DEFINITION FOR MCI:

Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individuals age and education level But that does not interfere notably with activities of daily life.

CRITERIA FOR MCI:

PETERSEN -1997

The most widely accepted diagnostic criteria for probable AD are those offered by the National Institute of Neurological and Communicative Disorders and Stroke and by the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA; McKhann et al., 1984). These criteria include the presence of dementia established by clinical examination and confirmed by neuropsychological testing. The dementia is described as involving multiple, progressive cognitive deficits in older persons in the absence of disturbances of consciousness, presence of psychoactive substances, or any other medical, neurological, or psychiatric conditions that might in and of themselves account for these progressive
deficits.

EADC WORKING GROUP:

Cognitive complaint emanating from the patient and/or his/her family. The subject and/or informant report a cognitive decline compared to previous abilities during the past year Cognitive disorders evidenced by evaluation

 Cognitive impairment does not have major percussions in life. No dementia

GENERAL CRITERIA FOR MCI:

Not normal,not demented(does not meet DSM IV/ICD 10 criteria for dementia) Cognitive decline Self and/ or informant report on objective cognitive tasks And /or Evidence of decline over time on objective cognitive tasks Preserved basic activities of daily living /minimal impairment in complex instrumental functions

SUBTYPES OF MCI: BASED ON COGNITIVE FEATURES:

1) Amnestic MCI Impairment in memory 2) Multiple domain MCI Impairment noticed in more than one cognitive domain 3)Single domain non amnestic MCI Impairment in any one domain except memory. cognitive

BASED ON AETIOPATHOLOGY
1) Neurodegenerative PreAlzheimers,Lewy body,Frontotemporal and focal atrophy 2) Vascular Vascular and mixed dementia 3) Dysthymia or dysphoria (anxious and/or depressed states)

HISTORY
1962 Kral Benign senescent Forgetfulness(BSF) Malignant senescent Forgetfulness(MSF) 1986 NIMH Age associated memory impairment(AAMI) 1994 International Psychogeriatrics association Age associated cognitive decline 1997 Canadian study of health Cognitive impairment No dementia (CIND) MCI

EPIDEMIOLOGY:
Varies from 3 to 17% ( 3% at 60 yrs and 15 % at 75 yrs ) Men > women Conversion from MCI to AD 10% per year

ASSESSMENT:
CAMDEX - Minimal dementia CARE - limited cognitive disturbance Mini mental state examination(MMSE) Clinical dementia rating scale (CDR) Intelligence testing Global deterioration scale (GDS) NPI and NPI-Q IQ CODE Clock drawing test Tests of verbal fluency and verbal memory

MCI patients tend to overestimate their cognitive deficits compared to their caregivers assessment,AD patients in the early stages underestimate cognitive dysfunction.

SCREENING TESTS:
WAIS : Intelligence tests were also used to assess the cognitive decline.The discrepancy between verbal and performance tasks are evident in normal that become accentuated in early dementia.. MMSE: A score of 26(in the noneducated) and 28(educated) should be alerted . Widely used short screening instrument for dementia. MONTREAL COGNITIVE ASSESSMENT(MoCA): Screen patients with mild cognitive complaints and usually perform in the normal range on the MMSE. Sensitivity:MMSE:78%,MoCA:100% DEM TECT: High sensitivity of 80% in detecting MCI. It helps in deciding whether cognitive performance is adequate for age(13-18)points,or MCI(9-12),or dementia(8 points or below). Specificity:MMSE:18%,MoCA:90% It is a stand alone cognitive screening tool with superior sensitivity. Clinical dementia rating scale(CDR): Hughes and colleagues developed this scale(1980s).CDR score is obtained by information provided by the caregiver or an operator and by a cognitive examination that assesses memory,judgement,abstract reasonin g, spatial and temporal orientation, plus evaluation of social and working activity,hobbies and activities of daily living.The primary domain is memory while the five secondary domains are orientation ,judgement and problem solving,community affairs ,home and hobbies and personal care.The CDR has

now become the gold standard in global rating,not used in diagnosis of dementia but in rating the severity from no impairment to severe dementia.The scores are 0 normal(healthy) 0.5 Questionable dementia - Mild consistent forgetfulness,partial recollection of events,fully oriented,only doubtful impairment in solving problems& community affairs with well maintained or only slightly impaired life at home and hobbies with adequate self care. 1 Mild dementia 2 Moderate dementia 3 Severe dementia CAMDEX Cambridge Examination for Mental disorders of the Elderly - Is a standard ,structured interviews, and quantitative evaluation of a wide range of cognitive functions.It is aimed to diagnose dementia at an early stage.CAMCOG is the only significant predictor for the clinical diagnosis of dementia.The sensitivity and specificity of diagnosis with CAMCOG were also high: a cut off score of 79-80(out of 106) gave sensitivity and specificity results of 92% and 96% respectively,for cognitive impairment.No depressed patients were misclassified as having cognitive impairment using the CAMCOG at this cut off. GLOBAL DETERIORATION SCALE: A scale designed by Reisberg and colleagues.It is a clinician rated tool.It has seven stages . Stage -1:No cognitive decline Stage -2: Very mild cognitive decline complaints of daily forgetfulness of every day items and names Stage -3: Mild cognitive decline Evidence of cognitive decline starts to become apparent to the trained specialist at this stage.There may be some deterioration at work or complex social situations.Risk of progressing to alzheimers dementia is increased. Stage 4:Moderate cognitive decline Stage5: Moderately severe cognitive decline

Stage 6:Severe cognitive decline Stage 7: Very severe cognitive decline.

CONSORTIUM TO ESTABLISH A REGISTRY FOR ALZHEIMERS DISEASE: CERAD BATTERY consists of a neurological evaluation and a neuropsychological battery to assess the severity and extent to which various cognitive domains are affected. PSYCHOMETRIC ASSESSMENT FOR SPECIFIC COGNITIVE DOMAINS: MEMORY: SHORT TERM MEMORY: In the earliest stages ,there may be a clear dissociation between the impairment of central executive system and the relative preservation of the articulatory loop and the visuospatial sketch pad.Patients at this stage have difficulty in performing two tasks simultaneously and i manipulating information in working memory. Two tests widely used in clinical practice:The digit span and the Visuo spatial span.In digitspan test the patient is presented with a series of numbers and required to reproduce the series immediately in the correct order. CORSI TEST: This test is used for visuo spatial span .This consists of nine cubes fashioned in a random order in a board.Each time the examiner taps the blocks in a prearranged sequence ,the patient must copy the tapping pattern. EXPLICIT LONGTERM MEMORY:It is mandatory. Involvement of episodic memory is the earliest symptom.It is a powerful predictor of future dementia in individuals at risk. California verbal learning test(CVLT). ATTENTION: Cancellation test:The subject has to detect the series of stimuli,for example a letter or a digit,among a great number of distracters.Stroop test,the patients are exposed to ambiguous stimuli,namely names of colourswritten in an incongruous ink colour.The

subjects are required to name as fast as possible the colour of the ink in which the word is written and to ignore the word itself. EXECUTIVE FUNCTIONS: Verbal fluency:Words belonging to a particular category Trailmaking test:PartA:The subject must draw lines to connect consequently numbered and letter circles. PART B:Then connect the same number of consecutively numbered and lettered circles on another work sheet by alternating between the 2 sequences. Wisconsin card sorting test: LANGUAGE: Impaired naming involvement of semantic memory.Boston naming test used. PRAXIS: Reys complex figure test and constructional apraxia test. In patients with AD , all aspects of visuoconstruction are affected. VISUOSPATIAL ABILITIES: TMT B and Streets test are used.The spatial cognition tested in AD are mental rotation and judgement line of orientation. NEUROPSYCHIATRIC INVENTORY: The scale relies on caregivers and evaluates 12 common psychiatric disorders.NPI is a valid instrument in behavioural evaluation. CLOCK DRAWING:Can test progression of basic cognition and abilities,asimple bedside test. FUNCTIONAL SCALES: Living Instrumental activities of daily living(IADL): ADL( activities of daily living) questionnaire:conists of IADL and BADL .IADL evalutes complex skills such as managing money and basic adl which assesses self maintenance skills.The BARTHEL INDEX within BADL measures walking,bathing,eating,dressing and use of toilet.

Communicative activities of daily living( CADL): It has been used to investigate functional communication skills in subjects in patients with mild and moderate AD.The scores are compared with normal elderly and depressed elderly Individuals.

PATHOLOGY:

Gross pathology: - Neuritic plaques(NP )and neuro fibrillary tangles(NFT)

The most common characteristics of these subjects include neurofibrillary pathology in the medial temporal lobe and diffuse amyloid deposition in the neocortex. .

Microscopic changes:
Decreased neuron number and volumes are seen in the entorhinal cortex (nerve relay) and the hippocampus(memory) Betaamyloid deposition is intermeditate in MCI between normal and those with AD. Phosphorylated tau proteins and neurofibrillary tangles are seen in the vulnerable regions. Down regulation of TrKA RNA :There is a significant loss in the TrkA containing neurons in MCI and AD.The alterations in the nucleus basalis neurons containing TrkA immunoreactivity occur early in the disease and are accelerated on conversion from MCI to AD. Loss of ChAT activity: In individuals with MCI and mild AD ,ChAT was unchanged in the inferior parietal,superior temporal and anterior cingulate.But there is an elevation of ChaT activity in the superior frontal compared to normal people,whereas in the mild AD it was not.Hippocampal ChAT activity is significantly higher in MCI.The increase in superior and hippocampal ChAT activity could be an important factor in preventing the transition from MCI to AD.

Braack&Braack scheme: Topographic spreading spreading of neurofibrillary tangle(stage 1 6) Stage 1&2: Entorhinal Stage 3&4:hippocampus Stage 5&6:neocortical Stage I is defined by the appearanceof neurofibrillary tanglebearing neurons in the transentorhinal region, withprogression to the entorhinal region and hippocampal formation in stage II. Thesestages represent the presymptomatic phase of the disease. Further progressionleads to stages III and IV, which are characterized by severe involvement of the entorhinal region, amygdala, and hippocampalformation. This involvement leads to interruption of the limbic loop,which is responsible for data transfer back and forth between the neocortex and the hippocampal formation. In addition,there is also involvement of manysubcortical nuclei with diffuse projections to the cortex, among them the cholinergic system of the basal forebrain, includingthe nucleus basalis of Meynert. Patients with disease at these stages may present with symptoms of mild cognitiveimpairment (MCI) or prodromal AD, although symptoms may be masked by a high cognitive-reserve capacity. In stageV, there is extension to all major regions of the cerebral cortex, from association areas into primary areas. In stage VI, even the primary sensory areas are severely involved, although the motor area continues to be relatively spared. Stages V and VI are generally characterized by severe dementia. Three stages in the gradual evolutionof plaque deposition have been described. Stage A is characterized by deposition in the basal temporal neocortex, or entorhinal cortex. There then is extension through the hippocampal formation in stage B, eventually leading to deposits in virtually all cortical areas, including the highly myelinated primary areas of the neocortex in stage C. CERAD guidelines : Semiquanititative assessment of neuritic plaque(NP) density,graded by cartoon comparison.Sampling of multiple cortical areas and midbrain. Sparse NPs consisted of 1 to 5 NPs/100 x field (grade 1); moderate NPs, 6 to 19 NPs/100 x field (grade 2); and frequent NPs, 20 or more NPs/100 x field (grade 3). NIA RI criteria:(1997)

Probability statements based on topographic staging of NFT and SP.All lesions were considered(amyloid deposits,neuritic plaques,neuropil threads,NFT) Age related plaque score and topographic staging of NFT combined with clinical information. Probabilistic approach for diagnosis of dementia: Low probability: CERAD sparse and BRAAK stage I&II Intermediate probability:CERAD moderate and BRAAK stage III&IV High probability: CERAD frequent and BRAAK stage V&VI In MCI , neuropathological diagnosis may not play a definitive role. It has been found that many patients with CDR0.5 and CDR 1 ,have been graded as having low probability AD despite convincing clinical and psychometric data that they have rapidly progressive clinical dementia. Lewy Bodies and Vascular infarcts: Lewybodies and vascular infarcts were not significantly different in MCI compared to cognitively normal and demented patients.

BIOLOGICAL MARKERS:
CSF biomarkers beta amyloid A beta,total tau and phospho tau Isoprostane Significant rise in the monocyte producing cytokines

BETA AMYLOID PEPTIDE 42 AND 40: -Beta amyloid 42

decreased in CSF

- The levels were lower in patients with ApoE4 allele. The explanation for decreased Abeta42 level in csf :1)caused by deposition of Abeta plaques with lower amount free to diffuse into plasma2)Disturbances in formation of Abeta formation and breakdown . - Does not aid in dd of dementia

- Beta amyloid 40 appears late in the disease.Is prominent in vascular amyloid deposits.

 Ratio of Abeta 42/40 superior to Abeta42 in discriminating normal and patients with cognitive decline. A beta in plasma - Increased Abeta 42 and 40 levels.Abeta 42 is detected severalyears before the onset of symptoms. TAU PROTEIN:Neurofibrillary tangles consist of paired helical filamentsderived from abnormally hyperphosphorylatedmicrotubule associated protein tau. Total tau and phosphorylated tau TOTAL TAU: Reflects nonspecific process of axonal damage and neuronal degeneration.The effect of age should be considered when csf t-tau protein is measured.An age associated increase in t tau protein has been shown.Age dependent reference values are: 21-50 yrs <300pg/ml ,51-70 yrs -<450pg/ml,70-93 yrs - <500pg/ml. In patients suffering from MCI who converted to AD during follow-up,elevated t-tau levels at baseline were found in a relatively high number of individuals. PHOSPHORYLATED TAU: p tau 231 appears early in the pathological development of disease even before formation of paired helical filaments in the hippocampus.It predicts cognitive decline in patients with MCI.High p-tau levels at baseline denotes subsequent progressive cognitive decline . APOLIPOPROTEIN E: Is the major lipoprotein in the CNS where it is involved in the mobilization and redistribution of cholesterol,necessary for the maintenance of myelin and neuronal membranes.Increased levels of APOE has been found in CSF of patients with MCI. ISOPROSTANES: Oxidative damage to CNS tissue prominently manifests as lipid peroxidation(LPO).Isoprostanes are prostaglandin isomers that are produced exclusively from free-radical-catalyzed peroxidation of arachidonic acid.Isoprostanes are biochemically stable endproducts of LPO that are released by phospholipases,circulate in plasma and are excreted in urine.Therefore ,analysis of LPO by measuring Isoprostane levels have been performed in brain,CSF,serum and urine.Isomers of F2 Isoprostanes(F2alpha-iPS),especially 8,12 iso iPF2alpha VI has been

focused.Studies have shown elevated levels in blood ,urine,CSF and correlates with memory impairment. CRP: CRP is not normally found in the brain,but has been found in neurofibrillary tangles and plaques in the brains of demented patients. High serum CRP has a 3 fold increased risk of developing all dementias.CRP might play a causal role or merely an inflammatory marker. OXYSTEROLS AND CHOLESTEROL: Cholesterol is converted to 24s - OH cholesterol by 24s hydroxylase in the brain.Excessive removal of cholesterol occurs in the brain during neurodegenerative processes. The 24s hydroxy cholesterol levels in CSF are elevated in patients with MCI . CYTOKINES: There is a significant rise in the monocyte producing cytokines(IL-1beta,IL-6,TNFalpha,IL-12)

GENETIC MARKERS:
Apo E4 PON(Paraoxanase) ACE gene COMT and BDNF

NEUROIMAGING:
Structural : Structurally, MCI is characterized by atrophy of the medial temporal lobe (MTL) structures such as the hippocampus and entorhinal cortex, and the amount of atrophy in MCI is intermediate between healthy aging and ADAdditionally, atrophy of the posteromedial cortices such as the posterior cingulum and precuneus as well as of the lateral temporal cortices has been reported. The pattern of atrophy appears to vary according to the subtype of MCI.

Functional MRI studies in MCI, compared to healthy aging and AD, have demonstrated both increased and decreased MTL activity during encoding novel visually presented material. Differences in the MTL activation pattern in MCI subjects may relate to differences in the severity of cognitive decline. It is suggested that both altered MTL and posteromedial cortical function may be indicative of future cognitive decline from MCI to clinical AD.Decreased temporal lobe activity is seen in AD whereas in some studies there is an enlarged area of activationin medial temporal lobe in MCI which is probably a compensatory mechanism in the early stages of disease.(recruitment of wider networks). aMCI had significantly lower scores on tests of memory and a pattern of atrophy including bilateral hippocampi and entorhinal cortex, right inferior parietal cortex, and posterior cingulate gyrus. dMCI had significantly lower scores on the majority of executive function tests, increased behavioral symptoms, and left prefrontal cortex atrophy on MRI when compared to controls. Voxel based morphometry analysis in MCI had shown that patients have patients have highly significant gray matter loss predominantly affecting the medial temporal lobe , the hippocampal regions,the thalamus and into the neocortex. MRS NAA/Creatinine ratio , Myoinosithol - NAA and myo-inositol metabolite levels in patients with MCI to be between those of cognitively normal subjects and patients with AD. Diffusion weighted imaging: High apparent diffusion coefficients(ADC) in hippocampus , posterior cingulate,temporal lobe gray matter,amygdalae and corpus callosum. SPECT: Tc99mHMPAO orTc99m ECD SPECT- Reduced cerebral blood flow in posterior cingulate,precuneus and then hippocampal and amygdala involvement and then decreased perfusion in the tempero parietalasso.Cortices. FDG PET: A consistent finding in the Alzheimers dementia is the hypometabolism of the temperoparietal cortices.In MCI there is decreased local cerebral metabolic rate of glucose (lCMRglc) in the entorhinal cortex with later additional involvement of temperoparietal cortex and the posterior cingulate.The hypometabolism can be detected decades before the onset of AD in vulnerable persons.The glucose metabolism of temperoparietal and posterior cingulate decreases by 2% per year in asymptomatic middle aged and elderly subjects with positive APO E4 allele. Studies have shown that lCMRglc with neuropsychological testing were most effective in predicting the future development of AD.

Reduced uptake in DLB is seen in the primary visual cortex which is not involved in AD. FTD: Mesial frontal metabolic impairment can be found in nearly all cases. BETA AMYLOID IMAGING : PET radioligands that bind to cerebral amyloid and potentially to tau proteins have been developed.T hese include - Pittsburg Compound B(PiB) for amyloid - FDDNP for amyloid and tau.

MANAGEMENT AND TREATMENT:

There are no standard therapies for MCI. A clinical management plan is formulated on an individual basis in consideration with the cognitive pattern of MCI and its aetiology.There are 2 goals for treatment: 1)To alleviate the cognitive symptoms of MCI 2) To attempt to delay the onset of dementia in those at risk. PHARMACOTHERAPY: Choline esterase inhibitors:Donepezil has been shown to have transient effects on the conversion from MCI to AD, which does not hold for more than 18 months. Memantine has not been of any benefit. COX 2 Inhibitors Anti amyloid :Secretase inhibitors have been developed which inhibit the formation of amyloid .Fibrillogenesis inhibtors (alzhmed and clinoquinol)are being explored. Antioxidants like Vitamin E ,Vitamin C,turmeric are hypothesized to reduce oxidative stress and aging. Dopamine agonists: Piribedil , a dopamine agonist showed an improvement in global cognitive function in MCI. Drugs under trial -AL-208,C-105,MEM -1003,MEM -1414 SGS -518

NON PHARMACOLOGICAL:
Treatment of associated Comorbidities sleep,depression Treatment of Vascular Risk factors HT, DM,Weight gain. Social networking: Isolation exacerbates cognitive decline .Patients with MCI should be encouraged to socialize. Cognitive training and activities: Cognitive activities like crossword puzzles,novels,Sudoku etc all help against cognitive decline.Cognitive training as a specialised therapeutic intervention helps. Physical exercise: Physical exercise does improve cognitive ability or defivitely slows down decline.

Be supportive & encouraging

Accept the memory loss as real.
of MCI. Treat theperson like an adult. Include the person in social events and community activities. Respond to the same question as if it were the first time, every time. Avoid beginning or ending sentences with I already told you Avoid interrupting people with MCI when they are speaking. Avoid talking about people with MCI without including them in the conversation. Simplify speaking style only if those with MCI tell you that they do not understand you

Be patient & respectful

Allow people with MCI to complete their
daily routine at their own pace. Provide uninterrupted moments to allow for recalling information. Encourage nurturance by suggesting responsibility for caring for a pet or plants. Encourage usefulness by suggesting responsibility for completing household tasks. Promote feelings of success by giving one task to complete at a time. Help the person stay physically healthy Avoid becoming overprotective.

CONCLUSION:
There are no standard criteria for MCI. MCI is not related to one specific disorder. Subjects with MCI have a high risk for Alzheimertype Dementia. A combination of variables may be useful to identify subjects with MCI who are at high risk for Alzheimertype dementia. Not everyone with MCI or CIND has prodromal dementia,although everyone with Progressive dementia that began insidiously first must have had cognitive impairment insufficient to interfere with everyday function.

MCI should be considered as a syndrome rather than as a disease.

REFERENCES:
1) The Dementias Early diagnosis and evaluation Textbook by KarlHerholz,Daniela Perani,Chris Morris. 2) Guide to assessment scales in dementia Cornelius Kelly,GilesNewton Howes 3) Mild cognitive impairment The dilemma Indian journal of psychiatry51:supplement January 2009(S44-51) 4) Principles and Practice of Geriatric Medicine, 4th Edition. Edited by M.S. John Pathy, Alan J. Sinclair and John E. Morley. 5) Neuroimaging and Early Diagnosis of Alzheimer sDisease: A Look to the Future. Jeffrey R. Petrella, MD,R. Edward Coleman, MDP. Murali Doraiswamy, MDRadiology 2003

6) Comprehensive textbook of psychiatry

7) Oxford textbook of psychiatry.