RECENT ADVANCES IN ALZHEIMER'S RESEARCH

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Good morning NETRUMIANS

We are in the 2nd day of our discussion and take up the salient pathological findings and the stages that AD shows up clinically. We will find in subsequent days that these are key to appreciating the various hypotheses that are doing the rounds of AD research platforms.

5. Alzheimer's disease: Neuropathological hallmarks

There is cortical atrophy with narrowing of gyri, widening of sulci and hydrocephalus ex vacuo. Most severely affected are temporal lobes (hippocampus, parahippocampus, and amygdala), than frontal and parietal lobes. Occipital lobes and motor cortex are

usually spared.

The disease is characterized by deposition of beta amyloid protein in cerebral cortex and dramatic loss of neurones and synapses. The most striking neuropathological changes occur in the brains of AD are as under

Neurofibrillary tangles

Neurofibrillary tangles (NFTs) NFTs are considered to be a major pathological hallmark of

AD. Alois Alzheimer first described the NFT in the soma of cortical neurons in a 51-years

old women who had a five-year history of progressive dementia. NFTs develop within the pyramidal neuronal soma as argentophilic filamentous inclusions, which extend into the neuronal processes. They are flame or globoid in shape.

The major subcortical neurones affected by NFT are cholinergic neurones of the basal nucleus of Meynert, noradrenergic neurones of locus coeruleus and serotonergic neurones of raphe nuclei. The loss of these systems leads to the disconnection between hippocampus and neocortex and between neocortical association areas resulting in the disintegration of intellectual function. NFTs can also be found in several other disorders (Down's syndrome, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, parkinson-dementia complex etc.) as well as in normal aging brains of nondemented individuals. Because NFTs are characteristic but not specific findings of AD, the diagnosis of AD must be based on correlation between clinical features (dementia) and neuropathological findings (NFT density and characteristic distribution). They can be visualized by various silver stains (von Brownm.hl, Bielschowsky etc.), using histochemical methods such as thioflavine S, immunohistochemically with anti tau antibody and by electronmicroscopical investigations.

Neuritic plaques (NP)

Neuritic plaques are foci of enlarged axons, synaptic terminals and dendrites, associated with extracellular beta/A4 amyloid. They appear as spherical areas with amyloid positive core surrounded by argentophilic material. NPs are generally confined to the cerebral cortex. The sites of predilection are amygdala, CA1 area of hippocampus, subiculum and layers II, III and V of the entorhinal cortex. Classic plaque consists of fibrils of aggregated beta/A4 core surrounded by clear halo with dystrophic neurites (DN), activated microglia and reactive astrocytes at the periphery. DN within plaque consists of distended axons, dendrites and synaptic terminals. DN exhibits immunoreactivity for amyloid precursor protein, growth associated protein (GAP43), tau, ubiquitin and neurofilaments

Neuropil threads (NTs)

NTs appear as argentophilic network of fragmented and twisted fibers in the neuropil. They are formed within axons, dendrites and presynaptic terminals. NTs are often associated with NFTs, but are independent of NPs. Immunohistochemical techniques revealed that they contain tau and ubiquitin.

Hirano's bodies (HBs)

HBs are eosinophilic intraneural structures, most often found in the hippocampal pyramidal neurones. They are best seen in H & E preparations. Ultrastructurally HB consists of crystalloid arrays of interlacing filaments displaying either a lattice-like or herringbone configuration.

Granulovacuolar bodies (GVB)

GVBs appear as round vacuoles (3-4 microns) with a dense core which stains blue in H & E and are argentophilic. They are confined to the soma of hippocampal pyramidal neurone.

6. Alzheimer's disease: Stages

Experts have documented common patterns of symptom progression that occur in many individuals with AD and developed several methods of "staging" based on these patterns. Progression of symptoms corresponds in a general way to the underlying nerve cell degeneration that takes place in AD.

Nerve cell damage typically begins with cells involved in learning and memory and gradually spreads to cells that control other aspects of thinking, judgment and behaviour. The damage eventually affects cells that control and coordinate movements.

But it is important to note that all stages are artificial benchmarks in a continuous process that can vary greatly from one person to another. Not everyone will experience every symptom and symptoms may occur at different times in different individuals. People with Alzheimer's die an average of four to six years after diagnosis, but the duration of the disease can vary from three to 20 years.

The framework for this fact sheet is a system that outlines key symptoms characterizing seven stages ranging from unimpaired function to very severe cognitive decline. This framework is based on a system developed by Barry Reisberg, Clinical Director of the New York University School of Medicine's Silberstein Aging and Dementia Research Center.

Stage 1: No cognitive impairment

Unimpaired individuals experience no memory problems and none are evident to a health care professional during a medical interview.

Stage 2: Very mild decline

Individuals at this stage feel as if they have memory lapses, forgetting familiar words or names or the location of keys, eyeglasses or other everyday objects. But these problems are not evident during a medical examination or apparent to friends, family or co-workers.

Stage 3: Mild cognitive decline

Early-stage Alzheimer's can be diagnosed in some, but not all, individuals with these symptoms

Friends, family or co-workers begin to notice deficiencies. Problems with memory or concentration may be measurable in clinical testing or discernible during a detailed medical interview. Common difficulties include:

• Word- or name-finding problems noticeable to family or close associates

• Decreased ability to remember names when introduced to new people

• Performance issues in social and work settings noticeable to others

• Reading a passage and retaining little material

• Losing or misplacing a valuable object

• Decline in ability to plan or organize

Stage 4: Moderate cognitive decline

(Mild or early-stage AD)

At this stage, a careful medical interview detects clear-cut deficiencies in the following areas:

• Decreased knowledge of recent events

• Impaired ability to perform challenging mental arithmetic. For example, to count backward from 100 by 7s

• Decreased capacity to perform complex tasks, such as marketing, planning dinner for guests, or paying bills and managing finances

• Reduced memory of personal history

• The affected individual may seem subdued and withdrawn, especially in socially or mentally challenging situations

Stage 5: Moderately severe cognitive decline

(Moderate or mid-stage AD)

Major gaps in memory and deficits in cognitive function emerge. Some assistance with day-to-day activities becomes essential. At this stage, individuals may:

• Be unable during a medical interview to recall such important details as their current address, their telephone number, or the name of the college or high school from which they graduated

• Become confused about where they are or about the date, day of the week or season

• Have trouble with less challenging mental arithmetic; for example, counting backward from 40 by 4s or from 20 by 2s

• Need help choosing proper clothing for the season or the occasion

• Usually retain substantial knowledge about themselves and know their own name and the names of their spouse or children

• Usually require no assistance with eating or using the toilet

Stage 6: Severe cognitive decline

(Moderately severe or mid-stage AD)

Memory difficulties continue to worsen, significant personality changes may emerge, and affected individuals need extensive help with daily activities. At this stage, individuals may:

• Lose most awareness of recent experiences and events as well as of their surroundings

• Recollect their personal history imperfectly, although they generally recall their own name

• Occasionally forget the name of their spouse or primary caregiver but generally can distinguish familiar from unfamiliar faces

• Need help getting dressed properly; without supervision, may make such errors as putting pajamas over daytime clothes or shoes on wrong feet

• Experience disruption of their normal sleep/waking cycle

• Need help with handling details of toileting (flushing toilet, wiping and disposing of tissue properly)

• Have increasing episodes of urinary or fecal incontinence

• Experience significant personality changes and behavioral symptoms, including suspiciousness and delusions (for example, believing that their caregiver is an impostor); hallucinations (seeing or hearing things that are not really there); or compulsive, repetitive behaviors such as hand-wringing or tissue shredding

• Tend to wander and become lost

Stage 7: Very severe cognitive decline

(Severe or late-stage AD)

This is the final stage of the disease when individuals lose the ability to respond to their environment, the ability to speak, and, ultimately, the ability to control movement.

• Frequently individuals lose their capacity for recognizable speech, although words or phrases may occasionally be uttered

• Individuals need help with eating and toileting and there is general incontinence

• Individuals lose the ability to walk without assistance, then the ability to sit without support, the ability to smile, and the ability to hold their head up. Reflexes become abnormal and muscles grow rigid. Swallowing is impaired.

References

Braak H, Braak E (1997) Diagnostic criteria for neuropathologic assessment of Alzheimer's disease. Neurobiology of Aging. 18(4): s85-88.569-80.

Schochet SS (1998) Neuropathology of Aging. Neurologic Clinics. 16(3): 569-80.

Perl D (2000) Neuropathology of Alzheimer's disease and related disorders. Neurologic Clinics. 18(4):847-64.

G. Sclan and Barry Reisberg (1992). Functional Assessment Staging (FAST) in Alzheimer's Disease: Reliability, Validity, and Ordinality. International Psychogeriatrics, 4, pp 55-69.