DEMENTIA

Dementia is defined as a global impairment or loss of intellectual function. It is a devastating disease that places a significant physical, emotional and financial burden on patients, their care taker and society.
It refers to a clinical syndrome characterized by progressive cognitive decline that interferes with the ability to function independently (particularly loss of short-term memory). Symptoms of dementia are gradual, persistent and progressive.
The clinical presentation of dementia varies greatly among individuals, and the cognitive deficits it causes can present as memory loss, communication and language impairment, agnosia (inability to recognize objects), apraxia (inability to previously learned task) and impaired execution function.
Dementia is not a specific disease. It is an overall term that describes a group of symptoms associated with a reduction in a person's ability to perform everyday activities.

Subtypes of Dementia:

Dementia is an overall term used to describe the clinical syndrome, but its subtypes are classified according to the cause of dementia. The four common types of dementia are:

• Alzheimer's disease
• Cerebrovascular disease
• Lewy bodies dementia
• Frontotemporal dementia

A. Alzheimer's disease

AD is the most common neurodegenerative disease responsible for dementia, comprising 60% to 80% of causes. It is believed to derive from the accumulation of beta-amyloid plaques and neuro-fibrillary tangles, first in the brain areas of the hippocampus which induces neuronal injury and subsequently, neuronal death. The resulting decrease in cholinergic transmission gives rise to loss of memory and cognition. More precisely neurotransmitters abnormalities include reduced activity of choline acetyl transferase and reduce the number of cholinergic neurons. Early onset AD is associated with autosomal dominant mutation in three genes: PSEN1, APP and PSEN2. Late onset AD is most commonly diagnosed in patients after the age of 60.

B. Cerebrovascular disease:

It is the second most prevalent form of dementia. Also called multi-infract dementia, it results from neuronal deprivation of oxygen caused by conditions that either block or reduce blood flow to the brain. Stroke is the most common cause. Its symptoms can vary widely, depending on the affected regions of the brain and the severity of the blood vessels damage. Some prominent symptoms include confusion, disorientation, vision loss, difficulty in speaking and understanding speech. Mixed dementia refers to the co-existence of AD and vascular dementia.

C. Lewy body dementia:

LBD is a form of dementia caused by abnormal deposits of alpha-synuclein protein (Lewy bodies) inside neurons. It accounts for 5% to 15% of all dementia. The most distinctive feature of LBD include fluctuation cognitive impairment with variations in attention and alertness, complex visual hallucinations and spontaneous Parkinsonism. Furthermore, rigidity and rapid eye movement (REM) sleep disorders are more commonly observed in early stages of LBD.

D. Frontotemporal dementia:

FTD is a general term used to describe disorders, such as Pick's disease, that affects the frontal and temporal lobes of the brain. FTD tends to occur at a younger age (40-75years) than does AD. Personality changes and behavioral disturbances are key features of FTD and occur early in the disease. In contrast to AD, visuospatial functions are usually not affected.

 CAUSES OF DEMENTIA:

Dementia can be caused by brain cell death and neurogenerative disease progressive brain cell death that happens overtime- is associated with most dementia.

But, as well as progressive brain cell death, like that seen in AD, dementia can be caused by head injury, a stroke or a brain tumor.

• Vascular dementia is resulting from brain cell death caused by conditions such as cerebrovascular disease. e.g., stroke. This prevents normal blood flow, depriving brain cells of oxygen.
•  Post traumatic dementia is directly related to brain cell death caused by injury. Some types of traumatic brain injury particularly, if repetitive. such as those received by athletes have been linked to certain dementias appearing late.
• Prion disease such as  CID (Creutzfeldt-Jakob Disease) is a fatal brain disorder which leads to dementia.
• HIV Viruses damage the brain cell.
• Deposits of amyloid, called plaques, build up around brain cell. Deposits of tau from 'tangles' within brain cell.
• There is also decrease in neurotransmitter like, acetylcholine in the brains of people of dementia.
• The hippocampus is often affected early in AD.
• People who smoke or have high blood pressure or diabetes have vascular dementia due to the narrowing of small blood vessels (subcortical vascular dementia).
• "Strokes" where part of the blood supply to brain is suddenly cut off is called post-stroke dementia. Lots of mini-strokes cause widespread damage to brain and is known as multi-infract dementia.
• Tiny clumps of a protein called alpha-synuclein than can develop into the brain cell and damage the cells work and communication, eventually dies. 
• Moreover, there are more than 50 identified causes of dementia including various infectious diseases; metabolic disorders (Wilson disease and Leukodystrophies); malignancies; epilepsies; traumatic brain disease; systemic disorders such as endocrine disease and vitamin deficiencies; toxic disorders including alcohol dependency and drug toxicity as well as mental illness such as depression and schizophrenia. 

RISK FACTORS FOR DEMENTIA:

Some dementia risk factors are difficult or impossible to change. These include:

AGE: 

Older people are more likely to develop dementia. However, dementia is not an evitable part of ageing.

GENES:

Certain genetic factors are involved with some more unusual forms of dementia, for the most part, dementia develops as a combination of genetic and environmental factors such as smoking and lack of regular exercise.

REVERSIBLE FACTORS:

Some dementias can be treated by reversing causes, including medication, interactions, depression, vitamin deficiencies and thyroid abnormalities.

MEDICATION:

• Antihypertensive:   Some studies say AD and other dementias may be caused by high BP, since it can cause blood vessel damage through constriction. The etiology of vascular dementia includes hypertension, and thus, lowering BP with antihypertensive may have a positive effect in prevention of dementia.
• Steroid Hormones: Estrogen may also help in the prevention of dementia but cannot help when it is already present and when cognitive function is already impaired. It increases cerebral blood flow and is an anti-inflammatory agent, enhancing activity at the neuronal synapses in the brain. It may also help to increase brain activation in regions that are affected by dementia which is mainly the hippocampus region.
• NSAIDS (Non-steroidal anti-inflammatory drugs) : It can decrease the risk of developing AD and Parkinson's disease. NSAIDS inhibit formation of some inflammatory and prevent the deteriorating effects.

MOLECULAR BASIS OF DEMENTIA:

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. Familial FTD has been linked to mutations in several genes, including those encoding the microtubule associated protein tau (MAPT), progranulin (GRN), valosin- containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B). The associated neuropathy is characterized by selective degeneration of the frontal and temporal lobes (frontotemporal lobar degeneration, FTLD), usually with the presence of abnormal intracellular protein accumulations. FTD is often associated with an extrapyramidal movement disorder (Parkinsonism or corticobasal syndrome) or with motor neuron disease (MND). Major subgroups include those characterized by the physiological tau, TDP-43, intermediate filaments and a group with cellular inclusions composed of an unidentified  ubiquitinated protein.

FTLD-tau : Tau is a microtubule associated phosphoprotein (MAP) that is abundantly expressed in both the central and peripheral nervous system. The tau gene is located (MAPT) on chromosome 17q21 and has two major haplotypes. H1 and H2, which are defined by a set of single nucleotide polymorphisms and a 238 base pair deletion in intron 9.

In AD, abnormally hyper phosphorylated tau is the major component of the neurofibrillary lesions (neuropil-threads and dystrophic neurites). The abnormal accumulation of intracellular tau is characteristic of a number of other neurodegenerative disorders collectively known as 'tauopathies'. A  number of tauopathies may be associated with clinical FTD (FTLD-tau), including Pick disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD) and hereditary frontotemporal dementia and parkinsonism linked to chromosome 17, as a result of MAPT mutations (FTDP-17T).

FTLD-TDP: TDP-43 is encoded by TARDBP gene on chromosome 1. It is involved in cellular processes such as microRNA biogenesis, apoptosis, cell-division, mRNA stabilization and regulation of neuronal plasticity of acting as neuronal activity response factor. The exon skipping and splicing inhibitory activity requires the C-terminal region of TDP-43, which interact with the hnRNP family. TAR DNA-binding protein 43 (TDP-43) was identified as the pathological protein in most common subtypes of FTD and amyotrophic lateral sclerosis (ALS). The dramatic change in subcellular distribution of TDP-43 from the nucleus to the cytoplasm in inclusion bearing cells suggests that loss of pivotal nuclear TDP-43 have a pathogenic role. Cortical inclusions in FTLD-TDP are selectively enriched for hyper-phosphorylated C-terminal fragments (CTFs). Overexpression of this CTF is the key feature of the formation of ubiquitinated and phosphorylated cytoplasmic aggregates.

SIGNS AND SYMPTOMS:

The symptoms of dementia vary across types and stages of the diagnosis. The most common affected areas include memory, visual-spatial, language, attention and problem-solving. Most types of dementia are slow and progressive. By the time the person shows signs of the disorder, the process in the brain has been happening for a long time. It is possible for a patient to have two types of dementia at the same time. About 10% of people have mixed dementia, which is usually a combination of AD and another type of dementia.

Neuropsychiatric symptoms that may be present are termed behavioral and physiological symptoms of dementia (BPSD) and these include:

• Balance problem
• Speech and language difficulty
• Trouble eating and swallowing
• Memory distortions
• Restlessness
• Perception and visual problems
• Agitation
• Depression
• Anxiety and Irritability
• Delusions or hallucination
• Changes in sleep or appetite
• Abnormal motor behavior.

When people with dementia are put in circumstances beyond their abilities, there may be a sudden change to crying or anger (catastrophic reaction). Psychosis and agitation also often accompany dementia.

Mild Cognitive Impairment:

The earliest stage of dementia is called mild cognitive impairment (MCI). 70% off those diagnosed with MCI progress to dementia at some point. MCI shows the symptoms of dementia late.

Alzheimer's Disease:

• Difficulties in forming new memories
• Regularly forgetting recent events
• Becoming increasingly repetitive
• Misplacing items and getting confused
• Loss of interest in daily activities, becoming upset 

Vascular Dementia:

• Problems in attention, planning and reasoning
• Personality changes- depression, apathy, emotional
• Movements problems
• Bladder problems- frequent urge o urinate
• People need help in eating, dressing or using toilets.

Lewy bodies Dementia:

• Muscle stiffness and tremors.
• Repeatedly, realistic and well-formed hallucinations
• Shouting out while sleeping
• Fainting and unsteadiness.

Frontotemporal Dementia:

• Lack of personnel and social awareness
• Over-eating
• Develop unusual beliefs, interests and obsessions
• Twitching of muscles

At early stages of dementia, the symptoms interfere with person's daily activities. The person usually score 20-22 on the mini-mental state examination (MMSE).

At middle stage, the symptoms experienced get worsen. Moderate dementia patient score 6-17 on the MMSE. Person requires assistance for personal care. 

At last stage, person requires 24 hours supervision to ensure safety. They does not recognize common danger and are unable to control their bladder or bowels. Does not recognize familiar faces or people.

DIAGNOSIS:

Clinicians can diagnose the syndrome of dementia based on history, examination and appropriate objective assessments, using standard criteria such as DSH-5. Dementia is typically diagnosed when acquired cognitive impairment has become severe enough to compromise social and occupational functioning.

Diagnosis criteria for dementia:

The presence of an acquired impairment in memory, associated with impairment in one or more cognitive domains including:

• Executive function (e.g., obstruct thinking, reasoning, judgement)
• Language (expressive or receptive)
• Praxis (learned motor sequence)
• Agnosies (ability to recognize objects, faces or info.)

Diagnosis may be aided by brain scanning technique i.e., brain biopsy (rarely recommended).

COGNITIVE TESTING:

There are some brief tests (5-15 min.) that have reasonable reability to screen for dementia. presently mini-mental state examination (MMSE) is the best studied and most commonly used with high sensitivity and specificity for separating moderate dementia from normal cognition. A patient with mild dementia usually have a score of 18-26 out of 30, those with moderate dementia scores 10-18 and severe scores less than 10.

Other tests include Abbreviated Mental Test Score (AMTs), Modified mini mental state exam (3MS) Cognitive Abilities Screening Instrument (CASI), the Trait Making test and the clock-drawing test.

LABORATORY TESTS:

Routine blood tests are usually performed to rule out treatable causes. These tests include vitamin B12, folic acid, TSH, C-reactive protein, full blood count, electrolyte, calcium, renal function and liver enzymes. Abnormalities may suggest vitamin deficiency, infection or other problems that commonly cause confusion or disorientation in elders.

IMAGING:

A CT scan or magnetic resonance imaging (MRI scan) is commonly performed. These can yield relevant info to other type of dementia such as stroke.

The functional neuroimaging of SPECT and PET are more useful in assessing long-standing cognitive dysfunction. The ability of SPECT to differentiate the vascular cause from AD, appear superior to differentiation.

CSF ANALYSIS:

Cerebrospinal fluid analysis in dementia is generally intended to exclude an infective or demyelinated disorder. CSF concentration is generally raises only when there is extensive neuronal loss occurring over a short time period.

• A comprehensive examination of blood hemostasis factors including platelet count, specific clotting factors and anti-phospholipid-antibodies may be helpful.
• In individuals with history of alcohol abuse, thiamine deficiency should be considered but is usually diagnosed on the basis of therapeutic response to an intravenous bolus of thiamine.

TREATMENT:

• MEDICATION

The following are used to temporarily improve dementia symptoms:

CHOLINESTERASE INHIBITORS: These medications including donepezil, rivastigmine (Exelon) and galantamine (Raza dyne) work by boosting levels of a chemical messenger involved in memory and judgement. Side effects can include nausea, vomiting and diarrhea . With these types of drugs deterioration of the disease could be delayed by at least 12 months.

MEMANTINE (Namenda) works by regulating the activity of glutamate, another chemical messenger involved in brain functions such as learning and memory. Sometimes, it is prescribed along with donepezil in combination drug for moderate to severe dementia.

PSYCHOTROPHIC DRUGS can be used as supportive therapy in the treatment of behavioral problems in dementia.

ANTI-ANXIETY MEDICATIONS OR ANXIOLYTICS such as lorazepam (Ativan) can ease anxiety or restlessness.

ANTIDEPRESSANTS like serotonin reuptake inhibitors (SSRIs), can improve low mood and irritability.

ANTIPSYCHOTIC MEDICINES such as ariprazole, olanzapine etc. can help control feelings and behaviors such as delusions, agitation.

Treatment of dementia begins with the treatment of the underlying disease. The underlying causes of nutritional, hormonal,  tumor-caused or drug related dementia may be  eversible to some extent.

THERAPIES:

• Reminiscence therapy
• Cognitive stimulation therapy (CST)
• Reality Orientation therapy 
• Behavior orientated therapy
• Emotion-oriented therapy
• Stimulation oriented therapy

LIFESTYLE CHANGES:

• Stay active and organized
• Focus on food.
• Prioritize good sleep
• Challenge the brain