that the search strategy was intentionally kept broad and also included both mind-body (e.g., yoga) and manual treatments (e.g., acupuncture); due to the large volume of results, only studies assessing nutritional and herbal interventions were included. Reviews, commentaries, conference proceedings, editorials, preclinical (in vitro and in vivo), and acute clinical studies were excluded, as were studies that were not published in English, or when the full text could not be retrieved.
The research team and an experienced librarian reviewed the search strategy before systematic searching commenced. Six databases were searched for studies published in peer-reviewed journals. Abstracts were retrieved from PubMed, ScienceDirect, Web of Science, ProQuest, Scopus, and PsycINFO ranging from databases’ dates of inception to August 28, 2016. A full list of keywords and an example of the search strategy for the Scopus database are detailed in Supplementary Material available online at
One reviewer examined the titles and abstracts of each article. If there was any doubt regarding the eligibility of an article, the full-text was retrieved for clarification. Articles deemed eligible by one reviewer were further assessed by two other independent reviewers to ensure inclusion criteria were met. Any disagreements were resolved by reviewing the full papers and a subsequent discussion.
Study characteristics were extracted from each full-text article. Data extracted included title, authors, publication date, aim, study type, disease focus, study population characteristics, number of participants (target cohort and controls), age (mean/median and SD), gender ratio, participant recruitment, diagnostic criteria, neuroimaging technique and analysis method, neuropsychological test battery, definition and dosage of CM, length of intervention, follow-up, and findings.
An assessment of methodological risk of bias in individual studies was conducted. A 10-item scale was constructed to suit the relevancy of studies in this review. The scale was informed by the Cochrane Handbook [
Risk of bias scale item descriptions.
Risk of bias item | Label | Description |
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1 | Random sequence generation | Was the allocation sequence adequately generated? |
2 | Allocation concealment | Was allocation adequately concealed? |
3 | Participant characteristics | Are the characteristics of the participants included in the study clearly described (inclusion/exclusion criteria)? |
4 | Blinding of participants, personnel, and outcome assessors | Was knowledge of the allocated intervention adequately prevented during the study? |
5 | Intervention description | Is the intervention of interest sufficiently described to allow replication? |
6 | Neuroimaging methodology | Are the neuroimaging methods clearly described? Description should include data-acquisition parameters and pre- and postprocessing pipelines. |
7 | Outcome measurement validity and reliability | Were the outcome measures used accurate and appropriate (valid and reliable)? |
8 | Selective reporting | Were all outcome measures detailed in the methods reported in the results? |
9 | Adverse events | Have all important adverse events that may be a consequence of the intervention been reported? |
10 | Reporting of power calculation and attrition rate effect on power | Was a power calculation reported and was the study adequately powered to detect hypothesised relationships? |
As there was substantial heterogeneity across included studies (in neuroimaging methods, intervention types, and study quality), quantitative analyses (i.e., meta-analysis) were not appropriate. Consequently, this review assumed a qualitative approach with a narrative analysis. The characteristics of each study were extracted, and data were described using a narrative synthesis approach.
Figure
Flow diagram illustrating the study selection process.
Table
Summary of study characteristics, intervention, neuroimaging, and neuropsychological methodologies, efficacy, and study design.
Author (reference) | Aim, recruitment | Study population | Intervention and duration | Neuroimaging and neuropsychological measures | Efficacy on cognition, neuroimaging measures, any associations, adherence, retention, and adverse events | Study design |
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Bi et al. (2011) [ | Aim: to test the efficacy of fuzhisan (FZS) in people with AD. | Mild to moderate AD ( | Intervention: 1 × 10 g FZS (or placebo) per day, orally. | PET (30 min) | Cognition: significant but small improvements in ADAS-Cog and NPI scores (versus no change in placebo). | Randomised, double-blind, placebo-controlled pilot study. |
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Cohen et al. (2003) [ | Aim: to investigate whether citicoline improves neurocognition & neuroimaging in people with VaD. | VaD ( | Intervention: 2 × 500 mg citicoline (or placebo) per day, orally. | MRI total brain volume | Cognition: no difference between citicoline and placebo in neuropsychological performance (i.e., both groups significantly declined from baseline to both 6- and 12-month follow-up). | Randomised, double-blind, placebo-controlled trial. |
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de Waal et al. (2014) [ | Aim: to investigate the effect of Souvenaid on brain-activity based networks in people with AD. | Mild AD ( | Intervention: 1 × 125 mL drink (active Souvenaid or isocaloric control) per day. | EEG functional connectivity networks | Cognition: no relationship between EEG network and NTB memory performance. Association between beta activity and memory performance at midpoint in the treatment group only. | Randomised, double-blind, placebo-controlled, multisite trial. |
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Douaud et al. (2013) [ | Aim: (1) to investigate the effect of B-vitamin treatment on brain atrophy in people with MCI. (2) To investigate the effect of (a) plasma | MCI ( | Intervention: high dose B-vitamin treatment (folic acid 0.8 mg/d, vit. B6 (pyridoxine HCl) 20 mg/d, vit. B12 (cyanocobalamin) 0.5 mg/d). | MRI regional grey matter volume [ | Neuroimaging: significantly reduced brain atrophy (0.5% versus 3.7%) in posterior brain regions (bilateral hippocampus, parahippocampal gyrus, retrosplenial precuneus, lingual and fusiform gyrus, cerebellum). Rate of brain atrophy was significantly slower (by 29.6%) with B-vitamin treatment than placebo. | Randomised, double-blind, placebo-controlled trial (VITACOG study). |
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Heo et al. (2016) [ | Aim: To investigate the effect of Korean red ginseng (KRG) on brain activity in people with AD. | AD ( | Intervention: 4.5 g/d KRG, orally (total powder capsule, 6-yr-old root; KT&G Corporation, Daedeok District, Korea; 8.54% Ginsenosides). | qEEG (resting, eyes closed) | Cognition: significant improvement in cognitive function (FAB). | Open, case series study. |
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Hofferberth (1994) [ | Aim: to investigate the effect of | AD ( | Intervention: 80 mg/d GBE (or placebo), orally. | EEG (theta/alpha quotient) | Cognition: significant improvement in cognitive function following 1 month and 2 months and maintained following 3 months of GBE. | Randomised, double-blind, placebo-controlled trial. |
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Köbe et al. (2015) [ | Aim: to investigate the combined effects of omega-3 fatty acids (FA), aerobic exercise, and cognitive stimulation on brain atrophy in people with MCI. | MCI ( | Intervention: both target and control groups received omega-3 FA (2.2 g/d; 4x oral capsules daily). | MRI brain volume | Cognition: no change in executive function, memory, sensorimotor speed, or attention. | Randomised controlled trial |
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Matsuoka et al. (2012) [ | Aim: to investigate the effect of toki-shakuyaku-san (TSS) on rCBF in people with MCI or AD. | MCI/AD ( | Intervention: 7.5 g TSS, orally (powder). | rCBF (SPECT) | Cognition: no change in MMSE scores (trend toward improved orientation to place). | Open, case series study. |
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Muresanu et al. (2010) [ | Aim: to investigate persistence of the effects of cerebrolysin on cognition & qEEG in people with VaD. | VaD ( | Intervention: 50 mL i.v. infusions of cerebrolysin (10 mL + 40 mL saline or 30 mL + 20 mL saline) or placebo (saline) 5 days/wk. | qEEG, eyes closed resting state | Cognition: significant improvement in cognitive performance maintained at follow-up. | Open-label extension of a randomised, double-blind, placebo-controlled trial. |
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Nilsson et al. (2000) [ | Aim: to investigate the effect of cobalamin (vitamin B12) treatment on brain function in people with a medical history of cognitive deterioration. | Mild to severe dementia ( | Intervention: intramuscular injection of hydroxycobalamin (vit. B12); 1 mg every second day, total 10x. | rCBF (xenon 133 inhalation and cortexplorer with 254 scintillation detectors) | Cognition: | Open, case series study. |
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Oishi et al. (1998) [ | Aim: to investigate the effect of traditional Chinese medicine treatment on brain function in people with AD. | AD ( | Intervention: traditional Chinese medicine (astragalus root 8 g, | ERP (auditory oddball P300) | Cognition: significant improvement in MMSE scores (though still below normal range). | Open, case series study. |
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Onofrj et al. (2002) [ | Aim: to test the effects of donepezil (DPZ) versus vitamin E on brain function in people with varying severities of AD. | Mild to severe AD ( | Titration: 14 days, 5 mg/day DPZ or 1000 IU/day vit E, orally. | ERP (P300 auditory oddball) | Cognition: DPZ: significant improvement in neuropsychological test performance, regardless of AD severity, though more pronounced for moderate-severe than mild AD. | Pseudo-randomised, double-blind, controlled trial. |
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Saletu et al. (1995) [ | Aim: to test the efficacy of nicergoline (NIC) in people with unspecified dementia (all-cause). | Mild to moderate dementia ( | Intervention: 2 × 30 mg NIC (or placebo) per day, orally. | EEG mapping (3 min V-EEG) | Cognition: significant improvements in CGI, MMSE, and SCAG (versus pretreatment and placebo group). | Randomised, double-blind, placebo-controlled crossover trial. |
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Thomas et al. (2001) [ | Aim: to test the effects of donepezil (DPZ) versus vitamin E versus rivastigmine (Riv) on brain function in people with AD. | Mild to moderately severe AD ( | Titration: 1 month, 5 mg/d DPZ, 2000 IU/d vit E, or 1.5 mg/d Riv, orally. | ERP (P300 auditory oddball) | Cognition: DPZ and Riv: significant improvement in neuropsychological test performance. | Randomised three-arm trial with one open-label arm and two double-blind arms. |
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Tsolaki et al. (in press) [ | Aim: to test the effects of | aMCI ( | Intervention: Crocus (no further information available). | MRI (global maxima of case “a”; | Cognition: significant improvement in MMSE (versus nonsignificant decline in the wait-list group). | Single-blind, nonrandomised, waitlist-controlled pilot trial. |
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Yamaguchi et al. (2004) [ | Aim: to test the effects of choto-san on brain function in people with VaD/MCI. | VaD/MCI ( | Intervention: 3x choto-san extract (TJ-47, Tsumura, 7.5 g/day) orally, daily [contains 4.5 g of extract of 11 kinds of dried medical herbs: Uncariae Uncis Cum Ramulus (3 g hooks and branch of | ERP (P300 novelty auditory oddball) | Cognition: significantly faster RT and increased accuracy on auditory oddball task. Significant improvement in MMSE and verbal fluency. | Open, cohort study. |
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Zhang et al. (2015) [ | Aim: to investigate the effect of Bushen capsule (BSC) on brain function in people with aMCI. | aMCI ( | Intervention: 4 × 300 mg BSC [main components Zexie ( | fMRI (episodic memory encoding task). | Cognition: significant improvement in MMSE, stroop, and AVLT. | Randomised, double-blind, placebo-controlled trial |
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Zhang et al. (2014) [ | Aim: to investigate the effect of Congrongyizhi capsule (CCRC) on brain function in people with aMCI. | aMCI ( | Intervention: 4x CCRC [main components Cistanche and Polygonum multiflorum thunb] or 4x placebo tablet, 3x/day or nothing (control). | fMRI (n-back task). | Cognition: significant improvement in MMSE and digit span, which were significantly associated with increased brain deactivation in posterior cingulate cortex. | Randomised, double-blind, placebo-controlled trial. |
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Zhang et al. (2012) [ | Aim: to investigate the effect of | VaD ( | Intervention: 19.2 mg GBT + 75 mg aspirin or 75 mg aspirin tablet, 3x/day. | rCBF (transcranial Doppler) | Cognition: significant improvement in global score MoCA, as well as MoCA score indices for executive function, attention, delayed memory, and orientation. | Randomised, controlled trial. |
Across all the included studies (taking into account the 3 studies on the same RCT [
Nine studies tested 399 participants with AD [
Four studies recruited from memory clinics [
All studies examined chronic administration with treatment duration ranging from 4 weeks [
Ten studies used EEG [
A range of analyses were conducted for EEG, MRI, and fMRI studies. For the EEG studies, 1 examined functional connectivity using phase lag index [
A variety of neuropsychological measures were used to assess cognition. The most common were the MMSE (
Nine studies reported on compliance [
Table
Risk of bias ratings for included studies. Studies are detailed in alphabetical order of authors’ names. Studies with low risk of bias (total scores ≥ 9) are italicised.
Study | Item 1 | Item 2 | Item 3 | Item 4 | Item 5 | Item 6 | Item 7 | Item 8 | Item 9 | Item 10 | Total |
---|---|---|---|---|---|---|---|---|---|---|---|
Bi et al. (2011) | 0 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 5 |
Cohen et al. (2003) | 0 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 5 |
| | | | | | | | | | | |
| | | | | | | | | | | |
Heo et al. (2016) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 3 |
Hofferberth (1994) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| | | | | | | | | | | |
Köbe et al. (2015) | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 0 | 5 |
Matsuoka et al. (2012) | 0 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 0 | 6 |
Muresanu et al. (2010) | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 3 |
Nilsson et al. (2000) | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 4 |
Oishi et al. (1998) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 |
Onofrj et al. (2002) | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 1 | 1 | 0 | 5 |
Saletu et al. (1995) | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 6 |
| | | | | | | | | | | |
Thomas et al. (2001) | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 5 |
Tsolaki et al. (in press) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Yamaguchi et al. (2004) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
Zhang et al. (2015) | 0 | 0 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 6 |
Zhang et al. (2014) | 0 | 0 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 6 |
Zhang et al. (2012) | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 4 |
Four of the 21 studies were reported particularly well and demonstrated a low risk of bias (scoring ≥ 9) [
Three of the 4 studies reported associations between cognitive test scores and neuroimaging outcome measures [
Eighteen studies reported positive neuroimaging findings associated with CM treatment [
Out of the 6 studies that assessed auditory oddball P300 ERP component amplitudes and latencies, 4 reported reduced P300 latencies [
One MRI study showed significantly increased whole brain volume after 26 weeks of the target multimodal intervention (see Table
One CBF study reported an increase in white matter CBF with stable xenon CT after 12 weeks of a traditional Chinese medicine [
Across all studies, 13 reported positive effects on cognition [
Five studies [
Six of 21 studies reported associations between measures of cognition and neuroimaging markers [
Four studies did not report neuropsychological test battery findings alone as they had already been published previously [
This systematic review summarised and critically appraised intervention studies that incorporated neuroimaging outcome measures to assess nutritional and herbal medicines for MCI and dementia. The majority of studies focused on participants with AD [
(1) Study Characteristics: (a) Research needs to follow the most recent guidelines stipulating diagnostic criteria for subjective cognitive complaints, MCI, and dementia, and should be closely adhered to when formulating protocols to ensure that the study population is as homogeneous as possible. (b) Essential baseline characteristics, particularly ones known to increase the risk of dementia, should be reported. (c) Recruitment setting needs to be carefully considered and always reported. (2) Methodologies: (a) All information on neuroimaging data collection, pre- and post-processing pipelines, and quantification needs to be reported to ensure that the results can be adequately scrutinised and replicated. (b) Optimal analytic techniques should be utilised for the quantification of neuroimaging data. (c) Standardised neuropsychological tests that are appropriate clinical trial endpoints for the level of cognitive impairment should be used. (3) Intervention Efficacy: (a) Standardised herbal extracts should be used to reduce the variability between studies. (b) Multi-herb formulas require substantial preclinical research to optimise ratios of active components, and determine their efficacy and safety as a formula. (c) Dosage should be kept similar to other research (unless there is a rationale for adjusting dose) to reduce variability between studies. (d) The length of trials should be carefully determined and have a rationale to allow for greater comparability between studies. (e) An appropriate control group, such as a placebo matched to colour, shape, taste and smell of the active treatment, should always be included.
The majority of studies reported information on how a diagnosis of MCI or dementia was made or confirmed and included sufficient inclusion and exclusion criteria to allow replication [
The majority of studies recruited from memory clinics [
The majority of studies tested a Chinese herbal medicine [
Although the majority of studies included a control group [
Most studies incorporated functional neuroimaging methods [
Neuroimaging data acquisition, pre- and postprocessing pipelines, and analyses were adequately reported in only 12 of 21 studies [
Although the majority of studies reported positive results [
The majority of studies utilised the MMSE [
The majority of studies assessed in this systematic review were at high risk of bias [
The focus of the 4 high quality studies that scored a low risk of bias [
Three of those studies also reported an association between cognitive test scores and neuroimaging outcome measures [
This systematic review has identified a number of consistent shortcomings in CM neuroimaging research into cognitive decline. In an effort to improve the rigour and validity of this important and developing field, the authors suggest 11 key recommendations emerging from the 3 review aims that future work should adhere to. These are detailed in Box
This systematic review focused on studies reporting a chronic intervention only. Acute studies may necessarily utilise a different range of neuroimaging methods than those reported here. For example, structural MRI is not appropriate for acute treatment administration as structural brain changes take longer than a few hours to be detected. Future research should systematically summarise and critically appraise acute CM studies [
This review not only focused on efficacy but also on summarising the characteristics of studies, intervention efficacy, and methods utilised. Particular consideration was given to identifying risks of bias. Neuroimaging and CM are a rapidly evolving area of research; thus the findings reported here highlight a number of significant strengths and weaknesses in this field that can be addressed in future work in an effort to improve the evidence base.
This systematic review summarised and critically appraised CM research on people with cognitive decline, MCI, or dementia that incorporated neuroimaging as an outcome measure. It was found that most studies focused on people with AD, utilised a herbal medicine intervention that was on average 12 weeks long, and used EEG or structural MRI as neuroimaging outcome measures. Nearly all studies reported positive results, despite the majority having a high risk of bias. The most common issues were a lack of reporting on randomisation, allocation concealment, blinding, and the lack of a power calculation. Eleven recommendations to improve future neuroimaging CM research on people with MCI and dementia have been highlighted in the recommendations box. The authors hope that the pragmatic approach taken to this systematic review will lead to an uptake of these recommendations and a subsequent increase in the quality of CM neuroimaging research on people with MCI or dementia.
As a medical research institute, NICM receives research grants and donations from foundations, universities, government agencies, individuals and industry. Sponsors and donors provide untied funding for work to advance the vision and mission of the Institute. The project that is the subject of this article was not undertaken as part of a contractual relationship with any organisation other than the funding declared in the Acknowledgements. It should also be noted that NICM conducts clinical trials relevant to this topic area, for which further details can be provided on request.
This manuscript was supported by funding from a National Health and Medical Research Council (NHMRC)-Australian Research Council (ARC) Dementia Research Development Fellowship (APP1102532).