JAPAN IS NOW enjoying the longest life span in the world (83 years old in 2010). Accordingly, the ratio of the elderly population (65 years old and above) is the highest in the world (23% in 2010), and the ratio of the late elderly population (75 years old and above) is also the highest in the world (10% in 2010). Furthermore, Japan spent just 24 years in transit from an aging society to an aged society, which is the fastest transition in the world. Considering these aspects, Japan is seen as the world top runner in terms of society aging.1 Alzheimer's disease is considered the most 'malignant' disease in this century, considering the high prevalence rate, the degree of disability and dysfunction, and long duration of the disease. Alzheimer's disease is a neurodegenerative disorder characterized by progressive deficits in memory and cognitive function, together with impairment in the ability to perform activities of daily life. Behavioral problems and psychiatric symptoms are also frequently associated with Alzheimer's disease.2 Due to the rapid aging of the Japanese society, there are 1.16 million patients with Alzheimer's disease in Japan, which is 4% of the elderly population (28.74 million) in Japan in 2010. The number of Alzheimer's disease patients in Japan is expected to increase to 1.42 million in 2015, 1.67 million in 2020, and 2.2 million in 2025. The prevalence of Alzheimer's disease has increased the need for research aimed at identifying the risk,3, 4 pathogenesis,5-8 diagnosis,9 drugs,10, 11 non-pharmacological intervention,12-15 care,16-18 and support19, 20 for this disease. A diverse range of compounds has been evaluated as potential treatments for Alzheimer's disease, and five compounds have been approved in the world for the treatment of Alzheimer's disease. This review will focus on the pharmacological properties of cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) and an N-methyl-D-aspartate (NMDA) antagonist (memantine), which are used for the symptomatic treatment of Alzheimer's disease, because rivastigmine, galantamine and memantine have finally been approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan for the symptomatic treatment of Alzheimer's disease this year. Tacrine, the prototypical cholinesterase inhibitor for the treatment of Alzheimer's disease, was the first centrally acting cholinesterase inhibitor approved by the Food and Drug Administration (FDA), USA, for treatment of mild to moderate Alzheimer's disease, and was marketed by Warner–Lambert under the trade name Cognex in 1993. Studies have found that it may have a small beneficial effect on cognition and other clinical measures, though adequate study data is limited and the clinical relevance of these findings is unclear. The use of tacrine is limited due to poor oral bioavailability, the necessity for four-times daily dose, and considerable adverse drug reactions (including nausea, diarrhea, urinary incontinence and hepatotoxicity) such that few patients could tolerate therapeutic doses. Tacrine is not developed in Japan and it is no longer used worldwide since the introduction of newer cholinesterase inhibitors (Fig. 1). Structural formula of tacrine. The phase 1 trial of donepezil was started in Japan in 1989, and in the USA in 1991. The FDA approved donepezil for treatment of mild to moderate Alzheimer's disease in November 1996. Three years later it was approved by the PMDA of Japan (November 1999) and was marketed by Eisai and Pfizer under the registered name of Aricept. Owing to the superior properties of donepezil, such as (i) significantly less hepatotoxicity; (ii) high selectivity to acetylcholinesterase (AChE) inhibition (IC50 = 6.7 nM vs butyrylcholinesterase [BuChE] inhibition [IC50 = 7400 nM]); and (iii) long duration of action (t1/2 = 90 h), donepezil has been widely used to treat Alzheimer's disease patients worldwide. In 2006, donepezil was prescribed in more than 75 countries and regions in the world, and occupied 56% of the entire sales market of drugs for Alzheimer's disease. In 2007, donepezil was approved for its use for severe Alzheimer's disease and the FDA approved a higher-dose 23-mg tablet in 2010. Alzheimer's disease is associated with loss of cholinergic neurons in parts of the brain. Acetylcholinesterase inhibitors, such as donepezil, delay the breakdown of acetylcholine released into synaptic clefts and so enhance cholinergic neurotransmission. Donepezil is beneficial for patients with mild, moderate and severe dementia of Alzheimer's disease, showing improvements in cognitive function and activities of daily living. Adverse effects were consistent with the cholinergic actions of the drug and were the most likely cause of withdrawal from treatment in the first 12 weeks. Effects on cognition remained measurable and statistically significant at 52 weeks of treatment in one study. There is some evidence that use of donepezil is neither more nor less expensive compared with placebo when assessing total health-care resource costs. Benefits to patients on the 10-mg/day doses were marginally more significant than to those on the 5-mg/day doses. Taking into consideration the better tolerability of the 5-mg/day donepezil compared with the 10-mg/day doses, together with the lower cost, the lower dose may be the better option. The debate on whether donepezil is effective continues despite the evidence of efficacy from the clinical studies because the treatment effects are small and are not always apparent in practice, and because of the cost of the drug (Fig. 2).21 Structural formula of donepezil. Rivastigmine was developed at the Hebrew University of Jerusalem and sold to Novartis for commercial development. It has been available in capsule and liquid formulations since 1997. In 2006, it was approved for treatment of mild to moderate dementia associated with Parkinson's disease and the rivastigmine transdermal patch was approved for the first patch treatment for dementia in 2007. Rivastigmine is a cholinesterase inhibitor that inhibits both AChE and BuChE. In Alzheimer's disease, brain BuChE levels are reported to increase, whereas AChE levels decrease. BuChE is widely distributed in the brain regions affected in Alzheimer's disease, such as the temporal cortex, hippocampus and amygdala. This has led to the theory that acetylcholine metabolism may become more dependent on BuChE activity than on AChE activity as Alzheimer's disease progresses. The increase in BuChE activity may result from a combination of reactive gliosis and an accumulation of BuChE in neuritic plaques. It has been reported that the area of plaques displaying BuChE reactivity is five- to sixfold higher in dementia versus age-matched controls. It is thought that rivastigmine may function by inhibiting AChE and BuChE, leading to better improvement of cognitive function of Alzheimer's disease patients (Fig. 3). Structural formula of rivastigmine. Galantamine was originally extracted as a natural alkaloid from Galanthus elwesii, for AChE inhibitor activity in the Soviet Union in the 1950s. Galantamine was used for decades in Eastern Europe for various indications, such as treatment of myasthenia, myopathy, and sensory and motor dysfunction associated with disorders of the central nervous system, and it has been sold as a supplement for memory and dream support in the USA. The synthesized galanthamine hydrobromide was deployed by Janssen Pharmaceutica as the drug for Alzheimer's disease, and the galantamine tablet was approved by the FDA for Alzheimer's disease in February 2001. Galantamine solution was approved in July 2001 and the galantamine extended-release capsule was approved in 2003 aiming for once a day administration. Galantamine is indicated for the treatment of mild to moderate vascular dementia and Alzheimer's disease. Galantamine shows specific inhibition of AChE and it also acts as the allosteric potentiation ligand (APL) of nicotinic receptor. Due to this APL effect, galantamine is believed to potentiate nicotinic receptor signals, which results in the increased release of transmitters, such as dopamine, norepinephrine, serotonin, gamma-aminobutyric acid and glutamate. Galantamine is shown to have the suppression of neurotoxicity by amyloid beta peptide (Fig. 4). Structural formula of galantamine. Memantine was first synthesized by Eli Lilly in 1968, and then developed by Merz in Germany, which is licensed to Forest for the USA and Lundbeck for selected European and international markets. Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm. Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system. It is a voltage-dependent, moderate-affinity, uncompetitive NMDA receptor antagonist that blocks the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction. Glutamate aids in memory and learning at normal levels, but if levels are too high, glutamate may overstimulate nerve cells, leading to neuronal death by its toxicity. Memantine is approved for treatment of moderate to severe Alzheimer's disease, and has now received a limited recommendation by the UK's National Institute for Clinical Excellence for patients who fail other treatment options. Within the new guidance, memantine is recommended as an option for managing Alzheimer's disease for people with moderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors or those with severe Alzheimer's disease. Despite years of research, whether memantine has any effect in mild to moderate Alzheimer's disease is unknown (Fig. 5). Structural formula of memantine. Historically, many drugs for improving cerebral metabolism and/or cerebral circulation were developed and widely used in Japan to treat dementia patients, including Alzheimer's disease and vascular dementia.22 Examples of cerebral metabolic enhancers include adenosine triphosphate, calcium hopantenate, cytidine5′-diphosphocholine, dihydroergotamine mesylate, gamma-aminobutyric acid, meclofenoxate, pyrithioxine and idebenone. Drugs for cerebral circulation are bencyclane, brovincamine, cinnarizine, cinepazide, cyclandelate, dilazep, flunarizine, moxisylyte, ifenprodil, tocopherol, kallidinogenase, pentoxifylline, trapidil and vinpocetine. Many of these drugs were evaluated for their efficacy in comparison with calcium hopantenate as the standard drug. When calcium hopantenate failed to demonstrate its efficacy to dementia patients in its re-evaluation, the Japanese Ministry of Health and Welfare denied approval of most cerebral metabolic enhancers and cerebral circulation enhancers in 1999. Most of those cerebral metabolic enhancers and cerebral circulation enhancers cited above were abandoned from clinical use, and only five compounds, nicergoline, nilvadipine, ibudilast, vinpocetine, ifenprodil, and aniracetam, remained on the market based on indications other than dementia or cerebral circulation insufficiency. The new stage of pharmacotherapy for Alzheimer's disease was initiated by the introduction of donepezil in 1999. Donepezil was approved by the PMDA in November 1999, and was used to treat mild to moderate Alzheimer's disease patients. It was approved for severe Alzheimer's disease in 2007. Partly due to the actual increase in the number of Alzheimer's disease patients and also due to the better recognition of Alzheimer's disease in public, prescription of donepezil increased significantly during these 10 years. The sales of donepezil were estimated to be ¥100bn in 2010. As donepezil was the only drug available for Alzheimer's disease in Japan for 12 years, new drug options have been long awaited. Galantamine and memantine were filed for approval by the PMDA in February 2010 and rivastigmine was also filed 1 month later, in March 2010. As donepezil was the only drug to be used for Alzheimer's disease for more than 10 years in Japan, new drugs have been eagerly awaited by medical doctors, patients and families of patients. Pushed by public needs and also by public opinions issued by academic organizations and Alzheimer associations, the process of evaluation of these filed drugs for Alzheimer's disease was significantly accelerated. Eleven months after the filing, galantamine was approved by the PMDA on 21 January 2011, and galantamine was released on 22 March 2011, as the second drug for Alzheimer's disease. Considering the handling capacity of PMDA, it is unusual the approval was made after such a short period because 1.5–2 years is usually required for the PMDA to complete the evaluation process of a new drug. New drugs for Alzheimer's disease were approved after 11–13 months, which is probably due to the public need and the endeavors by the PMDA to hasten the evaluation process of new compounds for Alzheimer's disease. The product (Remynil) is supplied in twice-a-day tablets (4 mg, 8 mg, and 12 mg), once-a-day extended release capsules (8 mg, 16 mg, and 24 mg), and in an oral solution (4 mg/mL). Janssen Japan together with Takeda Pharmaceuticals is co-promoting the product, under the brand name Remynil. Memantine (Memary) was approved on 21 January 2011 and it was scheduled to be released on 18 March 2011. Due to the plant damage of Daiichi Sankyo Co. by the Great Eastern Japan Earthquake on 11 March 2011, however, the release of memantine (Memary) was postponed and it was released on 8 June 2011 in the form of Mamary tablets of 5 mg, 10 mg, and 20 mg. Since the failure of clinical trials of rivastigmine tablets, Novartis Japan has switched from the oral tablet to the transdermal patch of rivastigmine. The data of rivastigmine patch clinical trials were filed for approval in March 2010 and it was approved by the PMDA on 22 April 2011. Novartis Japan will start selling rivastigmine under the brand name of Exelon Patch and Ono Pharmaceuticals Co. will do so under the name Rivastach Patch in July 2011. Aricept is distributed in tablets (3 mg, 5 mg, and 10 mg), oral disintegrant tablets (3 mg, 5 mg, 10 mg), fine granule (0.5%), and jelly form (3 mg, 5 mg, and 10 mg). Aricept is started with 3 mg once a day for mild to moderate patients. After 1–2 weeks, it is raised to 5 mg/day, which is the maintenance dose of Aricept for mild to moderate Alzheimer's disease patients. In cases of severe Alzheimer's disease, after maintaining a dose of 5 mg for at least 4 weeks, it is raised to 10 mg/day. Since donepezil has been used for 12 years in Japan, there have been enough data accumulated for its efficacy and adverse side-effects in Japan.23 Reminyl is used for mild to moderate Alzheimer's disease patients. It is started at 8 mg/day (a 4-mg tablet twice), and it is increased to 16 mg/day (an 8-mg tablet twice) and maintained for clinical effects. In case the 16-mg/day dose is not sufficient, it will be increased to 24 mg/day (a 12-mg tablet twice) after the 16-mg dose has been taken for at least 4 weeks. Exelon Patch (Rivastach Patch) is available as a transdermal patch in a 4.5-mg, 9-mg, 13.5-mg, and 18-mg dose, which is indicated for mild to moderate Alzheimer's disease. It is started with 4.5 mg once a day and increased by 4.5 mg every 4 weeks and maintained at 18 mg/day. Donepezil, galantamine, and rivastigmine are all AChE inhibitors, and some additional difference in mechanism of action is theoretically speculated. However, clinical data have not been reported indicating different target signs and symptoms of Alzheimer's disease patients among these three drugs. Even though there is a possibility that some patients are responsive to some AChE inhibitors and others are not,24 the choice of these drugs may be determined mainly by the tolerability of the patients. Especially for the patients who have difficulty in per-os medication, the transdermal patch of rivastigmine is used. Memary is indicated for moderate to severe Alzheimer's disease, which is started at 5 mg once a day. It is increased by 5 mg per week and the maintenance dose is 20 mg/day. As memantine is an NMDA antagonist acting on glutamatergic receptors, it could be used with AChE inhibitors. It should be noted that all of these drugs (donepezil, galantamine, rivastigmine, and memantine) do not suppress the pathological process of Alzheimer's disease, which implies that patients treated by any of these drugs still show deterioration due to the disease process. Considering the limitations of the drugs available, clinicians should be prepared for the progression of the disease of the patients in the long run. Controlling of behavioral and psychological symptoms of the patients is important for the family and caregivers of the patients.11, 18, 25-29 Non-pharmacological intervention,12-14, 30 a care program,31 and support of the patients and family19, 32 will be even more important for the treatment of Alzheimer's disease patients.
Change in calcium response was studied to clarify the pathological process of Alzheimer''s disease (AD). Cultured fibroblasts from patients with familial Alzheimer''s disease (FAD; n = 6), sporadic Alzheimer’s disease (SAD; n = 4), and age-matched healthy control subjects (n = 4) were studied with an ACAS Interactive Laser Cytometer (ACAS-470). Fibroblasts from two independent families with FAD (OS-1, and OS-2 families) showed a suppressed calcium response after stimulation by 100 n<i>M</i> bradykinin (BK) 100 n<i>M</i> Vasopressin (VP)or 10% FCS in Ca<sup>2+</sup>-free condition compared with control fibroblasts at 48 h after plating. However, on the 7th day after plating, the abnormal calcium response was no longer observed. The height of the calcium peak showed periodic variation, indicating a relationship of calcium response with the cell cycle. When fibroblasts from OS-1 and OS-2 families were arrested in S phase, they showed a significantly suppressed calcium peak after BK stimulation. However, when those fibroblasts were arrested in other phases, they showed the same calcium peak as the other cells. The suppression of calcium response in S phase was indistinguishable from the calcium suppression induced by A23187 administration. Since Hardy type mutation on amyIoid precursor protein gene is found in the OS-1 family, the observed abnormalities in calcium response might be related with pathological processing of amyloid precursor protein in AD. The reported abnormal calcium response, which is observed most obviously in fibroblasts in S phase, may indicate participation of the cell-cycle-dependent process in the pathology of AD.
Recent advances in genomics and pharmacogenomics pose new challenges for the clinical management of dementia. Alzheimer's disease (AD), as the most frequent form of dementia, is a multifactorial/poligenic complex disorder in which hundreds of different genes are potentially involved, leading to the phenotypic expression of the disease in conjunction with epigenetic and environmental phenomena. Disease-related genomic profiles and genetic variants in genes involved in drug metabolism are responsible for drug efficacy and safety. The field of pharmacogenomics of AD is rapidly expanding and the clinical data of cytochrome c P450 enzymes (CYPs) have been accumulated for clinical application. Interaction of CYP2D6, CYP3A4/5 and AD-related genes will be discussed in this review. To achieve a mature discipline of pharmacogenomics of AD, the following three aspects are proposed: (a) education of physicians and the public on the use of genetic/genomic screening in daily clinical practice; (b) standardization of genetic testing for major categories of drugs; and (c) validation of pharmacogenomic procedures according to drug category and pathology.
Objectives. A meta-analysis of the associations between genetic variants in the AKT1 gene and schizophrenia found that a single nucleotide polymorphism (SNP5; rs2494732) was associated with schizophrenia in Asian populations. Methods. In this study, we investigated the effects of this SNP on memory and attentional performance and brain structure using magnetic resonance imaging in a Japanese population (117 patients with schizophrenia and 189 healthy subjects). Results. The memory performance, particularly attention/concentration score, measured by the Wechsler Memory Scale-Revised in A carriers of SNP5, which was found to be enriched in patients with schizophrenia, was lower than that in individuals with the G/G genotype. We confirmed the association of the SNP with attentional performance using the Continuous Performance Test, which assessed sustained attention and vigilance of attentional function. Patients with A allele demonstrated lower attentional performance than patients with the G/G genotype. Patients with the A allele had smaller gray matter volumes in the right inferior parietal lobule related to attentional processes and in the frontostriatal region related to different SNPs in AKT1 than patients with the G/G genotype. Conclusions. Our results suggest that a genetic variant of AKT1 might be associated with attentional deficits and brain morphological vulnerability in patients with schizophrenia.
The increase in the ratio of Aβ42 production has been widely accepted as pathological “gain of function” which determines the onset of familial AD pathology. However, it has not been studied whether the increase in the ratio of Aβ42 production plays a role in the pathological process of sporadic AD that occupies most of AD cases. Instead, many studies concerning an aspect of Aβ degradation/metabolism in sporadic AD have been conducted and indicated the importance of the Aβ degradation mechanism. To understand this trend, it is important to consider the highly aggregatable biochemical feature of Aβ42. Remarkably, in the CSF of sporadic AD patients, the Aβ42 level does not correspond to its generation in the brain. That is, insoluble Aβ42 levels are extremely high and soluble Aβ42 levels decrease in the sporadic AD brains. So far, there are no plans to address the level of Aβ42 production in sporadic AD brains without pathological mutations. Therefore, one of the most important issues remains unsolved. Cultured cells and Human CSF samples were used. Here, we indicated that the ratio of Aβ42 production increases in brains of sporadic AD patients bearing wt βAPP and presenilins as well as familial AD patients. This was made possible by our discovery of a novel peptide that is an elongated form of APLP1-derived Aβ-like peptide and is produced by the same process as Aβ42 but does not accumulate in the brain. We were able to make conclusions by using the level of the peptide in the CSF as a surrogate marker for Aβ42 in the brain of AD patients. First, this study addresses the pathogenesis of sporadic AD. Second, the discovery of this novel Aβ42 surrogate marker has clinical importance. Accumulation of Aβ42 is thought to begin long before onset of AD. If an increase in the relative Aβ42 production in the brain contributes to Aβ42 aggregation of sporadic AD patients, an elevated ratio of the elongated peptide in the CSF should precede accumulation of Aβ42 in the brain and should therefore serve as a biomarker for the disease onset.
Making the final cut: pathogenic amyloid-β peptide generation by γ-secretase – Alzheimer´s disease (AD) is a devastating neurodegenerative disease of the elderly population. Genetic evidence strongly suggests that aberrant generation and/or clearance of the neurotoxic amyloid-β peptide (Aβ) is triggering the disease. Aβ is generated from the amyloid precursor protein (APP) by the sequential cleavages of β- and γ-secretase. The latter cleavage by γ-secretase, a unique and fascinating four-component protease complex, occurs in the APP transmembrane domain thereby releasing Aβ species of 37-43 amino acids in length including the longer, highly pathogenic peptides Aβ42 and Aβ43. The lack of a precise understanding of Aβ generation as well as of the functions of other γ-secretase substrates has been one factor underlying the disappointing failure of γ-secretase inhibitors in clinical trials, but on the other side also been a major driving force for structural and in depth mechanistic studies on this key AD drug target in the past few years. Here we (...)
Changes in the production ratio of Aβ42/total might play a role in Alzheimer Disease pathology. However, any physiological mechanism regulating the ratio of Aβ42 production has not been known, so far. Any physiological substances that alter the cleavage precision of presenilin/γ-secretase cleavage were searched. Cell-free γ-secretase assay and purified in vitro γ-secretase assay were performed. The membrane-bound substances from pig brains or cultured cells were fractioned, and supplemented to the assays. We found evidence indicating the existence of physiological substance that dramatically changes the ϵ-cleavage precision, though it was not indispensable for the γ-secretase activity. The factor increases the production ratio of shorter AICDϵ51 (52-99) to longer AICDϵ49 (50-99). Our data suggests that the cleavage precision of γ-secretase could be under physiological regulation in vivo.
Until a decade ago, the common understanding was that forgetfulness in the elderly is a physiological phenomenon and that all elderly people show memory loss to some extent, with considerable variations in the severity of memory loss between individuals. Commonly observed memory loss in the elderly was termed ‘benign senescent forgetfulness’,1 which was regarded as different from the pathological state of dementia. Kral described benign senescent forgetfulness as follows: (i) impossible to recall unimportant things and part of the experience; (ii) able to recall these forgotten things at other times and on other occasions; (iii) more memory loss with older things compared with recent things; and (iv) subjects recognize this forgetfulness and try to compensate for it by several means.2 In the 1980s, there was an interest in ‘age-associated memory impairment’ (AAMI), which was also regarded as different from Alzheimer's disease, in which only memory function is disturbed without an affect on other cognitive functions.3,4 In those days, memory loss in the elderly was regarded as common and different from the pathological conditions leading to dementia, including Alzheimer's disease. Recent findings in neuroscience do not necessarily support the notions described above, and it is conceived that memory loss in the elderly is not inevitable, because newer findings show fully functioning brain activity in the elderly. For example, there is no significant decrease in the number of neurons in the elderly brain,5 even though the size of the neurons is smaller, and there is no reduction in cerebral blood flow and cerebral glucose metabolism in the brain of healthy elderly people compared with the younger brain.6 Neurogenesis is observed in the dentate gyrus of the hippocampus of brains over 50 years of age.7 We have now abundant data that support the hypothesis that the human brain can function properly over 50 years of age if the elderly person is not affected by dementia. Furthermore, this new understanding has been accelerated by research into the pathogenesis of Alzheimer's disease that explores possible means of intervention and prevention. Since 1996, drugs for the symptomatic treatment of Alzheimer's disease have been used widely, including acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and an N-methyl-d-aspartate (NMDA) antagonist (memantine), and we are now at the stage of developing disease-modifying drugs, which will give more benefit to the patients if administrated in earlier stages of the disease. Considering these situations, the initial stage, or even prestage, of the disease attracts more attention in research because it would be the period when the disease-modifying drugs would exert their maximum effect. The onset of neurodegenerative dementia, including Alzheimer's disease, is usually insidious; often, it is not possible to determine the exact time of onset. The diagnosis of dementia is often given to the patients retrospectively after identifying a certain set of behaviors caused by cognitive impairment. There is a relatively long period when patients are somewhat impaired but have not yet fully developed the symptoms of dementia. The prodromal stage of dementia has been described by many clinicians, and scales to assess the prodromal stage of dementia are used in clinical settings, such as the Clinical Dementia Rating Scale (CDR) developed by Hughes et al.8 and the Global Deterioration Scale (GDS) developed by Reisberg et al.9 The CDR breaks down the span between the healthy brain to severe dementia into five stages: 0, normal healthy; 1, mild dementia; 2, moderate dementia; and 3, for severe dementia. Between Stages 0 and 1 on the CDR is the Stage 0.5, ‘questionalble dementia’, which is described as mild memory loss with intact orientation, full achievement on the activities of daily living (ADL), with slight impairment in social activity but fully independent activity in daily life. Individuals in CDR Stage 0.5 show only slight forgetfulness, partial memory loss, with little impairment in time recognition and full recognition in space and person. Owing to the slightly impaired function of problem solving, these people may show slight impairment in social activity, but are usually able to live quite independent lives. The GDS divides the span between the healthy brain to severe dementia into seven stages: Stage 1 is normal healthy, Stages 2–4 are prodromal stage of dementia, and Stages 5–7 are dementia. More precisely, GDS-1 is defined as the normal healthy stage, with full operation of all cognitive functions; GDS-2 represents the stage where subjective memory loss is noticed by subjects, but no objective memory dysfunction is revealed by clinical investigation; GDS-3 is the stage at which memory dysfunction is disclosed by clinical examination and this stage is named initially ‘mild cognitive decline’, which can be similar to ‘mild cognitive impairment’ (MCI), later proposed by Petersen et al.10 Subjects with GDS-3 may show slight impairment in social and professional activities, but full function in most of their daily life (Fig. 1). Scheme of ‘retrogenesis’ proposed by Reisberg and Gauthier.15 CDR, Clinical Dementia Rating Scale; FAST, Functional assessment of dementia of the Alzheimer type; MMSE, Mini-Mental State Examination; AD, Alzheimer's disease; SCI, Subjective cognitive impairment; MCI, Mild Cognitive Impairment. Many concepts were proposed in the 1990s that describe the predementia stage with slightly different definitions. Examples include isolated memory impairment, incipient dementia, dementia prodrome, mild cognitive disorder, age-related cognitive decline, and mild neurocogntive disorder. In the late 1990s, psychometric data were included to define the predementia stage in addition to clinical observations. Petersen et al. proposed MCI10 and Graham et al. proposed ‘cognitive impairment no dementia’.11 Originally, MCI was defined as: (i) subjective memory complaints; (ii) objective memory impairment; (iii) no cognitive impairment; (iv) full ADL; and (v) no dementia.10 Elderly people living in the community who fulfilled the MCI criteria (n = 66; mean age 81 years) were followed up to determine the rate of dementia 4 years later. The MCI subjects showed a rate of dementia of 12%/year, which is significantly higher than that of the general population.10 In European countries, the concept of ‘age-associated cognitive decline’ (AACD) was proposed,12 which is defined by more than one standard deviation (1 SD) below than the age-match general population in at least one of the five cognitive domains (memory, attention, spatial recognition, language, and speculation). The AACD takes into equal consideration the five domains of cognitive function, whereas the MCI regards memory as the main criterion. In one study,13 an elderly population living in the community was investigated; 19.3% of people matched the criteria given by the AACD, but only 3.2% matched the criteria of the MCI. After 3 years follow up, 28.6% of AACD subjects had developed dementia, compared with only 11.1% of MCI subjects. Based on these findings, the concept of the AACD is claimed to depict a more stable cohort of cognitively impaired elderly, and the AACD can more specifically select predementia subjects who are likely to develop dementia.13 Petersen et al. later developed the original MCI (amnestic MCI) into a broader concept of MCI.14 An amnestic MCI is an individual with memory impairment, and there may be multiple-domain MCI showing deficits in one of the five cognitive functions: memory, language, attention, executive function, and spatial recognition. In this way, the MCI can be subdivided into subtypes, multiple-domain MCI with and without amnesia, and single non-memory domain MCI. These subclassifications of MCI subjects may correspond to the prestage of Alzheimer's disease, Lewy body disease, frontotemporal dementia, vascular dementia, or depression, respectively14 (Fig. 2). Multiple domain mild cognitive impairment (MCI). AD, Alzheimer's disease; DLB, diffuse Lewy body disease; FTD, frontotemporal dementia; VaD, vascular dementia; Depr, depression. (Modified from Peterson et al.10). However, the development of the MCI concept into subtypes is rather complicated and it can be better seen as the prestage of each corresponding disorder. In a sense, different subtypes of the MCI lose the significance of the concept of the MCI because it implies that MCI subjects are heterogeneous by nature, suggesting less usefulness of the conceptualization of the MCI as a whole. The main criteria of the original MCI of Petersen et al.10 are subjective memory loss and objective memory dysfunction. The other three criteria are to exclude subjects with cognitive impairment other than memory, ADL disability, and dementia. Discussions have been raised as to whether there is any difference between subjective and objective memory loss, because these two criteria can be dependent on each other. More specifically, the question can be raised, what is the condition where subjective memory impairment is recognized without any evidence of objective memory dysfunction? This is an important question because it relates to the question whether subjective cognitive impairment (SCI) should be regarded as prestage of MCI. Many people feel that their memory worsened after middle age. Many people admit that their memory worsened at 40–50 years of age, with people reporting having trouble recalling names of old friends or familiar places. Unfortunately, there is no scale or psychometric test to measure this type of subjective forgetfulness. The memory tests used routinely are not sensitive enough for this type of forgetfulness because they are designed to discriminate more severe cases of memory problems. We need more sensitive measures to detect fine decrements in memory function to show evidence related to impairment of subjective memory. As described in literature, memory capacity is quite different between individuals, especially in the elderly. More differences in memory function are observed in older populations. What we need is a measure to estimate the reduction in memory function compared with the highest level of a given individual. The goal is so simple: we need to measure and compare the decrease in memory function of individual subjects from their highest level of memory function. Dementia patients complain of memory loss only in the initial stages of the disease. The memory complaint will gradually disappear as the disease progresses. Alzheimer patients in earlier stage often recognize the fact that their memory function has been lost and complain of it. However, in the moderate to severe stages of Alzheimer's disease, most patients do not complain of memory loss because they lose the subjective recognition of memory function. Conversely, patients with depression often complain about their memory function. Even though they feel subjectively strong impairment in memory function, they often show almost normal or little impaired memory on objective evaluation. Extreme cases have been observed, termed pseudodementia, who show significantly deteriorated ADL function with relatively preserved memory function. When such patients are examined for memory function, they show almost normal levels, but still complain of memory loss. The patients are good examples of cases in which subjective memory impairment does not parallel objective memory impairment. Subjective memory impairment is affected by emotion and mood. Then, we have to ask the question whether memory function or cognitive function, which can be affected by an individual's emotional state, can really be objective markers of cognitive function. A more important question is whether this type of subjective memory impairment can be a precedent for objective memory dysfunction. If SCI can be regarded as an earlier stage of MCI, we can draw a scheme of SCI, MCI, and dementia, as shown in Figure 3. Sequential scheme of subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and dementia. ADAS.cog, Alzheimer's Disease Assessment Scale cognitive domain. On the GDS staging, Reisberg and Gauthier15 differentiated GDS-2 and GDS-3 as two different prestages of dementia, the former with subjective memory complaints without objective memory dysfunction, and the latter with objective memory dysfunction. In this sense, GDS-2 corresponds to SCI and GDS-3 corresponds to MCI. As shown in Figure 3, Reisberg and Gauthier estimate the duration of MCI as 2 years and that of SCI as 15 years.15 Under the concept of retrogenesis,16 Reisberg et al. understand the process of functional changes in the brain after the highest level of functioning has been reached, most probably in people in their 30s.17 Human brain function is very primitive just after birth. We are not capable of memory, language, or communication, implying that most cognitive function is not yet equipped at birth. Even though most of the component material for network formation exists, neuronal networks are not yet established due to immature myelination of neuronal axons. In the human brain, myelination will be accomplished in interaction with environmental factors along with actual experience. The function of the neural networks is adjusted and fine-tuned for the best accomplishment through experience in actual life. It may take 15–30 years to reach the highest level of accomplishment. This process is controlled not only by biological factors, but also by psychosocial dynamics, in which parental bonding, human relationships, and social interaction will have a dominant influence on the functional level of the neuronal networks of a given individual. The highest level of cognitive functioning is quite different between individuals. There is a variety of behavioral patterns that is described as personality (i.e. temperaments or characteristics of individuals). Then, after 30 years of age, the highest level of functioning will begin to deteriorate. As is postulated by Reisberg et al.,16 this downward process is retrogenetic because it goes back against the process of neural development, eventually leading to total disability of brain function. The long period of retrogenesis can be labeled as SCI. Figure 4 shows the life-long variation in cognitive function, including SCI, MCI, and dementia stage. It is proposed that MCI corresponds to the stage where social life capacity is impaired with the full functioning of personal life capacity and biological life capacity. During the course of dementia, personal life capacity will deteriorate, but it is important to note that biological life capacity is well preserved, even in the late stage of dementia (Fig. 4). Life-long view of cognitive function. SCI, subjective cognitive impairment; MCI, mild cognitive impairment. Even though the concept of SCI is immature and still has many problems that need to be resolved, the authors regard the concept of SCI useful. It should be refined further and the pathophysiology of SCI will attract more research attention, because earlier intervention in the pathogenesis of Alzheimer's disease is highly anticipated. It is well described that amyloid deposition is observed 15–20 years before the onset of clinical symptoms. After the era of symptomatic pharmacotherapy, which ameliorates some symptoms of Alzheimer's disease, we are now aiming for disease-modifying therapy, and even its prevention. Early detection and prevention of Alzheimer's disease is a more important strategy for this disorder; therefore, the concept of MCI has been characterized and the methodology for the prevention of Alzheimer's disease has been studied.18–21 Among the three hallmarks of Alzheimer's disease of amyloid deposition, tau pathology, and neuronal degeneration, amyloid deposition is observed in the earliest stage, and the suppression of amyloid pathology is naturally the main target for drug development. The timing of amyloid deposition is certainly much earlier than the onset of clinical symptoms and even earlier than the onset of MCI. This is the why SCI should be the target of studies to develop therapies for the prevention of and early intervention in Alzheimer's disease. If SCI, MCI, and dementia can be arranged in this sequential order, of course the first pathological state should be the target of intervention. Even though it is not easy to develop a clear definition of SCI, clinical researchers will be expected to work more with subjects with SCI.
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