Memory and Dementia
PKGhatak,MD
What is memory.
Memory is the ability to recall previously learned somatic sensory, visual, auditory, taste and smell sensations, abstract ideas, dreams, subconscious experiences, and a combination of any of these, at an instance when required. Memories result from nerve cell reactivation, in specific areas of the brain, at various levels of activities and the role of the interconnecting pathways to the neurons play.
Location of memory centers in the Brain.
Hippocampus. Amygdala and Prefrontal Cortex are chief memory centers.
Memories are three different kinds. 1. Short term memory. 2. Permanent memory and, 3. Working Memory.
Short term memory.
Memories are stored mainly in the Hippocampus and outlines of those experiences are also kept in the prefrontal cortex at the same time. The gradual consolidation of memory takes place in the prefrontal cortex and short term memory from the hippocampus disappears at the same rate. Others believe permanent memory develops at the same time the short time memory is developing in the hippocampus.
Permanent memory.
The prefrontal cortex memory is known as the permanent memory.
Working memory.
The working memory is a complex short term memory where many other mental faculties work in harmony for the execution of a work plan. Example- driving an automobile to an address given to the driver over the telephone.
What is Dementia.
Dementia is defined as loss of memory, language, problem-solving and other thinking abilities that are severe enough to interfere with daily life.
Incidence of dementia in the USA.
The incidence of dementia among individuals aged 71 and older is about 14%. The incidence increases with increasing age.
Causes of Dementia.
The
cause of dementia is due to loss of function of memory cells due to disease or death.
Classification of Dementia.
The classification is based on the common link among the different entities.
1. Progressive dementia. Dementia is not reversible.
Example- Alzheimer's disease, Lewy body dementia.
2. Vascular dementia. Damage to the blood vessels and to memory centers of the brain.
3. Frontotemporal dementia. Degeneration of the nerve cells in the frontotemporal cortex.
4.
Mixed dementia. Vascular dementia and progressive dementia often coexist.
5. Dementia as a part of other diseases. Examples. a) Huntington's disease
b) Traumatic Brain Injuries (TBI). c) Creutzfeldt-Jakob disease. d) Parkinson's disease
6. Reversible dementia.
Subdural hematoma, normal pressure hydrocephalus, certain medications taken for various illnesses- like antihistamines, antidepressants. Alcoholism, Vitamin B1 and Vitamin B12 deficiency. Infections, Hypothyroidism, hypoglycemia, Lead poisoning, Hypoxemia and brain tumors are some of the examples of reversible dementia.
7. Inherited and familial. Huntington's disease, Down syndrome. Alzheimer's disease.
Alzheimer's disease.
Alzheimer's disease (AD) is the most common dementia in the elderly population. AD is an irreversible and progressive disease. The onset of AD is invidious. The changes in the brain begin years before the first signs of dementia. Forgetfulness is the earliest symptom, slowly and steadily progressive loss of memory occurs, then progress to loss of cognitive function, motor skills, logical thinking, social isolation and finally complete loss of activities of daily living develop.
Clinically AD is discussed under 1. Early,2. Moderately advanced and 3. Late stages based on the degree of disability
Basic biological changes are due
to Two abnormal proteins accumulate in the brain. Beta Amyloid
protein -- due to an abnormal gene of an Amyloid Precursor Protein (APP)
on chromosome 21. Apolipoprotein APOE 4 is produced
instead of normal APOE protein. The abnormal beta amyloid protein
accumulates in between microglia cells, astrocytes and neurons. The microglia cells, normally function as immunocytes of the brain and have phagocytic properties. They are unable to break
down the beta amyloid. Accumulated beta amyloid forms plaques. The connecting neuronal fibers
and synapses gradually lose function and neurons
gradually die, the brain shrinks in size.
The second abnormal protein is Tau protein. TREM 2 gene encodes tau protein. This protein is present in the membrane receptors of microglia. The mutant TREM2 generated abnormal tau protein - hyperphosphorylated abnormally folded protein destroys the microtubules. Microtubules require ATP energy to transmit chemicals from one spot to the other within the cell. Hyperphosphorylations prevent microtubules from using ATP. Dying microglia releases cytokines which further damages neurons.
Pathologically the loss of nerve fibers, synapses, and neurons is most noticeable in the hippocampus, cingulate gyrus, temporal lobes and parietal lobes.
Diagnosis of AD.
Diseased and damaged areas of the brain are detected by MRI, CT scan and Positron Emission Tomogram
(PET) scan. A definitive diagnosis is made on brain tissue obtained by
biopsy or at autopsy. Neurofibrillary triangles and a decrease in the number of neurons are demonstrated. Beta amyloid and tau proteins are identified by staining.
Treatment.
Based on the clinical stage of the disease management of AD varies. All aspects of medical therapeutics, physiotherapy, occupational therapy, behavior modifications, social integration and experimental treatment modalities are employed.
Therapeutics.
Two groups of drugs are used in the treatment of AD. 1. Acetylcholine esterase inhibitors. 2. N-Methyl D Aspartate Receptor Antagonists (NMDAR).
Acetylcholine esterase inhibitors. Acetylcholine is a neurotransmitter, in normal conditions, it is degraded from the synapses by the enzyme acetylcholine esterase. Increasing the local concentration of acetylcholine by blocking this enzyme shows some improvement of memory at least initially. The commonly prescribed drugs are Donepezil, Rivastigmine and Galantamine.
NMDAR. Glutamine is another neurotransmitter. But the excess accumulation of glutamine within the neuron is harmful to neurons. NMDAR blocks glutamine uptake by neurons. The approved drug is Memantine.
Prognosis. The prognosis of AD is poor. It is the 6th common cause of death in the USA.
Lewy Body Dementia (LBD)
Lewy body dementia is common in people over 50 years of age. An abnormal protein
alpha synuclein accumulates in neurons of the brain. The neurons swell
up with like a balloon due to accumulation of alpha synuclein. The neurotransmitters - Acetylcholine and Dopamine production are
diminished.
Acetylcholine deficiency causes a decline in cognition, behavior change
and alteration of sleep rhythm. Motor
function abnormality and rigidity like Parkinson's disease develop due to dopamine deficiency.
Areas of the brain affected in LBD and consequences.
Neurons of the cerebral cortex – defective reception, thought and language difficulties.
Limbic area of brain - emotion and behavior changes and fluctuations from time to time.
Hippocampus – difficulty in new memory formation.
Brain stem – sleep disturbance and fluctuating alertness.
Olfactory lobe – loss of smell sensation or abnormal sense perception.
Distinguishing features of LBD from other forms of dementia.
Fluctuating level of alertness. 2. Visual hallucination. 3. acting out dreams.4. Gross impairment of abstract thinking and reasoning. 4. frequent episodes of delirium.
Risk factors.
Increasing age, presence of gene mutation of APOE e4, SNCA and GBA genes,
Treatment.
No specific medication is available for LBD. Symptomatic treatment is recommended. Prevention of falls and fractures of bones requires special attention. In most patients with various levels of assistance are required for activities of daily living.
Prognosis. It is not good. From the time of LBD diagnosis, most people die between 5 to 8 years.
Huntington's Disease (HD) and Dementia.
Huntington's disease is an autosomal dominant inherited disease. As the disease progresses the short term memory, permanent memory and work memory are all profoundly lost leading to dementia.
HD results due to the accumulation of an abnormal protein - Mutant Huntingtin protein (mHTT) within the neuron in a wide area of the brain but the highest concentration is present in the Striatum. A moderate amount of accumulation of mHTT is present in caudate nuclei, putamen, hippocampus, Purkinje cells of the motor cortex, cerebellum, hypothalamus, and cerebral cortex.
The mHTT protein starts to accumulate in the cells. It is broken down by the enzyme Caspase. But the fragments quickly reform in a haphazard manner. This abnormally folded mHTT protein structurally resembles beta amyloid protein. The mHTT protein is present in both the nucleus and cytoplasm of the neurons and is known as inclusion bodies. The mHTT protein is toxic to the cells and results in cell death.
The mHTT protein deposition is also
seen in the heart, testicles, liver, and lungs and produces symptoms from the damaged tissues of these organs.
Huntinton's Disease is an autosomal dominance inheritance disease. A mutation of a gene in the short arm of chromosome 4 is responsible for HD. The European population has more HD; the incidence is about 15 per 100,000 population. The symptoms of HD appear at ages 30 to 50 years of age. Less frequently, young adults in their 20s show signs of HD. Rigidity is the prominent symptom and features that resemble Parkinson's disease are present. In contrast to the older population, HD seizures are rare occurrences. But the disease progresses rapidly in the Juvenile form of HD.
Some special features of HD. Seizures are not unusual; the presence of a characteristic eye movement is called saccadic eye movement. Muscle rigidity, incoordination, unstable gait resembles Parkinson's disease. Patients are emotionally labile. An increased rate of suicide is noted.
Diagnosis. Detection of abnormal chromosome 4 is essential. Siblings, children and close relatives, even with no symptoms of HD, can have chromosome analysis done to detect their chance of HD if they wish and properly counseled.
Treatment. In general, medications are prescribed for the control of symptoms and complications that arise from HD. No cure is possible at present. Stem cell transplants are discussed but not performed.
For control chorea (abnormal purposeless dance-like movements) in HD Tetrabenazine is approved.
Prognosis. For most patients' deaths usually take place in 15 to 20 years.
Dementia of Parkinson's disease (PD).
Parkinson's disease is a
progressive, irreversible degenerative disease of the brain.
Substantial nigra is primarily affected and results in a decrease in
Dopamine production from the deaths of the neurons. About 2 % of
people over 65 have Parkinson's disease.
Older PD patients with dementia suffer from repeated hallucinations and excessive daytime sleepiness.
Some special symptoms associated with dementia of Parkinson's disease.
Delusions and paranoid ideas are common, have difficulty in interpreting visual images, display conceptual memory loss, and react adversely to antipsychotic drugs, often lapses into coma from their use.
Frontotemporal Dementia.
Of all the different causes of dementia, frontotemporal dementia has the most devastating impact on the patient and the family. Frontotemporal dementia appears at age 40, the incidence is equal in both sexes, has a strong family history and is inherited due to multiple genetic defects. The disease involves degeneration of neurons due to the accumulation of an abnormal protein- pink bodies in the neurons, involving many areas of the brain simultaneously, including the Limbic area and Neocortex.
Features of frontotemporal dementia (FTD).
Abnormal behavior like stealing, swearing, excessive indulgence in sexual activities, apathy, language difficulties, halting speech, and carelessness about personal hygiene. Some develop poor muscle coordination, tremors, muscle spasms and swallowing difficulty. Hallucinations and delusions are present in others.
Classification of FTD.
Frontal variant where behavioral changes predominate. In Primary progressive- aphasic- semantic dementia patients have great difficulties in understanding spoken words and initiate a conversation due to delayed speech. Degenerative diseases of the nervous system like Amyotrophic lateral sclerosis may also have this dementia.
Diagnosis of FTD.
The neuropsychological examination is the first step followed by an MRI or CT scan of the brain demonstrating multiple areas of involvement including the center of primitive functions in the Limbic area and behavior modification areas in the neocortex.
Treatment.
No treatment can change the basic defect in the brain but symptomatic treatment can control some symptoms.
Vascular Dementia.
Vascular dementia develops due to diseases of cerebral blood vessels.
One major event, like strokes, may produce dementia or dementia follows from many mini strokes or vascular insufficiency. The symptoms of vascular dementia are variable based on the areas of the brain that are damaged. Dementia is a dominant symptom when the hippocampus and prefrontal area of the cortex of the brain bear the brunt of anoxia.
Predominant symptoms of vascular dementia are confusion, restlessness and agitation, poor attention span and mixed memory loss.
Risk factors include high blood pressure, cigarette smoking, drug use, diabetes mellitus, obesity and high blood cholesterol and triglyceride.
Treatment.
The main goal of therapy is to prevent further neurological episodes. Risk factors reduction, rehabilitation and symptomatic treatment.
Dementia associated with Traumatic Brain Injury.
Because of wide circulation in print media
and electronic media regarding traumatic brain injury and its
consequences Traumatic brain injury (TBI) is a familiar
subject. The attention of public was drawn to this subject when
Mohammad Ali, the famous heavyweight boxing legend, developed
Parkinson's disease. More news soon followed detailing
accounts of veterans struggling with this poorly understood entity at
that time and also because of the news that many veterans committed suicide.
Incidence. About 2 % of the adult population is known to have CTE. About 50% of CTE patients have a history of loss of consciousness.
Inheritance. The incidence of CTE is 10 times higher when the abnormal AOPE e4 gene is present. The mode of inheritance is not known, probably multiple gene mutations are possible.
Pathology. Beta amyloid protein, Tau protein, accumulation in the brain of 30 % CTE patients detected by autopsy examination. The most common areas of the brain showing abnormality are the hippocampus, amygdala, precuneus, parietal and frontal lobes of the brain.
Distinguishing features of CTE are headaches, sudden mood swings, explosive rage, drug abuse and suicide. Ataxia, dysarthria, rigidity and tremor are evident during examinations.
Treatment. Multidisciplinary medical therapies including psychological counseling are called for. The outcome of coordinated therapy is encouraging.
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