**2. History of the concept of mild cognitive impairment**

During the last few decades various terms and definitions have been proposed to determine intermediate stage between normal aging and dementia. In 1962, V.A. Kral first described two types of age related cognitive changes in his works. One of them is "benign senescent forgetfulness" (BSF), which is characterized by mild and non-progressive memory decline and presumably implies non-specific histopathological changes in the brain. The second form, "malignant senescent forgetfulness" (MSF) includes progressive cognitive and behavioral changes which involves specific brain histopathology [2]. Introduction of the term "benign senescent forgetfulness" was the first attempt to conceptualize MCI [3].

At the same time, in the medical literature of dementia and aging, the term "mild cognitive impairment" has emerged. In 1988 Reisberg and colleagues used this term to characterize subjects with the Global Deterioration Scale Score 3 [12]. The GDS is a seven-point rating instrument for the staging of the magnitude of cognitive and functional capacity from normal aging to severe dementia [13]. Points in GDS range from 1 to 7. A score 3 indicates mild but obvious cognitive decline leading to difficulties in handling complex situations and tasks - e.g. lack of orientation while traveling to unfamiliar places, failure to recall names of new acquaintances, concentration deficit, troubles with retaining large amount of information, word and name finding deficit.

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In 1995, in an observational study of aging at Mayo clinic, R.C. Petersen and colleagues adopted mild cognitive impairment as an independent diagnostic entity to categorize persons with memory complaints, who were not demented, retained global cognitive function and daily living skills, but scored below the age-adjusted norms on memory tests (Although, it was in 1991, when the term MCI first appeared in the headline of the article by Flicker et al.,

Petersen R.C. and colleagues provided Mayo clinic criteria for mild cognitive impairments: 1. Subjective complaint on memory disturbance (preferably supported by the informant); 2. Objective evidence of memory deficit: 3. Generally preserved cognitive functions; 4.

In 2001, the American Academy of Neurology (AAN) incorporated new diagnostic criteria in a guideline on mild cognitive impairment. The AAN criteria for MCI were as follows: 1. An individual's report of his or her own memory problems, preferably confirmed by another person; 2. Measurable, greater-than-normal memory impairment detected with standard memory assessment tests; 3. Normal general thinking and reasoning skills; 4. Ability to perform normal daily activities [17]. Early detection and monitoring of persons with mild cognitive

Based on clinical observations, it became clear that mild cognitive impairment is not limited to memory loss. In 2003, the first key symposium was held in Stockholm, with the aim to integrate clinical and epidemiological perspectives on the topic of mild cognitive impairment [18]. The proposed MCI criteria were no more focused on memory impairment alone and

2. There is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; 3. Activities of daily living are preserved and complex instrumen-

At the same time a comprehensive classification of MCI was proposed that categorizes individuals by the type or domain of cognitive deficit (memory vs. non-memory such as language, visuospatial, speed of processing or executive function) and the extent of the deficits (single domain vs. multiple domains). Based on these criteria, four MCI subtypes have been proposed: Amnestic MCI-Single Domain (a-MCI-sd), Amnestic MCI-Multiple Domain (a-MCImd), Non-Amnestic MCI Single Domain (na-MCI-sd) and Non-Amnestic MCI-Multiple

"Mild Cognitive Impairment in the elderly: predictors of dementia") [14, 15].

impairment was recommended, due to the high risk of progression to dementia.

included the following features: 1. The person is neither normal nor demented;

Intact activities of daily living; 5. Absence of dementia [16].

tal functions are either intact or minimally impaired.

Domain (na-MCI-md) [19].

In 1986, the working group at National Institute of Mental Health proposed the diagnosis of age-associated memory impairment (AAMI) to identify age-related memory changes [4]. The concept was based on the comparison of older persons to young adult norms on a variety of memory tests. The idea was criticized by the WHO and International Psychogeriatric Association, because it included only memory assessment and did not imply diversity of agesensitivity of memory tests [5]. The concept of AAMI did not develop further. Alternatively, in DSM-IV it evolved in the term aging-associated cognitive decline (AACD) [5, 6]. The AACD diagnosis is similar to age-associated memory impairment. However, the AAMI diagnosis is based on a less comprehensive evaluation which takes into account memory function only [7]. Subjects are classified as having AAMI if they score 1 SD below the mean of younger adults (not people of their own age) in a standardized memory test [4].

In 1989, Blackford and La Rue proposed modified version of age associated memory impairment, "late life forgetfulness" (LLF) [8]. LLF was defined as slight deterioration of memory compared with aged-match persons, but the absence of Dementia [5].

Before the introduction of MCI concept elderly persons with cognitive complains who were not demented were categorized as having questionable dementia [5]. In the 1980s, global clinical staging scales have been developed to classify the wide spectrum of cognitive dysfunction in geriatric population. Among them Global Deterioration Scale (GDS) and Clinical Dementia Rating (CDR) are the most frequently used [9]. These scales differentiate a type of cognitive impairment which is intermediate between dementia and normal cognition function. Subjects with GDS 3 or CDR stage 0.5 are classified as having "questionable," "borderline" or "preclinical" AD. Other terms, such as "minimal dementia," "limited cognitive disturbance," "isolated memory loss," "mild cognitive disorder," "mild neurocognitive disorder" and "cognitive impairment-no dementia" (CIND) have been used to reflect the similar intermediate level of cognitive performance [9].

The term "cognitive impairment no dementia" was introduced in the Canadian Study of Health and Aging [10]. It was a multicenter study evaluating epidemiological aspects of cognitive impairment among Canadians aged 65 and older. In this study individuals with some degree of cognitive decline, who did not meet criteria for dementia, were classified as having "cognitive impairment no dementia". Cognitive impairment no dementia is a broad concept and involves cognitive decline of any etiology, including delirium, alcoholism, drug addiction, depression, psychiatric disorders [11]. The prevalence of CIND among the Canadian elderly was reported to be twice that of all dementias combined [5, 10].

At the same time, in the medical literature of dementia and aging, the term "mild cognitive impairment" has emerged. In 1988 Reisberg and colleagues used this term to characterize subjects with the Global Deterioration Scale Score 3 [12]. The GDS is a seven-point rating instrument for the staging of the magnitude of cognitive and functional capacity from normal aging to severe dementia [13]. Points in GDS range from 1 to 7. A score 3 indicates mild but obvious cognitive decline leading to difficulties in handling complex situations and tasks - e.g. lack of orientation while traveling to unfamiliar places, failure to recall names of new acquaintances, concentration deficit, troubles with retaining large amount of information, word and name finding deficit.

**2. History of the concept of mild cognitive impairment**

92 Alzheimer's Disease - The 21st Century Challenge

senescent forgetfulness" was the first attempt to conceptualize MCI [3].

(not people of their own age) in a standardized memory test [4].

with aged-match persons, but the absence of Dementia [5].

to be twice that of all dementias combined [5, 10].

During the last few decades various terms and definitions have been proposed to determine intermediate stage between normal aging and dementia. In 1962, V.A. Kral first described two types of age related cognitive changes in his works. One of them is "benign senescent forgetfulness" (BSF), which is characterized by mild and non-progressive memory decline and presumably implies non-specific histopathological changes in the brain. The second form, "malignant senescent forgetfulness" (MSF) includes progressive cognitive and behavioral changes which involves specific brain histopathology [2]. Introduction of the term "benign

In 1986, the working group at National Institute of Mental Health proposed the diagnosis of age-associated memory impairment (AAMI) to identify age-related memory changes [4]. The concept was based on the comparison of older persons to young adult norms on a variety of memory tests. The idea was criticized by the WHO and International Psychogeriatric Association, because it included only memory assessment and did not imply diversity of agesensitivity of memory tests [5]. The concept of AAMI did not develop further. Alternatively, in DSM-IV it evolved in the term aging-associated cognitive decline (AACD) [5, 6]. The AACD diagnosis is similar to age-associated memory impairment. However, the AAMI diagnosis is based on a less comprehensive evaluation which takes into account memory function only [7]. Subjects are classified as having AAMI if they score 1 SD below the mean of younger adults

In 1989, Blackford and La Rue proposed modified version of age associated memory impairment, "late life forgetfulness" (LLF) [8]. LLF was defined as slight deterioration of memory compared

Before the introduction of MCI concept elderly persons with cognitive complains who were not demented were categorized as having questionable dementia [5]. In the 1980s, global clinical staging scales have been developed to classify the wide spectrum of cognitive dysfunction in geriatric population. Among them Global Deterioration Scale (GDS) and Clinical Dementia Rating (CDR) are the most frequently used [9]. These scales differentiate a type of cognitive impairment which is intermediate between dementia and normal cognition function. Subjects with GDS 3 or CDR stage 0.5 are classified as having "questionable," "borderline" or "preclinical" AD. Other terms, such as "minimal dementia," "limited cognitive disturbance," "isolated memory loss," "mild cognitive disorder," "mild neurocognitive disorder" and "cognitive impairment-no dementia" (CIND) have been used to reflect the similar intermediate level of cognitive performance [9].

The term "cognitive impairment no dementia" was introduced in the Canadian Study of Health and Aging [10]. It was a multicenter study evaluating epidemiological aspects of cognitive impairment among Canadians aged 65 and older. In this study individuals with some degree of cognitive decline, who did not meet criteria for dementia, were classified as having "cognitive impairment no dementia". Cognitive impairment no dementia is a broad concept and involves cognitive decline of any etiology, including delirium, alcoholism, drug addiction, depression, psychiatric disorders [11]. The prevalence of CIND among the Canadian elderly was reported In 1995, in an observational study of aging at Mayo clinic, R.C. Petersen and colleagues adopted mild cognitive impairment as an independent diagnostic entity to categorize persons with memory complaints, who were not demented, retained global cognitive function and daily living skills, but scored below the age-adjusted norms on memory tests (Although, it was in 1991, when the term MCI first appeared in the headline of the article by Flicker et al., "Mild Cognitive Impairment in the elderly: predictors of dementia") [14, 15].

Petersen R.C. and colleagues provided Mayo clinic criteria for mild cognitive impairments: 1. Subjective complaint on memory disturbance (preferably supported by the informant); 2. Objective evidence of memory deficit: 3. Generally preserved cognitive functions; 4. Intact activities of daily living; 5. Absence of dementia [16].

In 2001, the American Academy of Neurology (AAN) incorporated new diagnostic criteria in a guideline on mild cognitive impairment. The AAN criteria for MCI were as follows: 1. An individual's report of his or her own memory problems, preferably confirmed by another person; 2. Measurable, greater-than-normal memory impairment detected with standard memory assessment tests; 3. Normal general thinking and reasoning skills; 4. Ability to perform normal daily activities [17]. Early detection and monitoring of persons with mild cognitive impairment was recommended, due to the high risk of progression to dementia.

Based on clinical observations, it became clear that mild cognitive impairment is not limited to memory loss. In 2003, the first key symposium was held in Stockholm, with the aim to integrate clinical and epidemiological perspectives on the topic of mild cognitive impairment [18]. The proposed MCI criteria were no more focused on memory impairment alone and included the following features: 1. The person is neither normal nor demented;

2. There is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; 3. Activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.

At the same time a comprehensive classification of MCI was proposed that categorizes individuals by the type or domain of cognitive deficit (memory vs. non-memory such as language, visuospatial, speed of processing or executive function) and the extent of the deficits (single domain vs. multiple domains). Based on these criteria, four MCI subtypes have been proposed: Amnestic MCI-Single Domain (a-MCI-sd), Amnestic MCI-Multiple Domain (a-MCImd), Non-Amnestic MCI Single Domain (na-MCI-sd) and Non-Amnestic MCI-Multiple Domain (na-MCI-md) [19].

Presumably, the cognitive phenotype of MCI (a-MCI vs. na-MCI) and the number of cognitive domains affected (single vs. multiple) determine the future outcome of mild cognitive impairment. Amnestic single or multiple domain MCI is supposed to be precursor of Alzheimer disease, whereas persons with na-MCI likely progress to a non-AD dementia, such as dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease or Parkinson-Dementia [20] (**Table 1**).

**3. Preservation of independence in functional abilities.** Individuals with MCI usually experience some difficulties with handling complex situations, such as performance of financial operations, cooking, shopping. They may need more time, be less efficient, or make more

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**4. Not demented.** Observed cognitive dysfunction is usually mild and doesn't affect social or occupational activities. Objective demonstration of intra-individual change of cognitive

The *Clinical Research Criteria* which incorporate the use of biomarkers, are intended to be used only in research settings to assess the underlying etiology of MCI and the likelihood of progression to dementia. According to the NIA-AA recommendations, concomitant application of clinical and research criteria can increase the diagnostic certainty. For this purposes 2 main types of biomarkers are investigated: Biomarkers of beta-amyloid deposition and biomarkers of neuronal injury/neurodegeneration. Biomarkers of beta-amyloid accumulation are: low CSF concentration of amyloid β42 and PET (positron-emission tomography) evidence of amyloid deposition. Biomarkers of neuronal injury are: High concentration of Tau/ Phosphorylated protein in CSF; Hippocampal, or medial temporal lobe atrophy on MRI, and temporoparietal/

Based on biomarkers we can assess the risk of development of Alzheimer's disease. Currently, CSF Aβ42 and tau measures, the ratio of CSF tau/Aβ42, PET amyloid measures, and other biomarkers of neuronal injury such as hippocampal atrophy and temporoparietal hypometabo-

• The evidence of positive Aβ biomarker and a positive biomarker of neuronal injury indicate a high likelihood that the MCI syndrome is due to AD. In addition, individuals with this biomarker profile are more likely to decline or progress to dementia due to AD in

• The probability that MCI is due to AD is moderate in cases in which one of the biomarkers

• In a situation, where the biomarkers are negative, the likelihood of development of AD is low.

Since MCI imposes a health burden of its own and increases the risk of dementia, it is important to reliably estimate the prevalence of MCI around the globe [25]. However, reported prevalence of MCI significantly differs across studies and ranges between 3 and 54% [5]. It is thought that this difference can be explained by the difference in research methodology, such as employed diagnostic criteria for MCI, variability of used neuropsychological tests, selected cut-off scores (≥1 SD or ≥1.5 SD), subjects of trials - population based or clinic based. Some of the variation may be associated with regional and/or ethnic differences. For example, MCI prevalence in India is 5 times higher than in China, despite standardization for age, sex

errors during such activities. Nevertheless, they preserve functional independence.

function via the history or clinical assessment is required for the diagnosis of MCI.

precuneus hypometabolism or hypoperfusion on PET or SPECT [23, 24].

lism have all been shown to predict progression of MCI to dementia [5, 24].

is positive and the others have not been or cannot be tested.

**3. Epidemiology of mild cognitive impairment**

relatively short periods.

In the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-V) the term dementia is replaced by the term neurocognitive disorder. DSM-V recognizes the predementia stage of cognitive impairment and defines it as mild neurocognitive disorder (NCD) [21, 22]. Diagnostic criteria for mild NCD are almost identical to MCI criteria and include the following: 1. Clinical concern raised by the patient or an informant, or observations made by the clinician; 2. Cognitive impairment in one or more cognitive domains preferably relative to appropriate normative data for that individual; 3. Preservation of functional independence and 4. No dementia

In 2011, National Institute of Aging (NIA) and Alzheimer's Association (AA) developed diagnostic criteria for symptomatic pre-dementia phase of Alzheimer's disease [23]. The working group proposed two sets of criteria: core clinical criteria and clinical research criteria incorporating biomarkers. The NIA-AA criteria for MCI due to AD are as follows:



**Table 1.** MCI classification.

**3. Preservation of independence in functional abilities.** Individuals with MCI usually experience some difficulties with handling complex situations, such as performance of financial operations, cooking, shopping. They may need more time, be less efficient, or make more errors during such activities. Nevertheless, they preserve functional independence.

Presumably, the cognitive phenotype of MCI (a-MCI vs. na-MCI) and the number of cognitive domains affected (single vs. multiple) determine the future outcome of mild cognitive impairment. Amnestic single or multiple domain MCI is supposed to be precursor of Alzheimer disease, whereas persons with na-MCI likely progress to a non-AD dementia, such as dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease or Parkinson-Dementia [20] (**Table 1**).

In the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-V) the term dementia is replaced by the term neurocognitive disorder. DSM-V recognizes the predementia stage of cognitive impairment and defines it as mild neurocognitive disorder (NCD) [21, 22]. Diagnostic criteria for mild NCD are almost identical to MCI criteria and include the following: 1. Clinical concern raised by the patient or an informant, or observations made by the clinician; 2. Cognitive impairment in one or more cognitive domains preferably relative to appropriate normative data for that individual; 3. Preservation of functional independence

In 2011, National Institute of Aging (NIA) and Alzheimer's Association (AA) developed diagnostic criteria for symptomatic pre-dementia phase of Alzheimer's disease [23]. The working group proposed two sets of criteria: core clinical criteria and clinical research criteria incorpo-

**1. Concern regarding a change in cognition.** Concern about a cognitive decline compared to the previous level should be obtained from the patient, form an informant, or from a

**2. Impairment in one or more cognitive domains.** Evidence of dysfunction in one or more cognitive domains (memory, executive function, attention, language, and visuospatial

**Amnestic multiple domain Non-amnestic single domain Non-amnestic multiple** 

**Frontotemporal dementia Lewy body**

One of the following:

*Language Attention Executive function Visuospatial function Processing speed*

**domain**

*Language Attention Executive function Visuospatial function Processing speed*

**dementia**

**Vascular dementia**

>1 of the following

rating biomarkers. The NIA-AA criteria for MCI due to AD are as follows:

and 4. No dementia

**MCI subtypes and etiology**

**Table 1.** MCI classification.

**Amnestic single domain**

clinician observing the patient.

94 Alzheimer's Disease - The 21st Century Challenge

Memory only Memory plus ≥ 1 of the

**Alzheimer's disease Alzheimer's disease**

skills) should be objectively demonstrated.

following: *Language Attention Executive function Visuospatial function Processing speed*

**Vascular dementia**

**4. Not demented.** Observed cognitive dysfunction is usually mild and doesn't affect social or occupational activities. Objective demonstration of intra-individual change of cognitive function via the history or clinical assessment is required for the diagnosis of MCI.

The *Clinical Research Criteria* which incorporate the use of biomarkers, are intended to be used only in research settings to assess the underlying etiology of MCI and the likelihood of progression to dementia. According to the NIA-AA recommendations, concomitant application of clinical and research criteria can increase the diagnostic certainty. For this purposes 2 main types of biomarkers are investigated: Biomarkers of beta-amyloid deposition and biomarkers of neuronal injury/neurodegeneration. Biomarkers of beta-amyloid accumulation are: low CSF concentration of amyloid β42 and PET (positron-emission tomography) evidence of amyloid deposition. Biomarkers of neuronal injury are: High concentration of Tau/ Phosphorylated protein in CSF; Hippocampal, or medial temporal lobe atrophy on MRI, and temporoparietal/ precuneus hypometabolism or hypoperfusion on PET or SPECT [23, 24].

Based on biomarkers we can assess the risk of development of Alzheimer's disease. Currently, CSF Aβ42 and tau measures, the ratio of CSF tau/Aβ42, PET amyloid measures, and other biomarkers of neuronal injury such as hippocampal atrophy and temporoparietal hypometabolism have all been shown to predict progression of MCI to dementia [5, 24].

