DEMENTIA

Question 1

Definition

Answer 1

Acquired clinical syndrome characterized by impairment of main cognitive functions such as memory, language, praxic, gnostic and executive functions.

It is the chronic decline in two or more areas of cognition.

Question 2

Epidemiology

Answer 2

The prevalence is doubling every 20 years due to the increased life expectancy

Question 3

Classification is based on etiopathological mechanisms into:

Answer 3

• Primary (neurodegenerative process that has not specified origin)
  It can be subdivided in:
   Pure -> cognitive alterations are the only clinical manifestation
   Plus -> cognitive alterations are associate to other neurological signs and symptoms
• Secondary (pathological process that include systems or organs connected with the brain)

Question 4

RISK FACTORS

Answer 4

-Age
- Genetic factors (rare forms with mendelian transmission, favoring or protecting polymorphisms)
- Cardiovascular risk factors

Question 5

Diagnosis

Answer 5

• Anamnesis must be done in the presence of a family membe
• Hemato-chemical analysis are included in initial screening as it provides knowledge about possible comorbidites and risk factors for dementia. They include ESR, CBC, electrolytes, glycemia, hepatic and renal function test, thyroid hormones, vitamin B12, folic acid.
• Lumbar puncture is performed when inflammatory, infective or demyelinizating pathologies are suspected. It is also performed in rapidly progressive diseases and when the cognitive deterioration involves the white matter in a diffuse pattern.
• CT scan and MRI for every patient that refers cognitive disorders (especially those associated with vascular etiology)
• CT scan and MRI for every patient that refers cognitive disorders (especially those associated with vascular etiology)

Question 6

Primary dementia
ALZHEIMER DISEASE

Answer 6

Alzheimer disease is the most common cause of cognitive decline (50%of cases).

It is caused by the accumulation of extracellular amyloid plaque and intracellular neurofibrillary tangles.

Question 7

National Institute on Aging-Alzheimer’s Association

Answer 7

1. Alzheimer-sustained dementia = neurodegenerative process is manifested together with dementia
2. Alzheimer-sustained slight cognitive deterioration = cognitive deterioration is not so severe to interfere with social and occupational role of the patient
3. Prodromic Alzheimer = there are no clinical elements to diagnose dementia but there are instrumental, biochemical and genetical elements that can suggest a future development of the disease

Question 8

Etiopathogenesis

Answer 8

The amyloid plaques are formed by β-amyloid, which is an amino acid formed from the precursor of amyloid located on chromosome 21.

This β-amyloid forms the central nucleus of fibrils and it is surrounded by reactive glial cells to form the plaque (amyloid plaques are found in autopsy).

They are widely distributed in the cortex, in the cortical frontal- association areas.

Question 9

Etiopathogenesis TAU PROTEIN

Answer 9

The neurofibrillary tangles are composed of hyperphosphorylated Tau protein that loses its normal stabilizing function for microtubules and cytoskeleton.
Tau protein aggregates in tangles in the neurons and it becomes toxic and cause death of those neurons (It is like α-synuclein for PD intracellular accumulation).
Tau is found also in cortico-basal ganglia degeneration.

It is probably the excessive production of amyloid that causes the abnormal phosphorylation of Tau protein.

Question 10

WHEN THOSE PATHOLOGICAL ALTERATIONS ARE FOUND?

Answer 10

These pathological alterations are found years before the onset of clinical manifestations and they involve majorly the temporal lobes, hyppocampus, amygdala, entorinal cortex and subcortical structures. Later in the disease they involve the whole cerebral cortex.

Question 11

SPORADIC FORMS

Answer 11

Sporadic forms represent 90% of cases.

They are characterized by polymorphisms and mutations with protective or favoring functions.

Eg. Apolipoprotein E (ApoE) polymorphism that increases the risk of AD development of 2-3 (heterozygote) and 6-8 (homozygote) fold with respect to other genotypes

Question 12

FAMILIAL FORMS

Answer 12

The familiar forms are characterized by the presence of at least two affected first grade-family members.

Within the familiar diseases we can have genetical disorders with dominant autosomic transmission involving mutations in presenilin 1 (PSEN1), presenilin 2 (PSNE2) and amyloid precursor protein (APP).
These mutations cause an increased production of β-amyloid peptide.

Question 13

CLINICAL MANIFESTATIONS

Answer 13

It presents with insidious onset of cognitive disorders that evolve with a slow worsening progression.

-typical forms (memory deficit and progressive involvement of other cognitive domains)

-atypical forms (they start with posterior (visuospatial or gnosic) or anterior (executive, work memory) cognitive functions).

Question 14

HOW IS THE PROGRESS?

Answer 14

-concerns the episodic memory (short term) together with difficulty in finding the right word or temporal orientation.

-as the pathological process spreads beyond the medial temporal lobe (always affected at the beginning), you may notice a more generalized deficit: in addition to memory and orientation (both spatial and temporal) there are problems in planning, decision making, learning new tasks

-aphasia, apraxia, agraphia, patients won’t be able to walk, or language (both fluent and non fluent).

!!!!prosopagnosia : the inability to recognize familiar physiognomy and faces.

Question 15

ADVANCED STAGES OF THE DISEASE

Answer 15

-the patient is no more independent, both short term and long term memories are affected and usually it is mute and akinetic.

-MYCOLONUS : brisk rapid movement, that can appear in the late stage of Alzheimer disease.

-Behavior and psychic disorders are also common (delirium, hallucinations, aggression, inappropriate social behavior, depression, anxiety etc)
Death occurs because of comorbidities (usually infective).

Question 16

DIAGNOSIS

Answer 16

Mini-Mental

-Mini–Mental State Examination (MMSE) or Folstein test is a 30-point questionnaire

MoCa test

• The MoCA test is a one-page 30-point test administered in approximately 10 minute

CSF examination with lumbar puncture to find out increased level of tau protein and there are now neuroimaging methods that can detect amyloid directly in vivo like Nuclear medicine techniques, but they are still not widely used.

Question 17

MoCA TEST

Answer 17

• The MoCA test is a one-page 30-point test administered in approximately 10 minutes. There is also a basic form to test illiterate or subjects with lower education.The MoCA assesses several cognitive domains.
• The short-term memory recall task (5 points) involves two learning trials of five nouns and delayed recall after approximately 5 minutes.
• Visuospatial abilities are assessed using a clock-drawing task (3 points) and a three-dimensional cube copy (1 point).
• Multiple aspects of executive functions are assessed using an alternation task adapted from the trail-making B task (1 point), a phonemic fluency task (1 point), and a two-item verbal abstraction task (2 points).
• Attention, concentration and working memory are evaluated using a sustained attention task (target detection using tapping; 1 point), a serial subtraction task (3 points), and digits forward and backward (1 point each).
• Language is assessed using a three-item confrontation naming task with low-familiarity animals (lion, camel, rhinoceros; 3 points), repetition of two syntactically complex sentences (2 points), and the aforementioned fluency task.
• Finally, orientation to time and place is evaluated (6 points).

Question 18

LEWY’S BODIES DEMENTIA

Answer 18

It is the second cause of primary dementia (15% of cases)
- It is a synucleinopathy characterized by formation of eosinophilic inclusions in cytoplasm made by alpha-synuclein. They are found in monoaminergic nuclei (locus ceruleus and basal nucleus of Meynert).
Amyloid plaques and neurofibrillary tangles can coexist.
- It initially involves executive and visuospatial functions and then it progressively involves memory. It has a fluctuant trend among the day.
- Extrapyramidal signs include rigidity and bradykinesia. They are often bilateral and symmetrical with very low response to dopaminergic therapy. Their onset occurs months/years after the cognitive decline.
- Visual hallucination are complex and detailed, they appear quite early in the disease and they are helpful in diagnosis.
- Antidopaminergic and anticolinergic drugs have very bad effects by increasing the worsening of symptoms.

Question 19

PARKINSON-DEMENTIA

Answer 19

More common in familiar cases of PD. Major risk factors are age, severity of extrapyramidal disorders, postural instability and reduced cognitive performance already at the onset of disease
- Intellectual degeneration has an insidious onset and a slowly progression. It occurs after the development of motor symptoms (different from LBD).
- Executive function deficit is fluctuant among the day and it involves programmation, resolution of problems, short term memory, visuospatial ability.
- Also behavior-affection disorders are present (depression, hallucination, apathy, aggression, sleep disorders)

Question 20

PARKINSON-PLUS SYNDROME

Answer 20

Heterogenous group of neurodegenerative pathologies associated to parkinsonism, cognitive decay, and other signs and symptoms related to different structures of CNS.
Response to Parkinson’s therapy is very low.
* PSP is associated to subcortical deficit (attention and slowdown of ideas) and affection-behavior disorders
* CBD is associated with cognitive disorders such as ideomotor apraxia, sight and buccofacial apraxia, higher function deficit.
* MSA is not affected by involvement of cognitive functions (or at least not enough to cause dementia)

Question 21

Therapy of NOT reversible dementia

Answer 21

• Anticolinesterasic or antiglutamatergic drugs can decrease the progression of clinical signs and symptoms.
  Cholinesterase inhibitors (Donepezil, rivastigmine, and galantamine) are the only drugs approved by FDA and EMA for dementia treatment. They improve dementia by increasing Ach levels.
  Glutamate inhibitors (Memantine: has a more complex mechanism of action predominantly acting to glutamate and other neuromediators).

Suggest to this people to exercise the mind but also the body. Physical exercise has clearly demonstrated to improve plasticity of the brain and therefore improving the symptoms of dementia. Try to be active, learn things by memory.

Question 22

FRONTOTEMPORAL LOBAR DEGENERATION

Answer 22

Frontotemporal lobar degeneration is a group of pathologies characterized by dementia where personality changes are prevalent (these patients are disinhibited, euphoric).

This is due to the involvement of anterior regions of both cerebral hemisphere. There is a focalized atrophy in the frontal and anterior temporal lobe.

Question 23

LOCATION OF FRONTO

Answer 23

Later, as in Alzheimer, you have all brain atrophy.

They are different from Alzheimer because the process of degeneration is more localized in the fronto-temporal area.

Question 24

FRONTOTEMPORAL LOBAR DEGENERATION
- 2 CYTOPLASMIC INCLUSIONS

Answer 24

It is caused by two cytoplasmic inclusions:
* Tau protein (Pick’s bodies) that differ in patter of deposition and organization from neurofibrillary tangles
* Ubiquitin and TDP-43

Diagnosis can be easily done in the hospital using clinical criteria or also MRI.

Question 25

FRONTOTEMPORAL LOBAR DEGENERATION -
3 CLINICAL VARIANTS

Answer 25

There are three clinical variants. All of them present disorders in language and behavior, insidious onset and progressive trend (usually more rapid than other primary dementia forms).

• Frontal or behavior variant -> most common, with disorders in behavior and apathy, inertia and indifference toward others.
• Progressive nonfluent aphasia -> language disorder characterized by reduction of verbal fluency, it leads to mutism, agrammatism, phonic paraphasia. hey have problems in writing, reading and repeating but comprehension is maintained. Behavior disturbance are less severe and they appear later in the disease.
• Semantic dementia -> disorder of fluent language (logorrheic) with marked deficit of comprehension. It presents affection-behavior disorders.