Qi Fu Yin–a Ming Dynasty Prescription for the Treatment of Dementia

Introduction

Dementia is a progressive syndrome characterized by memory deficits, cognitive impairment, and deterioration in emotional control and social behavior [1, 2]. The loss in cognitive function is more than what is typically experienced in normal aging, and results from damage caused by the disease process, such as Alzheimer disease (AD), Parkinson disease (PD), and traumatic brain injury (TBI) [3]. Several types of dementia have been reported, including vascular dementia, progressive dementia, Lewy body dementia, Alzheimer’s dementia, and dementia as a result of diseases such as stroke, AIDS, or multiple sclerosis [4]. Age, prolonged consumption of “Western” diet, and physical and mental inactivity, as well as environmental factors are major risk factors that predispose one to dementia (Fig. 1). Other factors include cardiovascular and cerebrovascular complications, excessive alcohol intake, social isolation, prior head injury, and the possession of a single or two copies of the APOEϵ4 genetic variant [1, 2, 3]. The symptoms of dementia may be linked with alterations in neuroplasticity in corticolimbic brain regions. In particular, divergent responses have been reported; neuronal atrophy and synapse loss in the prefrontal cortex and hippocampus, and neuronal hypertrophy and increased synaptic density in the amygdala and nucleus accumbens are found [5]. Mild cognitive impairment (MCI) is a pathological condition of modest cognitive decline that does not interfere with one’s ability to perform activities of daily life, and is considered to be a symptomatic pre-dementia state [6]. Not everyone with MCI will progress to dementia, but individuals with MCI develop dementia at higher rates than those with normal cognition [6, 7].

Table 1

Herbs used in Qi Fu Yin

Fig. 1

Factors contributing to the pathogenesis of chronic kidney disease (CKD) and dementia

The prevalence of dementia increases exponentially with age, from 3.0% among those aged 65 to 74 years to 18.7% among 75 to 84 years old and 47.2% in individuals over the age of 85 years [8]. The worldwide prevalence of dementia is estimated to double every 20 years and reach over 81 million by 2040, due to an aging population [9]. An understanding of molecular mechanisms that contribute to the pathogenesis of dementia is essential for successful interventions. Dementia, like neurodegenerative diseases, cardiovascular disease, and cancer, requires early detection to potentially arrest or prevent further disease progression. The purpose of this review is to outline Traditional Chinese Medicine (TCM) concepts for the treatment of dementia and illustrated with a historical prescription for the treatment of the condition, with the hope that this description may lead to advances in its management.

TCM Ideas of Brain and Treatment of Dementia

According to TCM, the brain and bone marrow are the outgrowths of the kidneys. In Lingshu Meridians, it is stated that “at conception, essence is formed.” After essence is formed, the brain and bone marrow are formed. The kidneys contain the essence, the essence sustains the marrow, and the marrow nourishes the brain. According to “Lingshu Discussion on Seas,” humans have a marrow sea, a blood sea, a qi sea and a water/grain sea (stomach). This is the meaning of the four seas. Among the four seas in the human body, the marrow sea refers to the brain. According to the “Category Text” Volume 9: where there is bone, there is marrow, and the brain has the most. Thus, all marrow is related to the brain, and the marrow sea refers to the brain. <《灵枢·经脉》曰:“人始生,先成精,精成而脑髓生。” 肾藏精,精充髓,髓荣脑。《灵枢·海论》歧伯曰:“人有*髓海,有血海,有气海,有水谷之海,凡此四者,以应四海也。”人体四海之一,髓海即指脑。《类经》卷九注:“凡骨之有髓,惟脑为最巨,故诸髓皆属于脑,而脑为髓之海。> [10, 11]. This, TCM theory of “kidneys give rise to marrow, and the brain is the sea of marrow” has been a guiding principle behind traditional Chinese medicine’s clinical utilization of qi, blood and kidney tonics for the prevention/ treatment of dementia and improvement of memory for thousands of years. < 肾生髓,脑为髓海”的理论指导中医临床应用补充气血兼补肾中药来防治痴呆和提高记忆能力已经有数千年的历史。> [10] . Thus, in TCM, nourishing agents, such as Rehmannia; kidney essence astringents, such as rose fruit; and blood tonics such as angelica are used to benefit the brain. Memory and cognition are disordered if channels that connect the heart and brain are blocked by phlegm; hence, herbs such as zizyphus and polygala are also used to improve heart function, together with Qi tonic herbs such as ginseng [12].

TCM Ideas of Qi and Phlegm that Blocks Qi

TCM views the body as a single entity and an individual’s being depends on interactions between the different body parts. Qi, blood, and body fluids are essential for life. Qi is interpreted as “life energy” or “life force.” The Chinese character for “qi” (氣) means air or gas and may have some of the characteristics of air or oxygen gas. Original qi originates from the kidneys, the site where “congenital essence,” an essential and vital substance inherited from one’s parents upon conception is stored. Pectoral qi is formed from the combination of inhaled fresh air from the lungs and food essence from the stomach and spleen. It permeates the blood vessels and moves outward during expiration and inward during inspiration. Nutritive qi supplies nourishment to the body. It comes from food and digestive activities and circulates via blood vessels. Protective qi is similar to the immune system and helps in the prevention of illnesses.

Phlegm is a pathological substance generated by disturbance of body fluid that blocks qi. Substantial phlegm is visible such as sputum, whereas insubstantial phlegm is invisible. Lipids and lipoprotein metabolic disorders (atherosclerosis, diabetes and metabolic syndrome) are believed to contribute to phlegm in the blood, whereas platelet activation, thrombosis, endothelial injury, and atheromatous plaques contribute to blood stasis [13]. Small-molecule substances such as inflammatory factors (cytokines, chemokines, and platelet-activating factor) and arachidonic acid-derived enzymatic (prostaglandins, leukotrienes, and thromboxanes) and non-enzymatic (4-hydroxy-2-nonenal, isoprostanes, isofurans, isoketals, and acrolein) lipid mediators and free radicals (oxygen radicals, superoxides, and hydroxyl radicals) likely play a role in phlegm and blood stasis.

Physiological and Pathological Connections Between the Kidneys and Brain

The TCM theory of “kidneys give rise to marrow, and the brain is the sea of marrow” implies a close relationship between the kidneys, the marrow, and the brain. Chronic renal failure is asymptomatic at first, until kidney function has decreased to less than 25% of normal. Patients then present with nocturia and anorexia, and raised serum levels of nitrogenous compounds such as urea and creatinine. Advanced renal failure causes significant impairment of all renal function and affects virtually all body systems, and causes change in urea, electrolytes, and other blood constituents. End-stage renal disease is the term used when more than 90% of renal function is lost and may be complicated by anemia, bleeding, bone disease, hypertension, congestive heart failure, digestive tract problems, and dementia. It is proposed that part of the renal-cerebral connection may be due to small vessel disease in both the kidneys and brain. There are many hemodynamic similarities between the vascular beds of these organs [14]—both kidneys and brain are low resistance end-organs and subjected to blood flow of high volume throughout the cardiac cycle unlike those of other body organs [15]. Abnormalities in capillaries are found in the kidneys and brains of people who die of dementia, and similar capillary findings are observed in the kidneys of people with albuminuria, leading investigators to predict that albuminuria and small vessel disease of the brain go hand in hand [14, 16]. Patients with albuminuria have about 50% greater chance of developing dementia than people without albuminuria [17]. Persistent albuminuria indicates that the kidneys are damaged and starting to spill albumin into the urine. This supports the view that early detection and treatment of albuminuria and kidney disease may be important for protecting brain function. Drugs commonly used for the treatment of high blood pressure, e.g. ACE inhibitors and angiotensin-receptor blockers, may have a protective effect on the kidneys [16, 18]. Chronic kidney disease (CKD) patients are also often exposed to traditional risk factors, such as older age, hypertension, diabetes, and hyperlipidemia, as well as non-traditional risk factors, such as hyperhomocysteinemia, oxidative stress, and inflammation, that are associated with cognitive impairment in the general population [19, 20]. Oxidative stress and changes in redox status are closely associated with the pathogenesis of CKD. Both these processes increase the risk of stroke, induction of cognitive impairment, and onset of dementia in the aging brain [21, 22] (Fig. 1).

Anemia is a common finding in patients with CKD. Analyses of baseline data from adults with chronic kidney disease indicate that the prevalence of cognitive impairment is higher among those with lower eGFR, and this association is independent of traditional vascular risk factors, but rather, related to anemia [23]. The kidneys produce a glycoprotein hormone, erythropoietin (Epo), in response to hypoxia. It stimulates the production of red cells in the bone marrow and has been used for the treatment of anemia in humans [24]. Epo acts through a specific erythropoietin receptor (EpoR) on the surface of red cell precursors in the bone marrow and facilitates their transformation to mature red blood cells. Kidney dysfuntion may therefore lead to anemia, brain energy crisis, and slow excitotoxicity. Recent study shows anemia is associated with risk of dementia in older adults [25]. This could be a basis for the link between the kidneys, marrow, and brain in TCM theory. Epo and its receptor signaling via JAK2 activate multiple downstream signaling pathways including STAT5, PtdIns 3K/Akt, NF-κB, and MAPK (Fig. 2) [26]. These pathways are not only associated with red blood cell proliferation but also vasodilation [27] and insulin-sensitization [28].

Fig. 2

Hypothetical diagram showing interactions between excitotoxicity and erythropoietin receptor signaling along with the contribution of aging on dementia. Plasma membrane (PM); glutamate (Glu); N-methyl-D-aspartate receptor (NMDA-R); phosphatidylcholine (PtdCho); lyso-phosphatidylcholine (lyso-PtdCho); cytosolic phospholipase A₂ (cPLA₂); arachidonic acid (ARA); cyclooxygenase-2 (COX-2); 5-lipoxygenase (5-LOX); prostaglandins (PGs); leukotrienes (LTs); thromboxanes (TXs); platelet-activating factor (PAF); reactive oxygen species (ROS); nuclear factor kappa B (NF-κB); inhibitory form of nuclear factor kappa B (IκB/NF-κB); nuclear factor κB-response element (NF-κB-RE); inhibitory subunit of NF-κB (IκB); tumor necrosis factor-α (TNF-α); interleukin-1β (IL-1β); interleukin-6 (IL-6); Janus kinase 2 (JAK2); erythropoietin (Epo); erythropoietin receptor (EpoR); phosphatidylinositol 3Kinase (PtdIns 3K); serine/threonine kinase (Akt); Signal transducer and activator of transcription 5 (STAT5); and mitogen-activated protein kinases (MARK)

Epo and EpoR are also expressed in neurons of the CNS, including the neocortex, hippocampus, and hypothalamus, as well as dorsal root ganglia, and Schwann cells [29]. Epo improves sensorimotor and spatial learning functions, and peripherally administered Epo crosses the blood-brain barrier and stimulates neurogenesis and neural differentiation [30, 31]. Activation of NF-κB signaling contributes to EPO-mediated neuroprotection. During the “classical” activation of NF-κB, phosphorylation of inhibitor of NF-κB (IκB) by IκB kinase (IKK) leads to degradation of IκB by ubiquitination, NF-κB translocation to the nucleus and induction of gene expression. In contrast, after Epo treatment of neural cells, JAK2 phosphorylate IκB resulting in ubiquitination-independent dissociation of IκB from the NF-κB complex, translocation of NF-κB to the nucleus, and induction of neuroprotective genes [32]. NF-κB promotes neuroprotection via inhibitor of apoptotic protein (IAP), which reduces tumor necrosis factor-α (TNF-α) [33] and apoptotic JNK signaling [34], and activates Bcl-x_L [35]. In addition, activation of JAK kinases results in tyrosine phosphorylation and dimerization of STAT, which translocates to the nucleus and binds to specific DNA sequences in the promoters of responsive genes to promote gene transcription supporting neurogenesis and angiogenesis [36]. Collective evidence suggests that in the brain, Epo mediates neurotrophic, anti-apoptotic, antioxidant, and anti-inflammatory effects [37].

CKD patients also show raised serum levels of nitrogenous wastes. Decreased cognitive function has been associated with the retention of uremic toxins, with performance improving with more intensive dialysis or kidney transplantation [38]. The enzyme glutamine synthetase (l-glutamate:ammonia ligase (ADP-forming; E.C.6.3.1.2) is located in astrocytes and catalyzes the reaction of glutamate with ammonia to form glutamine [39, 40]. It is part of the glutamate-glutamine shuttle that is essential for normal glutamatergic neurotransmission. High levels of ammonia interferes with this shuttle, and increased serum ammonia is associated with symptoms such as impaired memory, shortened attention span, sleep-wake inversions, brain edema, intracranial hypertension, seizures, ataxia, and coma [41, 42]. This is a major factor in hepatic encephalopathy as a result of failure to metabolize ammonia to urea in liver disease, but less is known about whether it could have a role in CKD. Nevertheless, it is conceivable that failure of urea excretion as a result of kidney dysfunction could lead to buildup of ammonia and affect the brain via a similar mechanism.

Physiological and Pathological Connections Between the Circulatory System and Brain

The TCM theory that memory and cognition are disordered if channels that connect the heart and brain are blocked by phlegm implies a close relationship between the cardiovascular system and the brain, a connection which is also highly emphasized in Western medicine. Heart disease is any condition that impairs cardiac function regardless of the specific modality that is affected [43]. The functionality of other organs, including that of the brain is at risk in patients with heart disease [44]. There is an expanding body of literature indicating that heart disease and atrial fibrillation are risk factors for dementia [43, 45]. Additionally, several studies suggest that cardiovascular risk factors are independently associated with the development of dementia. These include hypertension, hypercholesterolemia, type 2 diabetes, obesity smoking, and elevated plasma levels of homocysteine [46, 47]. Reduced brain perfusion and reduced oxygen and/or glucose supply or utilization by the brain could cause an energy crisis in neurons and affect the function of ion pumps such as Na⁺/K⁺ ATPases that maintain resting potential in neurons. This results in depolarization, excessive calcium entry into neurons, activation of calcium dependent enzymes such as proteases, lipases, and endonucleases, and slow excitotoxicity [48]. Reduction in cerebral blood flow due to heart disease may also magnify any cognitive problems caused by the accumulation of endogenous toxic products such as ammonia, lactic acid, nitric oxide, proinflammatory eicosanoids, cytokines and chemokines. Accumulation of these molecules may contribute to the pathogenesis of heart disease, ischemic stroke, dementia, and AD. Reduced brain perfusion could also affect the clearance of amyloid beta (Aβ) and hyperphosphorylation of Tau protein, inducing the formation of amyloid beta plaques, neurofibrillary tangles, atherosclerosis, and inflammatory cascade (Fig. 1). These processes not only increase the risk of immune exhaustion [49], but are also magnified by type 2 diabetes, obesity, and hypertension [50]. They may not only induce synaptic dysfunctions and impairment in cerebral flow leading to dementia and AD [51, 52], but also disrupt the BBB and affect the process of neurogenesis [53–55]. Furthermore, changes in the cardiovascular and cerebrovascular systems along with induction of vascular inflammation and endothelial dysfunction may contribute to the onset of clinical cognitive decline and dementia. Aβ plaques are associated with upregulation of IL-1, IL6, and TNF-α, and levels correlate with disease severity [52]. Demyelination is also common in patients with heart disease [56], and reduction in axonal integrity of several brain circuits that are involved in cognition are found in these patients [57]. Dementia patients are more prone to structural and functional cardiac abnormality when compared with controls if they have suffered from heart disease previously [58].

Phytochemicals in Herbs

Increasing evidence indicates that consumption of bioactive compounds or phytochemicals in herbs produces antioxidant, anti-inflammatory, and anti-carcinogenic effects (fig. 2). Unlike food products such as sugars, amino acids, and lipids, which are absorbed efficiently, the bioavailability of phytochemicals is largely poor, since a large proportion undergoes conjugation in the liver and is rapidly excreted. The low levels of phytochemicals that are absorbed are, however, able to exert biochemical effects by inhibiting activities of cyclooxygenases and lipoxygenases and stimulating activities of a number of protein kinases, protein phosphatases, and lipid kinases [59–61]. There are at least two major molecular mechanisms associated with the beneficial effects of phytochemicals—downregulation of the transcription factor, NF-κB, and upregulation of the transcription factor nuclear factor erythroid-2 (NrF2) [59]. Some phytochemicals stimulate the synthesis of adaptive enzymes and proteins that favor resistance to cellular stress (detoxifying and antioxidant enzymes). They increase the activities of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and catalase) and reduce the levels of 8-hydroxy-2′-deoxyguanine, resulting in decreased DNA damage [59, 62]. Phytochemicals also modulate angiogenesis and ionic homeostasis, and up-regulate the redox status of cells through signaling networks that control energy metabolism [59, 63]. Other phytochemicals interact with metal ions (iron and other transition metal ions) to form chemical complexes. The binding of phytochemicals with iron retards the Fenton reaction, thereby inhibiting free radical generation [64]. Based on their cardioprotective, nephroprotective, and neuroprotective properties of phytochemicals, it is proposed that long-term consumption of phytochemicals may retard or prevent oxidative stress and inflammation and lead to the delaying or slowing the onset of heart disease, stroke, AD, and CKD [59]. However, many present-day herbal remedies have yet to undergo careful scientific assessment, and some herbs may produce serious toxic effects and major drug interactions. Patients must therefore inform their healthcare professionals of everything they are taking, including medications, supplements, and ”natural products,” and healthcare professionals should be aware of the effects of herbs on health.

Rationale for the Use of Multi-herb Formulas in TCM

Multi-herb formulas rather than single herbs are common in TCM medication. Each herb in a formula has a specific role—sovereign (君), minister (臣), assistant (佐), and courier (使). Sovereign and minister herbs treat the main symptoms and have a major role in the formula. Assistant herbs assist the sovereign and minister herbs to treat the accompanying symptoms, or reduce the side effects of the major herbs. Courier herbs help to lead the other components to the affected area. Interactions between the herbs, such as mutual reinforcement, antagonism, or detoxification, help to determine the formula’s therapeutic efficacy. The nature of the herbs, including the four properties (cold, hot, warm, and cool) and the five tastes (sour, sweet, bitter, acrid, and salty) as well as characteristics such as meridian-tropism, are taken into consideration by TCM physicians when formulating a prescription [65].

Dementia and its Treatment as Recorded in Jingyue Quanshu (Collected Works of Zhang Jingyue)

Zhang Jing-Yue 张景岳 (c.1563–1640) had a great influence on the development of TCM, towards the end of the Ming Dynasty in China. He was born in Shaoxing County of Zhejiang Province, the birthplace of many of the country’s most renowned scholars and writers. Zhang traveled with his father to Beijing, where he studied medicine, and became an imperial physician working for Emperor Wanli. Because he made good use of processed Rehmannia glutinosa, he was also called “Zhang Shudi.” He was an outstanding medical scientist, the representative of the ancient Chinese medicine practice of “warm tonification,” and his academic thought has a great influence on future generations. A chapter on dementia (痴呆) in the Ming dynasty book 《Jingyue Quanshu》 (景岳全书 Collected Works of Zhang Jingyue; 1637 A.D.) describes how the collapse of original qi, together with the presence of impure qi in the meridians and heart orifices, can lead to the problem of dementia.

In this chapter, Zhang Jing-Yue was of the opinion that “dementia syndrome is characterized by lack of sputum, or stagnation, or failure, or anxiety, or suspicion, or panic, gradually leading to dementia. Speech and words are in reverse order and movement is sluggish. There is excessive sweating and depression. The symptoms may be extremely unusual and bizarre. The pulse is stringy or increased in frequency, large or small, and often changes. Persons have pathological qi in the heart and liver and biliary systems. The qi is unclear. If the body is strong and there is no reduction in food intake or other weaknesses, it is appropriate to treat using Fu Man Jian. It is the most stable and wonderful prescription. Nevertheless, some cases will recover and some will not, depending on the strength or weakness of stomach qi and original qi. Time is needed for recovery, which cannot be speeded up. Those who have this syndrome may be exacerbated by anxiety or depression leading to absent-mindedness and confusion. In this case, it is important to quickly support the good qi, mostly through the use of Qi Fu Yin or Da Bu Yan”. < 明代《景岳全书》张景岳认为:“痴呆证,凡平素无痰,而或以郁结,或以不遂,或以思虑,或以疑贰,或以惊恐,而渐致痴呆。言辞颠倒,举动不经,或多汗,或善愁,其证则千奇万怪,无所不至。脉必或弦或数,或大或小,变易不常。此其逆气在心或肝胆二经,气有不清而然。但察其形体强壮,饮食不减,别无虚脱等证。则悉宜服蛮煎治之。最稳最妙。然此证有可愈者,有不可愈者,亦在乎胃气元气之强弱,待时而复,非可急也。凡此诸证,若以大惊猝恐,一时偶伤心胆,而致失神昏乱者。此当以速扶正气为主,宜七福饮,或大补元煎主之。> [66]

Description of Qi Fu Yin Herbs in Chinese Pharmacopeias

Qi Fu Yin (seven blessings decoction, 七福饮) is a mixture of seven herbs, Panax ginseng, Rehmannia glutinosa, Angelica polymorpha, Atractylodes macrocephala, Glycyrrhiza uralensis, Ziziphus jujube, and Polygala tenuifolia (Table 1).

Indications, Contraindications, and Possible Adverse Effects of Qi Fu Yin

Preparation and Use of Qi Fu Yin

The following herbs are boiled in 400 cc of water and left to simmer until the volume reduces to 280 cc. This can be divided into 2 servings per day, to be taken on an empty stomach, when warm. <上药用水400毫升,煎取280毫升,空腹时温服。> [66]. Review in 1-3 months.

Conclusion

Alzheimer’s disease and vascular dementia are two common causes of dementia, and it is increasingly recognized that many older adults with dementia have both AD and vascular pathologies. The underlying molecular mechanisms are incompletely understood, but may involve atherosclerosis, vascular dysfunction, hypertension, type 2 diabetes, history of cardiac disease, and total homocysteine, and possibly, lack of erythropoietin formation by the kidney. During the Ming Dynasty, Zhang Jing-Yue used Qi Fu Yin (seven blessings decoction), comprising Panax ginseng, Rehmannia glutinosa, Angelica polymorpha, Atractylodes macrocephala, Glycyrrhiza uralensis, Ziziphus jujube, and Polygala tenuifolia to boost qi and blood circulation, strengthen the heart, and calm the spirit—skillfully linking heart, spleen, kidney, qi, blood and brain as a whole to treat age-related dementia.