A Systematic Review of Intervention Studies Examining Nutritional and Herbal Therapies for Mild Cognitive Impairment and Dementia Using Neuroimaging Methods: Study Characteristics and Intervention Efficacy
Summary of study characteristics, intervention, neuroimaging, and neuropsychological methodologies, efficacy, and study design.
Intervention and duration
Neuroimaging and neuropsychological measures
Efficacy on cognition, neuroimaging measures, any associations, adherence, retention, and adverse events
Intervention: 1 × 10 g FZS (or placebo) per day, orally. Duration: 12 weeks. Free from over-the-counter medications for at least 2 weeks prior to study entry; free from psychotropic drugs for at least 4 weeks prior.
PET (30 min) NTB: MMSE, ADAS-cog, NPI.
Cognition: significant but small improvements in ADAS-Cog and NPI scores (versus no change in placebo). Neuroimaging: increased or stabilised rCMRglc across frontal, parietal, and temporal cortices, posterior cingulate gyrus, hippocampus, thalamus, cerebellum (versus decreased rCMRglc in placebo). Retention: total 3 withdrew: 1x FZS, 2x placebo (i.e., 88% completion rate). Adverse effects: 2x mild, transient side-effects (1x nausea, 1x constipation).
Randomised, double-blind, placebo-controlled pilot study.
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). Neuroimaging: no difference between citicoline and placebo in structural brain measures (i.e., both groups had significantly decreased total brain volume & increased SH from baseline to 12-month follow-up). Retention: total 9 withdrew prior to follow-up: 4x citicoline, 5x placebo.
Cognition: no relationship between EEG network and NTB memory performance. Association between beta activity and memory performance at midpoint in the treatment group only. Neuroimaging: decreased beta network EEG in the placebo but not Souvenaid group. Suggests improved synaptic integrity and function and counteraction of network decline. Retention: total 12 withdrew prior to follow-up; 14 excluded due to protocol deviations &/or <80% compliance: 4x Souvenaid, 10x placebo.
Douaud et al. (2013) , Jernerén et al. (2015)  and Smith et al. (2010) , UK
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 ω-3 fatty acid concentrations, (b) plasma tHCy concentrations, on B-vitamin treatment of brain atrophy in people with MCI. Recruitment location: community.
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. This effect was even greater (53% lower atrophy) for individuals with high baseline tHcy, a risk factor for brain atrophy. This effect was also even greater (40% lower atrophy) for individuals with high baseline ω-3 fatty acid concentrations, a risk factor for brain atrophy. Adherence: >78% took at least 75% of the tablets; 81.4% (70/84 active, 66/83 placebo) determined biologically compliant via blood samples. Retention: total 20 withdrew (11x B-vit, 9x placebo). Total 15 lost to death or cancer (7x B-vit, 8x placebo). Further 8 lost or excluded for “miscellaneous” reasons (5x B-vit, 3x placebo). Adverse effects: no significant safety issues or group differences in adverse events.
Cognition: significant improvement in cognitive function (FAB). Neuroimaging: relative alpha power increased in temporal regions for responders versus nonresponders. Suggests increased frontal lobe function.
Cognition: significant improvement in cognitive function following 1 month and 2 months and maintained following 3 months of GBE. Significant improvement in choice reaction time following 1 month and maintained following 2 and 3 months of GBE. Neuroimaging: significant reduction in theta wave component of theta/alpha quotient following 1 month and maintained following 2 and 3 months of GBE.
Intervention: both target and control groups received omega-3 FA (2.2 g/d; 4x oral capsules daily). Target intervention: aerobic training (cycle ergometer; 2 × 45 min/wk) + cognitive stimulation (AKTIVA: Aktive Kognitive Stimulation-Vorbeugung im Alter (active cognitive stimulation-prevention in the elderly); 1x individual + 12x group sessions, 90 min duration, plus daily home practice, beginning week 4). Control intervention: nonaerobic training (stretching & toning; 2 × 45 min/wk). Duration: 6 months.
Cognition: no change in executive function, memory, sensorimotor speed, or attention. Neuroimaging: increased or reduced atrophy in GM volume for target versus control intervention (middle and superior frontal cortices, frontal pole, angular cortex, posterior cingulate cortex). Significant decrease in total homocysteine concentration. Retention/adherence: original ; discontinued due to time constraints or poor compliance. Adverse effects: None.
Intervention: 7.5 g TSS, orally (powder). Duration: daily for 8 wks.
rCBF (SPECT) NTB: MMSE, NPI, PSMS.
Cognition: no change in MMSE scores (trend toward improved orientation to place). Neuroimaging: significant increase in rCBF in posterior cingulate. Retention/adherence: original ; discontinued due to poor compliance, change in location, or withdrawal. Adverse effects: none.
Aim: to investigate persistence of the effects of cerebrolysin on cognition & qEEG in people with VaD.
VaD (): randomised (2 : 3 : 3) to cerebrolysin 10 mL (4M : 9F, 72.46 ± 2.80 yrs, MMSE 18.92 ± 1.32), cerebrolysin 30 mL (7M : 4F, 70.36 ± 3.62 yrs, MMSE 20.27 ± 1.92), or placebo (5M : 4F, 71.89 ± 3.52 yrs, MMSE 18.89 ± 1.81).
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. Duration: 4 weeks. Follow-up: 12 weeks (±1).
qEEG, eyes closed resting state NTB: MMSE, ADAS-cog.
Cognition: significant improvement in cognitive performance maintained at follow-up. Neuroimaging: significant (dose-dependent) reduction in qEEG power ratio maintained at follow-up. Retention/adherence: original study ; lost to follow-up or due to poor compliance (i.e., receiving new drug treatment).
Open-label extension of a randomised, double-blind, placebo-controlled trial.
Aim: to investigate the effect of cobalamin (vitamin B12) treatment on brain function in people with a medical history of cognitive deterioration. Recruitment location: hospital outpatients.
Mild to severe dementia ( (VaD: ; AD: , mixed ); 15M : 14F, 78.9 ± 6.8 yrs; MMSE 9–23).
Intervention: intramuscular injection of hydroxycobalamin (vit. B12); 1 mg every second day, total 10x. Duration: 1 month.
rCBF (xenon 133 inhalation and cortexplorer with 254 scintillation detectors) NTB: MMSE, OBS.
Cognition: classified as “clinically improved” (orientation to time and space, recent memory), though dementia severity did not change. did not show any clinical improvements. Neuroimaging: “clinically improved” had significant increase in general blood flow level. slight trend towards a decrease in blood flow.
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 ( completed): first divided into mild AD (group I) versus moderate-severe AD (group II) then randomised to treatment: group I DPZ (6M : 9F, 65.2 ± 1.8 yrs, MMSE 21.5 ± 0.4, ADAS-Cog 22.3 ± 1.0), Group I vit E (7M : 8F, 65.5 ± 1.7 yrs, MMSE 21.5 ± 0.6, ADAS-Cog 22.5 ± 0.9), Group II DPZ (6M : 9F, 66.7 ± 1.5 yrs, MMSE 11.5 ± 0.6, ADAS-Cog 44.5 ± 1.2), Group II vit E (8M : 7F, 66.5 ± 1.6 yrs, MMSE 11.6 ± 0.4, ADAS-Cog 43.5 ± 1.4).
Titration: 14 days, 5 mg/day DPZ or 1000 IU/day vit E, orally. Intervention: 10 mg/day DPZ or 2000 IU/day vit E, orally. Duration: 6 months.
Cognition: DPZ: significant improvement in neuropsychological test performance, regardless of AD severity, though more pronounced for moderate-severe than mild AD. Vitamin E: severe deterioration of neuropsychological test performance, regardless of AD severity. Neuroimaging: DPZ: significantly reduced P300 latency, regardless of AD severity, though more pronounced for moderate-severe than mild AD. Vitamin E: significantly increased P300 latency, regardless of AD severity. Retention/adherence: total 7 withdrew during initial titration phase (6x DPZ (adverse effects), 1x Vit E (noncompliance)). Adverse effects: 6x DPZ (3x nausea or abdominal discomfort, 3x confused agitation).
Cognition: DPZ and Riv: significant improvement in neuropsychological test performance. Vitamin E: severe deterioration of neuropsychological test performance. Neuroimaging: DPZ and Riv: significant reduction in P300 latency (no difference between). Vitamin E: significantly increased P300 latency. P300 latency changes were significantly correlated with neuropsychological test scores. Retention/adherence: total 4 withdrew from Riv (3x nausea, 1x noncompliance). Total 2 excluded from vit E (no detectable P300). Adverse effects: 3x nausea.
Randomised three-arm trial with one open-label arm and two double-blind arms.
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 Uncaria sinensis Oliver), Aurantii Nobilis pericarpium (3 g peel of Citrus unshiu Markovich), Pinelliae tuber (3 g tuber of Pinellia ternate Breitenbach), Ophiopgonis tuber (3 g root of Ophiopogon japonicus Ker-Gawler), Hoelen (3 g fungus of Poria cocos Wolf), Ginseng radix (2 g root of Panax ginseng C.A. Meyer), Chrysanthemi flow (2 g flower of Chrysanthemum morifolium Ramatulle), Saphoshnikoviae radix (2 g root and rhizome of Saposhnikovia divaricata Schischkin), Glycyrrhizae radix (1 g root of Glycyrrhiza uralensis Fisher), Gypsum Fibrosum (5 g CaSO4 2H2O) and Zingiberis rhizoma (1 g, rhizome of Zingiber officinale Roscoe)]. Duration: 12 weeks.
Cognition: significantly faster RT and increased accuracy on auditory oddball task. Significant improvement in MMSE and verbal fluency. Neuroimaging: Significant reduction in P300 latency. Trend towards increased novelty P300 amplitude.
Cognition: significant improvement in MMSE, stroop, and AVLT. Neuroimaging: increased brain activation in right putamen; this was significantly associated with stroop performance. Reduced brain deactivation in right middle temporal gyrus; this was significantly associated with AVLT performance. Adverse effects: 1x decreased appetite for 3 days (BSC), 1x mild nausea for 1 week (placebo). Neither discontinued use or withdrew from study.
Cognition: significant improvement in MMSE and digit span, which were significantly associated with increased brain deactivation in posterior cingulate cortex. Neuroimaging: increased brain deactivation in posterior cingulate cortex, inferior frontal gyrus, and lingual gyrus. Adverse effects: 1x decreased appetite for 3 days (CCRC), 1x mild nausea for 1 week (placebo). Neither discontinued use or withdrew from study.
rCBF (transcranial Doppler) NBT: Montreal cognitive assessment (MoCA).
Cognition: significant improvement in global score MoCA, as well as MoCA score indices for executive function, attention, delayed memory, and orientation. Neuroimaging: significant increase in blood flow velocity in middle and anterior cerebral arteries.
Randomised, controlled trial.
Note. ACC = anterior cingulate cortex; AD = Alzheimer’s disease; ADAS-Cog = Alzheimer’s Disease Assessment Scale–cognitive subscale; aMCI = amnestic mild cognitive impairment; AVLT = Auditory Verbal Learning Test; BNT = Boston Naming Test; CGI = clinical global impression; COWAT = Controlled Oral Word Association Test; CVLT = California Verbal Learning Test; d = day (i.e., /d = per day); DMN = default mode networks; DRS = Dementia Rating Scale; EEG = electroencephalography; ERP = event-related potential; FAB = frontal assessment battery; F : M = females to males; fMRI = functional magnetic resonance imaging; GM = grey matter; HVLT-R = Hopkins Verbal Learning Test-Revised; MCI = mild cognitive impairment; MFG = medial frontal gyrus; MID = multi-infarct dementia; MMSE = Mini-Mental State Examination; MoCA = Montreal cognitive assessment; MRI = magnetic resonance imaging; MTG = medial tegmental gyrus; NPI = Neuropsychiatric Inventory; NTB = neuropsychological test battery; OBS = Organic Brain Syndrome Scale; PCC = posterior cingulate cortex; PET = positron emission tomography; PSMS = Physical Self-Maintenance Scale; RAVLT = Rey Auditory Verbal Learning Test; rCBF = regional cerebral blood flow; RCFT = Rey Complex Figure Test; rCMRglc = regional cerebral metabolic rate of glucose consumption; ReHo = regional homogeneity; RT = reaction time; SCAG = Sandoz Clinical Assessment-Geriatric; SDAT = senile dementia of the Alzheimer type; SH = subcortical/periventricular hypertensity; SPECT = single-photon emission computed tomography; tHcy = total homocysteine; TMT = Trail Making Test; VaD = vascular dementia; V-EEG = vigilance-controlled EEG; yrs = years (i.e., age in years); WAIS-R = Wechsler Adult Intelligence Scale–Revised; WMS-R = Wechsler Memory Scale–Revised.