ALZHEIMERS DISEASE NO TIME TO WAIT

DR KASI KRISHNA RAJA DNB ASST PROFF OF PSYCHIATRY DEPT OF PSYCHIATRY PMCH

ALOIS ALZHEIMER (18641915)

DEMENTIA

Dr Philippe Pinel (1745-1826), the founder of modern psychiatry, first used the word dementia in 1797. The concept of dementia and the word itself are clearly not new. Dementia is generally defined as the loss of intellectual abilities (medically called cognitive function) of sufficient severity to interfere with social or occupational functioning (Diagnostic and Statistical Manual of the American Psychiatric Association).

Components of cognitive faculties

Components of intellectual capability Attention, concentration and orientation Memory and learning Judgment and abstraction Thinking (e.g. problem-solving, sequential planning) Calculation visuo-spatial orientation Language (e.g. comprehension, word finding) Geographic orientation Dementia is a loss of multiple components of intellectual function. Contrary to popular belief, loss of memory is not the only deficit in dementia. However, since it is the most important component in day-to-day living, it causes significant impairment to patients, thus, bringing them to a doctor.

HISTORY

Alzheimer was of German origin who initially excelled as a professor of Psychology in Breslau . Together with Franz Nissl they established the pathologic anatomy of mental illness in Germany. Alzheimer published several treatises on cerebro arteriosclerosis in 1904 and on Huntingtons chorea early in 1911

In 1901, a 51-year-old woman, Auguste D, was admitted to the state asylum in Frankfurt. She was suffering from cognitive and language deficits, auditory hallucinations, delusions, paranoia and aggressive behaviour, and was studied by Alois Alzheimer (18641915)

Alzheimer moved to the Munich medical school in 1903 to work with Emil Kraepelin one of the foremost German psychiatrists of that era and when Auguste D died in April 1906, her brain was sent to him for examination. In November of that year, Alzheimer presented Auguste's case at a psychiatry meeting, and he published his talk in 1907. In 1910, Kraepelin coined the term 'Alzheimer's disease' a term still used to refer to the most common cause of senile dementia

All the markers that Alzheimer reported were well known at the time, and it is clear from his writings that he never meant to say that they were new. Five months before Alzheimer's report, the American worker Fuller whose contribution to this field has been neglected had drawn attention to the presence of "neurofibrillar bundles in senile dementia".

Nor was the association between plaques and dementia a novelty, as it had been reported in 1887 by Beljahow, and confirmed by Redlich and Leri a few years later Oskar Fischer, the neglected researcher from Prague, had also pointed out, in June 1907, that 'miliary necrosis' should be considered as a marker of senile dementia.

Other Eponyms
Alzheimer's baskets Condensed clumps of filaments between the nerve cells seen in advanced cases of Alzheimer's disease. Alzheimer's sclerosis Degeneration of the middle and smaller cerebral blood vessels at a cellular level. Alzheimer's stain A staining method for the detection of Negri bodies, a definitive indicator of rabies.

Famous sufferers

Ronald Reagan - 40th president of the United States Ralph Waldo Emerson - poet Rosa Parks - African American activist Nani palkhivala-famous jurist Sugar ray robinsonmiddle weight boxer

The burden

Most of the Indian studies have also reported MID to be more prevalent. In the first epidemiological study from the Indian subcontinent, the incidence of AD was reported to be amongst the lowest possible In a similar study in rural northern India an overall prevalence of AD has been described as very low (0.62% in the population over 55 years and 1.07% in those aged 65 and above) A community-based study in a rural population in Kerala reported 58% of patients with MID compared to 41% with AD. There were more women and positive family history was prominent in the AD group.

There are an estimated 24 million people with dementia worldwide. By 2040, it is projected that this figure will have increased to 81 million. Much of the increase will be in developing countries Already more than 60% of people with dementia live in developing countries, but by 2040 this will rise to 71%. The fastest growth in the elderly population is taking place in China, India, and their south Asian and western Pacific neighbours.

The number of elderly was about 56 million in 1991. The projected figures for the years 2003 and 2025 are 70 million and 177 million respectively The projected prevalence among the general population is close to 1.5%,and among the people aged 65yrs its above 10% and in people above 85 years it reaches 47%.

10 warning signs of Alzheimer's:

1. Memory loss. Forgetting recently learned information is one of the most common early signs of dementia. A person begins to forget more often and is unable to recall the information later. What's normal? Forgetting names or appointments occasionally. 2. Difficulty performing familiar tasks. People with dementia often find it hard to plan or complete everyday tasks. Individuals may lose track of the steps involved in preparing a meal, placing a telephone call or playing a game. What's normal? Occasionally forgetting why you came into a room or what you planned to say. 3. Problems with language. People with Alzheimers disease often forget simple words or substitute unusual words, making their speech or writing hard to understand. They may be unable to find the toothbrush, for example, and instead ask for "that thing for my mouth. What's normal? Sometimes having trouble finding the right word.

4. Disorientation to time and place. People with Alzheimers disease can become lost in their own neighborhood, forget where they are and how they got there, and not know how to get back home. What's normal? Forgetting the day of the week or where you were going. 5. Poor or decreased judgment. Those with Alzheimers may dress inappropriately, wearing several layers on a warm day or little clothing in the cold. They may show poor judgment, like giving away large sums of money to alms seekers,foolish business ventures etc. What's normal? Making a questionable or debatable decision from time to time. 6. Problems with abstract thinking. Someone with Alzheimers disease may have unusual difficulty performing complex mental tasks, like forgetting what numbers are for and how they should be used. What's normal? Finding it challenging to balance a checkbook.

7. Misplacing things. A person with Alzheimers disease may put things in unusual places: an iron in the stove or a wristwatch in the freezer. What's normal? Misplacing keys or a wallet temporarily. 8. Changes in mood or behavior. Someone with Alzheimers disease may show rapid mood swings from calm to tears to anger for no apparent reason. What's normal? Occasionally feeling sad or moody.

9. Changes in personality. The personalities of people with dementia can change dramatically. They may become extremely confused, suspicious, fearful or dependent on a family member. What's normal? Peoples personalities do change somewhat with age.
10. Loss of initiative. A person with Alzheimers disease may become very passive, sitting in front of the TV for hours, sleeping more than usual or not wanting to do usual activities. What's normal? Sometimes feeling weary of work or social obligations.

Causes--genetic

LOFAD

EOFAD

Regions

Region in Ch 14 ps1 gene--HGP

Region in Ch 1 PS2 gene--HGP

Fig 1 The central pathway leading to Alzheimer's disease involves the processing of amyloid precursor protein into A{beta} amyloid, which accumulates as amyloid plaques or perivascular amyloid. Concomitantly, degeneration occurs in neurons and their processes, leading to neurofibrillary tangles. (Images are from Spielmeyer's Histopathology of the Nervous System, 1922.) Mutations in the gene encoding amyloid precursor protein can cause Alzheimer's disease, as do mutations in the presenilin genes. Inheritance of particular polymorphisms in genes such as ApoE also can increase susceptibility for Alzheimer's disease. Major environmental risk factors for Alzheimer's disease remain to be determined

Masters, C. L et al. BMJ 1998;316:446-448

Copyright 1998 BMJ Publishing Group Ltd.

Fig 2 (a) Cleavage of amyloid precursor protein (APP) by enzymes (secretases) release the A{beta} amyloidogenic fragment. (b) The critical region of amyloid precursor protein shown schematically in the one letter amino acid code. The secretases act at three principal sites ({alpha}, {beta}, and {gamma}). Mutations in the gene for amyloid precursor protein at these sites can adversely affect the action of secretases: mutations towards the NH2 terminus increase the absolute rate of {beta}-secretion, while mutations near the COOH terminus affect the ratio of A{beta}42 to A{beta}40. The A{beta}42 forms are more damaging for nerve cells

Masters, C. L et al. BMJ 1998;316:446-448

Copyright 1998 BMJ Publishing Group Ltd.

Newer markers

Alzheimer's Marker Revealed in Eye The amyloid-beta protein that forms plaques in the brains of Alzheimer's disease patients also shows telltale patterns in the lenses of their eyes, The study, published in the April 12 Lancet, was led by investigators at Massachusetts General Hospital and the Medical School. "The formation of A-beta plaques in the brain and the development of cataracts in the lens are both examples of accumulated protein associated with age-related degenerative damage," -- author Lee Goldstein, HMS assistant professor of psychiatry at MGH. The researchers used immunologic assays and mass spectrometry to look for evidence of A-beta in lens tissue from nine autopsied Alzheimer's patients and eight controls. In specimens from both groups, they found the protein in concentrations similar to those found in aged brain tissue samples. They also found A-beta in samples of aqueous humor taken from three non-Alzheimer's patients who were having cataracts removed.

Most importantly, they found in Alzheimer's patients-but not controls--both cataracts and a distinctive pattern of cytoplasmic A-beta deposits in the outer, peripheral portion of the lenses. The lens does not clear protein deposits the way brain tissue does, and the researchers believe the protein deposits are the cause of the cataracts. "One of the most exciting aspects of this finding is the fact that these deposits are associated with a type of cataract seen rarely in the general population," known as equatorial supranuclear cataracts.

Newer therapeutic strategies

Inhibitors of excitotoxicity These include glutamate antagonists, calcium-channel blockers and protease inhibitors. Inhibitors of amyloid formation Beta-amyloid aggregation can also be blocked by the chemical chrysamine G and a dye called Congo red. Although they are both effective theoretically, they cannot cross the blood-brain barrier. Thus derivatives to overcome this difficulty are now being studied. They could also include secretase inhibitors and inhibitors of APP phosphorylation

Inhibitors of abnormal protein disposition

Chaperones are a large family of proteins that aid proteins in folding and discourage misfolding and inappropriate aggregation. Increasing the production of chaperones may help limit aggregation of toxic proteins in neurogenerative diseases, such as Alzheimers.

Curcumin (diferuloylmethane), a polyphenol, is a component of the culinary spice turmeric used in curry powder. It has antioxidant, anti-inflammatory, and antiamyloid activity. It can suppress Tumour Necrosis Factor (TNF)-induced NF-B (nuclear factor-B) Therapeutic agents that selectively inhibit the biologic activity of TNF-alpha have recently become available for human use. One of these is etanercept, a dimeric fusion protein that is produced with recombinant DNA technology and composed of 934 amino acids with a total molecular weight of 150,000 d.[25] , It is antioxidant. It inhibits brain lipid peroxidation five- to ten-fold better than vitamin E. It also has antiinflammatory properties, inhibits prion protein, prevents fibril formation, inhibits oligomer formation and A aggregation, lowers total cholesterol, raises HDL, chelates metal (iron),

There are three prominent amyloid-based therapeutic strategies: a) secretase modulation, b) inhibition of A aggregation, and c) immunization against A. Gamma-secretase inhibitors/modulators in clinical trials include LY450139 (phase II) and R-flurbiprofen (phase III) Alpha-cleavage of APP is beneficial. Rasagiline (Npropargyl-1R-aminoindan), a novel, highly potent, irreversible monoamine oxidase (MAO) B inhibitor, processes APP to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha)

INHIBITION OF A AGGREGATION

Resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers levels of secreted and intracellular A peptides produced from different cell lines. Resveratrol promotes a proteasome-dependent intracellular degradation of A

IMMUNIZATION AGAINST A

The phase II trial of vaccination with the synthetic A (AN1792; AIP-001) was halted early because of encephalitis, presumably induced by T-cell immune responses, in 6% of subjects. Humanized monoclonal antiamyloid antibody is under development by a number of companies

Another immunologic strategy involves intravenous immunoglobulin (IVIgG) which contains antibodies against A. These antibodies selectively target A and are capable of antagonizing the potential neurotoxic effects of A as well as its fibrillization--the prerequisite for plaque formation

Psychological approach

Reality orientation Reminiscence therapy Behavioural modification Occupational activities Environmental modifications Validation therapy--reflection and validation of the patients view of reality . Sensory stimulation Advice for caregivers

NO TIME TO LOSE

NO TIME TO LOSE

Album : Run For Your Life The Tarney-Spencer Band - 1979

Every day I walk in shadows And know not what it is I'm heading for As the evening lies dying .... lies near me sighing .... we can never understand We can now be like water Rolling on to find our way.... game No time to lose, no time to lose Go with the flow, never let go No time to lose...

Epiloguethe fate

Alzheimers dementia----A long and haunting good bye, And a slow sinking into the tunnel of darkness.