Alzheimers disease - mild cognitive impairment countdown

Alzheimers dementia is usually diagnosed when memory loss and behavioural symptoms are readily apparent to their caregivers. At this stage the primary concern is to slow further deterioration. Caregivers at the clinic have often wished they could have looked into the future. Many have a history of Alzheimers disease in their elderly and wondered whether there was an earlier way of knowing. New knowledge gives us hope in this direction.

Alzheimers disease before memory loss

We now have the beginnings of a time line in the countdown to dementia. It is now possible to trace the beginnings of Alzheimers Dementia up to 20 years before its manifestation with memory loss and impaired function.

20

Beta-amyloid levels in the cerebrospinal fluid (CSF)  begin to drop 20 years before the onset of dementia. Alzheimer's Disease is characterized by toxic deposition of specific beta-amyloid (Aβ1-42) plaques around the brain cells. In normal aging beta-amyloid continues to increase in the brain fluid. However, in Alzheimers Dementia brain fluid beta-amyloid is markedly reduced.This is due to reduce clearance of beta-amyloid from the brain to the blood and CSF, as well as increased beta-amyloid plaque deposition in the brain.

15

15 years before dementia onset, beta-amyloid deposits can be detected by amyloid imaging PET scans. The best known amyloid PET tracer is Pittsburgh Compound-B (PIB). PIB retention is found in over 90% clinically diagnosed AD patients.
Tau protein accumulation inside the brain cells (neurons) is the second hallmark of Alzheimer's disease.  Microtuble associated protein tau (MAPT) in the brain fluid (CSF) increases with age. In Alzheimer's disease tau levels are markedly increased and reflects damage to the neurons and axons (brain cells). High CSF tau level differentiates mild cognitive impairment (MCI) from that which progresses to Alzheimer's disease.
Shrinkage or atrophy of the brain becomes detectable by MRI. This atrophy is visible in brain structures that are essential for the conscious memory of facts and events. These areas are located in the brain’s medial temporal lobe. This shrinkage is apparent on using a visual rating system which also measures its severity. The more extensive the brain atrophy, the more advanced the clinical stage of Alzheimer’s disease.

10

PET Scan (FDG-PET) changes in the way the brain uses glucose are apparent 10 years before dementia. These PET scan changes correlate with progression of Alzheimers disease.
Episodic memory loss begins at this stage. Episodic memory loss is the inability to learn new information or to recall previously learned information. It manifests as forgetting of recent events and conversations, repetitive questions, repetitive retelling of stories, forgetting the date, forgetting appointments, misplacing objects, losing valuables, and forgetting that food is cooking on the stove. The formation of new episodic memories requires intact medial temporal lobes of the brain; these are progressively destroyed in Alzheimers disease.

5

Mild cognitive impairment (MCI) deveelops 5 years before dementia. People with mild cognitive impairment have problems with thinking and memory loss. Mild cognitive impairment does not interfere with everyday activities. Persons with mild cognitive impairment are often aware of their forgetfulness.
Preventive therapies for Alzheimers disease (AD) require the development of biomarkers that are sensitive to subtle brain changes occurring in the preclinical stage of the disease. Early diagnostics is necessary to identify and treat at risk individuals before irreversible neuronal loss occurs.
Sources

1. Bateman R. The dominantly inherited Alzheimer's network trials: an opportunity to prevent Alzheimer's disease. Program and abstracts of the Alzheimer's Association International Conference 2012; July 14-19, 2012; Vancouver, British Columbia, Canada. Featured research session F3-04
2. Christian Humpel. Identifying and validating biomarkers for Alzheimer's disease. Trends Biotechnol. 2011 January; 29(1): 26–32. doi: 10.1016/j.tibtech.2010.09.007
3. Duara R, Loewenstein DA, Potter E, Appel J, Greig MT, Urs R, Shen Q, Raj A, Small B, Barker W, Schofield E, Wu Y, Potter H. Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease. Neurology. 2008 Dec 9;71(24):1986-92.
4. Mosconi L, Berti V, Glodzik L, Pupi A, De Santi S, de Leon MJ. Pre-clinical detection of Alzheimers disease using FDG-PET, with or without amyloid imaging. J Alzheimers Dis. 2010;20(3):843-54.

Diagnosing Alzheimer's Dementia

Microscopic picture of the brain showing amyloid plaques and
 neurofibrillary tangles first seen by Alois Alzheimer in 1907

The diagnosis of Alzheimer's disease became headline news when the defence counsel of a prominent citizen of  Pune stated they were awaiting results of his brain MRI to finalise the diagnosis of dementia. Recently a patient's medication was stopped when his neuro-physician declared there were 'no plaques on MRI so it is not a case of Alzheimers'. The caregivers returned to me when his behaviour problems recurred.

Dementia including that of the Alzheimer's type is a clinical diagnosis (Grand 2011). Dementia is characterised by a triad of

1. Progressive deterioration of mental processes (cognitive abilities)
2. Behavioural and psychological symptoms of dementia (BPSD)
3. Difficulties carrying out day-to-day activities (activities of daily living or ADL).  

Alzheimer's Disease is commonest dementia after 65 years of age Alzheimer's dementia has an insidious onset, and progresses gradually and inexorably. This natural course is a key differentiator Alzheimer's from other forms of dementia. Dementia is suspected when a caregiver of an elderly person, or sometimes a person with a family history of dementia, becomes concerned about problems with memory. The diagnosis is purely clinical. No laboratory test or imaging (including MRI) is required to diagnose Alzheimer's disease. These investigations can only help differentiate the other forms of dementia when those are suspected.

Memory problems are a core feature of the disease. These manifest as

• Difficulty recalling details of recent events (forgets he has already dropped his grandchild to school), personal conversations, or specific elements of a task she is performing (eg, preparing a meal)
• Asking the same question multiple times while denying repeated questioning
• Tendency to make up events to fill memory gaps and to give inaccurate responses to questions (what he had for breakfast)

Other common cognitive concerns that could indicate dementia of the Alzheimer or any other type

• Disoreintation to time and place. As the illness progresses orientation worsens to include problems identifying familiar places, family members, or other well known people.
• Difficulties with activities of daily living (ADL). Problems with dressing or using common utensils
• Language impairments resulting in decreased conversational output, word-finding difficulties, and limited vocabulary.
• Visuo-spatial dysfunction manifest as impaired driving ability, and getting lost
• Problems with mathematical calculations impair ability to use money and balance finances.
• Impaired judgement in novel situations (difficulty planning a vacation).

Behavioural and psychological symptoms (BPSD)

• Depression occurs in up to 50% of individuals with Alzheimer's Dementia, and may be attributed to awareness of cognitive changes
• Lack of feeling or emotion (apathy) is associated with significant caregiver distress
• Psychosis generally occurs later in the disease course. Delusions are predominantly paranoid in nature, with fears of personal harm or mistreatment, theft of personal property (usually related to financial matters), and marital infidelity. Hallucinations are less common than delusions, and tend to be visual.
• Other behavioural symptoms include agitation, wandering, and sleep disturbances.

Diagnosis of Alzheimer's Disease is based on 

1. Detailed history to identify memory deficits, and other cognitive symptoms and assess their impact on the individual and family.
2. A thorough clinical exam (mental status examination) confirms the impairments in memory and cognition, and delineates the behavioural and psychiatric symptoms that cause caregivers concern. This usually includes using validated and standardised screening pencil and paper tests. 
3. Psychological testing confirms and quantifies the impairments across various areas of brain function (memory, language, visuo-spatial), assesses the treatment response, and documents progression of the illness with time.

Laboratory tests including MRI only differentiate Alzheimer's disease from other disorders such as subdural haematoma, brain tumour, hydrocephalus, and dementia associated with vascular disease. Magnetic Resonance Imaging (MRI) has no other clinical utility in Alzheimer's disease. These tests are not required or mandated by any classification system including that of the WHO (ICD) or the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA).

Amyloid plaques, and neurofibrillary tangles are the hallmark of Alzheimer's disease and are required for a definitive diagnosis. These were first discovered by Alois Alzheimer in 1907.  His slides were rediscovered in 1992 and 1997. The rediscovered images show the classical pathological signs of the disease named after him. Amyloid plaques and neurofibrillary tangles are seen on microscopic examination of brain tissue using special staining techniques or by electron microscopy. Therefore the only way to obtain a definitive diagnosis of Alzheimer's disease is to obtain a brain tissue sample by biopsy or on autopsy. No MRI, however advanced can detect plaques.

For the purpose of treatment a probable diagnosis using bedside techniques of history and clinical examination is all that is required to diagnose Alzheimer's disease.

References

1. Dickerson BC. Advances in quantitative magnetic resonance imaging-based biomarkers for Alzheimer disease. Alzheimers Res Ther. 2010 Jul 6;2(4):21.
2. Graeber MB, Kösel S, Egensperger R, Banati RB, Müller U, Bise K, Hoff P, Möller HJ, Fujisawa K, Mehraein P. Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis. Neurogenetics. 1997 May;1(1):73-80.
3. Grand JH, Caspar S, Macdonald SW. Clinical features and multidisciplinary approaches to dementia care. J Multidiscip Healthc. 2011;4:125-47. Epub 2011 May 15.
4. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44.