Effects of Melissa officinalis Extract Containing Rosmarinic Acid on Cognition in Older Adults Without Dementia: A Randomized Controlled Trial.

BACKGROUND: Previous in vitro and in vivo studies on Alzheimer's disease (AD) models have reported that rosmarinic acid (RA) can inhibit the formation of amyloid-ß fibrils as well as the oligomerization and deposition of amyloid-ß protein. Melissa officinalis (M. officinalis) extract containing 500 mg of RA is tolerable and safe in healthy individuals and patients with mild AD dementia. OBJECTIVE: This randomized placebo-controlled double-blind trial aimed to assess the effects of M. officinalis extract on cognition in older adults without dementia. METHODS: This study included individuals who were diagnosed with subjective or mild cognitive impairment (n = 323). The trial involved M. officinalis extract supplementation (500 mg of RA per day) period of 96 weeks followed by a washout period of 24 weeks. The primary endpoint was the Alzheimer's Disease Assessment Scale-cognitive subscale score, and the secondary endpoints were other cognitive measure results as well as safety and tolerability. RESULTS: There were no significant differences in cognitive measures between the placebo and M. officinalis groups from baseline to 96 weeks. However, based on the analysis of Clinical Dementia Rating Sum of Boxes scores in participants without hypertension, the score was found to be increased by 0.006 and decreased by 0.085 in the M. officinalis and placebo groups, respectively; this difference was statistically significant (p = 0.036). Furthermore, there were no differences in vital signs, physical and neurological measures, or hippocampal volume between the two groups. CONCLUSION: These results indicate that M. officinalis extract may help prevent cognitive decline in older adults without hypertension.

Safety and efficacy of Melissa officinalis extract containing rosmarinic acid in the prevention of Alzheimer's disease progression.

We conducted a randomized placebo-controlled double-blind 24-week trial using Melissa officinalis (M. officinalis) extract richly containing rosmarinic acid (RA) on patients with mild dementia due to Alzheimer's disease (AD) with the aim to examine the safety and tolerability (primary endpoint) of RA (500 mg daily) and its clinical effects and disease-related biomarker changes (secondary endpoints). Patients (n = 23) diagnosed with mild dementia due to probable AD were randomized to either the placebo or M. officinalis extract group. No differences in vital signs or physical and neurologic examination results were detected between the M. officinalis and placebo groups. No serious adverse events occurred. There were no significant differences in cognitive measures; however, the mean Neuropsychiatric Inventory Questionnaire (NPI-Q) score improved by 0.5 points in the M. officinalis group and worsened by 0.7 points in the placebo group between the baseline and 24-week visit, indicating a significant difference (P = 0.012). No significant differences were apparent in disease-related biomarkers between the groups. M. officinalis extract containing 500 mg of RA taken daily was safe and well-tolerated by patients with mild dementia due to AD. Our results suggest that RA may help prevent the worsening of AD-related neuropsychiatric symptoms.Trial registration: The registration number for this clinical trial is UMIN000007734 (16/04/2012).

MM2-type sporadic Creutzfeldt-Jakob disease: new diagnostic criteria for MM2-cortical type.

OBJECTIVE: To clinically diagnose MM2-cortical (MM2C) and MM2-thalamic (MM2T)-type sporadic Creutzfeldt-Jakob disease (sCJD) at early stage with high sensitivity and specificity. METHODS: We reviewed the results of Creutzfeldt-Jakob disease Surveillance Study in Japan between April 1999 and September 2019, which included 254 patients with pathologically confirmed prion diseases, including 9 with MM2C-type sCJD (MM2C-sCJD) and 10 with MM2T-type sCJD (MM2T-sCJD), and 607 with non-prion diseases. RESULTS: According to the conventional criteria of sCJD, 4 of 9 patients with MM2C- and 7 of 10 patients with MM2T-sCJD could not be diagnosed with probable sCJD until their death. Compared with other types of sCJD, patients with MM2C-sCJD showed slower progression of the disease and cortical distribution of hyperintensity lesions on diffusion-weighted images of brain MRI. Patients with MM2T-sCJD also showed relatively slow progression and negative results for most of currently established investigations for diagnosis of sCJD. To clinically diagnose MM2C-sCJD, we propose the new criteria; diagnostic sensitivity and specificity to distinguish 'probable' MM2C-sCJD from other subtypes of sCJD, genetic or acquired prion diseases and non-prion disease controls were 77.8% and 98.5%, respectively. As for MM2T-sCJD, clinical and laboratory features are not characterised enough to develop its diagnostic criteria. CONCLUSIONS: MM2C-sCJD can be diagnosed at earlier stage using the new criteria with high sensitivity and specificity, although it is still difficult to diagnose MM2T-sCJD clinically.

Rifampicin is a candidate preventive medicine against amyloid-ß and tau oligomers.

Amyloid-ß, tau, and α-synuclein, or more specifically their soluble oligomers, are the aetiologic molecules in Alzheimer's disease, tauopathies, and α-synucleinopathies, respectively. These proteins have been shown to interact to accelerate each other's pathology. Clinical studies of amyloid-ß-targeting therapies in Alzheimer's disease have revealed that the treatments after disease onset have little benefit on patient cognition. These findings prompted us to explore a preventive medicine which is orally available, has few adverse effects, and is effective at reducing neurotoxic oligomers with a broad spectrum. We initially tested five candidate compounds: rifampicin, curcumin, epigallocatechin-3-gallate, myricetin, and scyllo-inositol, in cells expressing amyloid precursor protein (APP) with the Osaka (E693Δ) mutation, which promotes amyloid-ß oligomerization. Among these compounds, rifampicin, a well-known antibiotic, showed the strongest activities against the accumulation and toxicity (i.e. cytochrome c release from mitochondria) of intracellular amyloid-ß oligomers. Under cell-free conditions, rifampicin inhibited oligomer formation of amyloid-ß, tau, and α-synuclein, indicating its broad spectrum. The inhibitory effects of rifampicin against amyloid-ß and tau oligomers were evaluated in APPOSK mice (amyloid-ß oligomer model), Tg2576 mice (Alzheimer's disease model), and tau609 mice (tauopathy model). When orally administered to 17-month-old APPOSK mice at 0.5 and 1 mg/day for 1 month, rifampicin reduced the accumulation of amyloid-ß oligomers as well as tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent manner. In the Morris water maze, rifampicin at 1 mg/day improved memory of the mice to a level similar to that in non-transgenic littermates. Rifampicin also inhibited cytochrome c release from the mitochondria and caspase 3 activation in the hippocampus. In 13-month-old Tg2576 mice, oral rifampicin at 0.5 mg/day for 1 month decreased amyloid-ß oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation, but not amyloid deposition. Rifampicin treatment to 14-15-month-old tau609 mice at 0.5 and 1 mg/day for 1 month also reduced tau oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent fashion, and improved the memory almost completely at 1 mg/day. In addition, rifampicin decreased the level of p62/sequestosome-1 in the brain without affecting the increased levels of LC3 (microtubule-associated protein light chain 3) conversion, suggesting the restoration of autophagy-lysosomal function. Considering its prescribed dose and safety in humans, these results indicate that rifampicin could be a promising, ready-to-use medicine for the prevention of Alzheimer's disease and other neurodegenerative diseases.

Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis.

Epidemiological studies have suggested that diets rich in phenolic compounds may have preventive effects on the development of dementia or Alzheimer's disease (AD). We investigated the effects of natural phenolic compounds, such as myricetin (Myr), rosmarinic acid (RA), ferulic acid (FA), curcumin (Cur) and nordihydroguaiaretic acid (NDGA) on the aggregation of amyloid ß-protein (Aß), using in vitro and in vivo models of cerebral Aß amyloidosis. The in vitro studies revealed that these phenolic compounds efficiently inhibit oligomerization as well as fibril formation of Aß through differential binding, whilst reducing Aß oligomer-induced synaptic and neuronal toxicity. Furthermore, a transgenic mouse model fed orally with such phenolic compounds showed significant reduction of soluble Aß oligomers as well as of insoluble Aß deposition in the brain. These data, together with an updated review of the literature, indicate that natural phenolic compounds have anti-amyloidogenic effects on Aß in addition to well-known anti-oxidative and anti-inflammatory effects, hence suggesting their potential as therapeutic and/or preventive agents for cerebral Aß amyloidosis, including AD and cerebral amyloid angiopathy (CAA). Well-designed clinical trials or preventive interventions with natural phenolic compounds are necessary to establish their efficacy as disease-modifying agents.

Phenolic compounds prevent the oligomerization of α-synuclein and reduce synaptic toxicity.

Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low-order αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds on α-synuclein (αS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited αS oligomerization and secondary structure conversion. Myr and RA ameliorated αS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent αS aggregation process and reduce the neurotoxicity of αS oligomers. Phenolic compounds are good candidates of disease modifying drugs for α-synucleinopathies.

Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial.

The aim of this study was to evaluate the safety, tolerability and pharmacokinetics of single dose of Melissa officinalis extract which contained rosmarinic acid, including food-effects in healthy individuals. A total of eleven healthy individuals were randomly assigned to treatment arms in the two studies [Study 1 (fasted state) and Study 2 (fed state)]. Rosmarinic acid in serum was measured by a coulometric detection method using High-Performance Liquid Chromatography electrochemical detector. The serum concentration of total rosmarinic acid peaked at 1 hour after administration of Melissa officinalis extract containing 500mg rosmarinic acid in fasted state, with a maximum serum concentration 162.20 nmol/ L. The area under the curve for intact rosmarinic acid was calculated from the serum concentration-time profile to be 832.13 nmol • hour/ L. Food intake increases area under the curve and delayed time at which the maximum serum concentration. Rosmarinic acid supplementation did not affect liver, kidney, or blood cell function parameters. No adverse event was reported by any of the participants due to the study treatment. Single dose of Melissa officinalis extract containing 500 mg rosmarinic acid appears to be safe and tolerable in healthy individuals. Food intake increased the exposure of rosmarinic acid and delayed absorption of rosmarinic acid in healthy individuals.

Cocoa extracts reduce oligomerization of amyloid-ß: implications for cognitive improvement in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, characterized by pathological aggregates of amyloid peptide-ß (Aß) and tau protein. Currently available therapies mediate AD symptoms without modifying disease progression. Polyphenol-rich diets are reported to reduce the risk for AD. OBJECTIVE: In the present study, we investigated the AD disease-modifying effects of cocoa, a rich source of flavanols, which are a class of polyphenols. We hypothesized that cocoa extracts interfere with amyloid-ß oligomerization to prevent synaptic deficits. METHODS: We tested the effects of three different cocoa extracts, viz. Natural, Dutched, and Lavado extracts, on Aß42 and Aß40 oligomerization, using photo-induced cross-linking of unmodified proteins technique. To assess the effects of cocoa extracts on synaptic function, we measured long term potentiation in mouse brain hippocampal slices exposed to oligomeric Aß. RESULTS: Our results indicate that cocoa extracts are effective in preventing the oligomerization of Aß, with Lavado extract being most effective. Lavado extract, but not Dutched extract, was effective in restoring the long term potentiation response reduced by oligomeric Aß. CONCLUSION: Our findings indicate that cocoa extracts have multiple disease-modifying properties in AD and present a promising route of therapeutic and/or preventative initiatives.

Consumption of green tea, but not black tea or coffee, is associated with reduced risk of cognitive decline.

Our objective was to determine whether the consumption of green tea, coffee, or black tea influences the incidence of dementia and mild cognitive impairment (MCI) in older people. We conducted a population-based prospective study with Japanese residents aged >60 years from Nakajima, Japan (the Nakajima Project). Participants received an evaluation of cognitive function and blood tests. The consumption of green tea, coffee, and black tea was also evaluated at baseline. Of 723 participants with normal cognitive function at a baseline survey (2007-2008), 490 completed the follow up survey in 2011-2013. The incidence of dementia during the follow-up period (mean ± SD: 4.9 ± 0.9 years) was 5.3%, and that of MCI was 13.1%. The multiple-adjusted odds ratio for the incidence of overall cognitive decline (dementia or MCI) was 0.32 (95% CI: 0.16-0.64) among individuals who consumed green tea every day and 0.47 (95% CI: 0.25-0.86) among those who consumed green tea 1-6 days per week compared with individuals who did not consume green tea at all. The multiple-adjusted odds ratio for the incidence of dementia was 0.26 (95% CI: 0.06-1.06) among individuals who consumed green tea every day compared with those who did not consume green tea at all. No association was found between coffee or black tea consumption and the incidence of dementia or MCI. Our results indicate that green tea consumption is significantly associated with reduced risk of cognitive decline, even after adjustment for possible confounding factors.

Molecular topology as novel strategy for discovery of drugs with aß lowering and anti-aggregation dual activities for Alzheimer's disease.

BACKGROUND AND PURPOSE: In this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer's disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy. EXPERIMENTAL APPROACH: We used MT to include multiple bioactive properties that allows for the identification of multi-functional single agent compounds, in this case, the dual functions of ß-amyloid (Aß) -lowering and anti-oligomerization. Using this technology, we identified and designed novel compounds in chemical classes unrelated to current anti-AD agents that exert dual Aß lowering and anti-Aß oligomerization activities in animal models of AD. AD is a multifaceted disease with different pathological features. CONCLUSION AND IMPLICATIONS: Our study, for the first time, demonstrated that MT can provide novel strategy for discovering drugs with Aß lowering and anti-aggregation dual activities for AD.

Coenzyme Q10 therapy in hereditary motor sensory neuropathy type VI with novel mitofusin 2 mutation.

Hereditary motor sensory neuropathy type VI (HMSN VI) is hereditary neuropathy accompanied by optic neuropathy. The feasibility of Coenzyme Q10 (CoQ10) as a treatment for subacute visual impairment of HMSN VI was examined. A 37-year-old patient with HMSN VI with a novel mitofusin 2 mutation was treated with high dose of CoQ10 (200 mg/day) for eight months. Visual impairment was partially resolved after CoQ10 therapy. High dose CoQ10 therapy may improve the prognosis of subacute visual impairment in HMSN VI. To confirm the effectiveness of CoQ10 on HMSN VI, further studies are needed.

REVIEW: Curcumin and Alzheimer's disease.

Curcumin has a long history of use as a traditional remedy and food in Asia. Many studies have reported that curcumin has various beneficial properties, such as antioxidant, antiinflammatory, and antitumor. Because of the reported effects of curcumin on tumors, many clinical trials have been performed to elucidate curcumin's effects on cancers. Recent reports have suggested therapeutic potential of curcumin in the pathophysiology of Alzheimer's disease (AD). In in vitro studies, curcumin has been reported to inhibit amyloid-ß-protein (Aß) aggregation, and Aß-induced inflammation, as well as the activities of ß-secretase and acetylcholinesterase. In in vivo studies, oral administration of curcumin has resulted in the inhibition of Aß deposition, Aß oligomerization, and tau phosphorylation in the brains of AD animal models, and improvements in behavioral impairment in animal models. These findings suggest that curcumin might be one of the most promising compounds for the development of AD therapies. At present, four clinical trials concerning the effects of curcumin on AD has been conducted. Two of them that were performed in China and USA have been reported no significant differences in changes in cognitive function between placebo and curcumin groups, and no results have been reported from two other clinical studies. Additional trials are necessary to determine the clinical usefulness of curcumin in the prevention and treatment of AD.

Alpha-synuclein assembly as a therapeutic target of Parkinson's disease and related disorders.

Lewy bodies (LBs) and Lewy neurites (LNs) in the brain constitute the main histopathological features of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and are comprised of amyloid-like fibrils composed of a small protein ( approximately 14 kDa) named alpha-synuclein (alphaS). As the aggregation of (alphaS in the brain has been implicated as a critical step in the development of the diseases, the current search for disease-modifying drugs is focused on modification of the process of (alpha S deposition in the brain. In this article, the recent developments on the molecules that inhibit the formation of alpha-synuclein fibrils (falphaS) as well as the oligomerization of alphaS are reviewed. Recently, various compounds such as curcumin, nicotine and wine-related polyphenols have been reported to inhibit the formation of falphaS, and to destabilize preformed falphaS at pH 7.5 at 37 degrees C in vitro. Although the mechanisms by which these compounds inhibit falphaS formation from falphaS, and destabilize preformed falphaS are still unclear, they could be key molecules for the development of preventives and therapeutics for PD and other alpha-synucleinopathies.

The development of preventives and therapeutics for Alzheimer's disease that inhibit the formation of beta-amyloid fibrils (fAbeta), as well as destabilize preformed fAbeta.

Neuritic plaques composed mainly of amyloid beta-protein (Abeta) in the brain are an early and invariant neuropathological feature of Alzheimer's disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of Abeta deposition in the brain. In this article, the recent development of the molecules that inhibit the formation of beta-amyloid fibrils (fAbeta), as well as destabilize preformed fAbeta is reviewed. Recently, various compounds such as curcumin, nicotine and wine-related polyphenols have been reported to inhibit the formation, extension of fAbeta, as well as destabilize preformed fAbeta at pH 7.5 at 37 degrees C in vitro. In cell culture experiments, destabilized fAbeta were suggested to be less toxic than intact fAbeta. In transgenic mice model study, some coumpounds such as curcumin and nicotine have also been reported to reduce plaque burden in vivo. Although the mechanisms by which these compounds inhibit fAbeta formation from Abeta, and destabilize preformed fAbeta are still unclear, they could be key molecules for the development of preventives and therapeutics for AD.

Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro.

The aggregation of alpha-synuclein (alphaS) in the brain has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Various antioxidants not only inhibit the formation of beta-amyloid fibrils (fAbeta), but also destabilize preformed fAb in vitro. Using fluorescence spectroscopy with thioflavin S and electron microscopy, here we examined the effects of the antioxidants nordihydroguaiaretic acid, curcumin, rosmarinic acid, ferulic acid, wine-related polyphenols [tannic acid, myricetin, kaempferol (+)-catechin and (-)-epicatechin], docosahexaenoic acid, eicosapentaenoic acid, rifampicin and tetracycline on the formation of alphaS fibrils (falphaS) and on preformed falphaS. All molecules, except for docosahexaenoic acid and eicosapentaenoic acid, dose-dependently inhibited the formation of falphaS. Moreover, these molecules dose-dependently destabilized preformed falphaS. The overall activity of the molecules examined was in the order of: tannic acid=nordihydroguaiaretic acid=curcumin=rosmarinic acid=myricetin>kaempferol=ferulic acid>(+)-catechin=(-)-epicatechin>rifampicin=tetracycline. These compounds with anti-fibrillogenic as well as antioxidant activities could be key molecules for the development of preventives and therapeutics for LBD and MSA as well as Alzheimer's disease.

Myoclonic involuntary movement associated with chronic manganese poisoning.

We report a 17-year-old man showing myoclonic involuntary movement (IVM) associated with chronic manganese (Mn) poisoning. The patient, a welder, showed myoclonic IVM mainly in the right upper and lower extremities, elevated levels of Mn in the blood and hair and high-intensity signals in the globus pallidus on T1-weighted MR images. Chelation therapy resulted in improvement of the myoclonic IVM and MRI abnormalities. This is the first report of Mn poisoning characterized by myoclonic IVM without parkinsonism.