Dementia & Memory Loss 1

Question 1

Memory types

Answer 1

1) Working (Άμεση) (a few seconds)

2) Recent (πρόσφατη) (a few minutes up to a few days)

3) Remote (απώτερη) memory

i) Explicit (συνειδητή) (declerative - δηλωτική)
a) Episodic (Επεισοδιακή) ανάκληση γεγονότων και εμπειριών που έζησε το άτομο με όλες τις χρονικές και χωρικές λεπτομέρειες
b) Semantic (Σημασιολογική) γενικές γνώσεις

ii) Implicit (μη συνειδητή) (procedural - διαδικαστική) π.χ. μια δεξιοτεχνία

Question 2

Types of memory and how are they tested

Answer 2

A commonly used memory classification includes immediate (working memory), recent (short-term), and remote (long-term).

1) Working memory refers to the circuits used to register, recall, and mentally manipulate information in short-term memory.
Digit span is a test of attention and immediate memory, a very short-term function in which the material is not actually committed to memory.

2) Recent, or short-term, memory is tested by giving the patient items to recall.
After ensuring the patient has registered the items, proceed with other testing.
After approximately 5 minutes, ask the patient to recall the items.

Some patients may fail to remember the items, but they can improve performance with hints or pick the items from a list. A distinction is made between retention and retrieval.
Patients who are able to remember items with cuing or by picking from a list are able to retain the information but not retrieve it.
When cuing or picking do not improve performance, the defect is in retention.
Patients with early dementing processes may have only a failure of retrieval.

3) A patient’s fund of information reflects her remote memory. The fund of information includes basic school facts, such as state capitals, famous presidents, and important dates, as well as current information, such as the sitting president, vice-president, governor, and similar public officials.
The patient should also know personal information, such as her address, phone number, social security number, wedding anniversary date, and names of children.
Mothers and grandmothers usually know the ages and birth dates of their children and grandchildren.

Asking directions is often useful, and tests both memory and spatial ability. Most patients are able to describe how to drive from their home to the place of the encounter, as well as the general direction and distance to major cities and local towns.

Question 3

What is episodic memory

Answer 3

Episodic memory refers to the system involved in remembering particular episodes or experiences (such as the movie you saw last weekend or the meeting you attended yesterday).

usually profoundly affected in AD

Question 4

Criteria for all-cause dementia

Answer 4

Question 5

Dementia classification

Answer 5

Alzheimer Disease

Atypical Alzheimer disease
i) Posterior Cortical Atrophy
ii) Logopenic primary progressive aphasia
iii) Behavioral/ Frontal or Dysexecutive variant Alzheimer disease

Neurodegenerative dementias associated with parkinsonism

i) Synucleinopathies
1) Dementia with lewy bodies
2) Parkinson disease dementia
3) Multiple system atrophy

ii) Tauopathies
1) Corticobasal degeneration
2) Progressive supranuclear palsy

Frontotemporal dementias
i) Behavioral variant
ii) Primary progressive aphasias
1) Nonfluent/agrammatic PPA
2) Semantic variant PPA

Vascular dementia

Normal pressure hydrocephalus

Post-traumatic dementia

Question 6

Alzheimer disease: Neuropathologic changes

Answer 6

1) Aβ protein in the form of extracellular plaques and
2) abnormally phosphorylated microtubule-associated protein tau in the form of neuronal neurofibrillary tangles

Question 7

Amyloid-β protein formation

Answer 7

This abnormal protein is cleaved (αποσχίζεται) from a much larger 695-amino acid amyloid precursor (πρόδρομος) protein, which is the predominant isoform expressed in neurons.

Amyloid precursor protein (a transmembrane protein) is cleaved by β-secretase, resulting in release of soluble amyloid precursor protein-β into the extracellular space.

Cleavage of the remaining fragment embedded in the plasma membrane by γ-secretase results in the production of the highly amyloidogenic β fragment, the Aβ protein, which accumulates and deposits in the brains of individuals with AD.

Presenilin forms part of the gamma-secretase complex, and mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2) appear to favor production of amyloid beta overall, or more neurotoxic forms of amyloid beta.

Question 8

Amyloid-β protein major subtypes

Answer 8

Two major subtypes of the amyloid-β protein exist, which differ in C-terminal length: Aβ40 and Aβ42.
Aβ42 is more amyloidogenic than Aβ40, whereas Aβ40 accumulates more often in neuritic plaques and exclusively comprises the amyloid within the blood vessels in cerebral amyloid angiopathy (CAA).

Question 9

Amyloid accumulation in the brain in AD over time

Answer 9

Amyloid accumulation begins in the neocortex and, over time, progresses to the hippocampus, basal ganglia, midbrain, and cerebellum

Question 10

Neurofibrillary tangles:
1) Formation
2) Location
3) Mechanism in AD

Answer 10

1) Neurofibrillary tangles are composed of abnormally phosphorylated tau protein in the form of paired helical filament neuronal tangles. Normal tau is a protein coded by the microtubule associated protein tau (MAPT) gene on chromosome 17q21.

2) neurofibrillary tangles are intracellular, residing in the neuronal cytoplasm

3) Tau is essential for microtubule structure and function, especially axonal transport.
In aging and disease, the phosphorylation of tau and the formation of neurofibrillary tangles result in loss of the ability to perform these and other pivotal cellular functions.

Question 11

Are neurofibrillary tangles specific for AD?

Answer 11

Neurofibrillary tangles are not specific to AD but also occur in normal aging and more than 30 different diseases.
In the context of dementia, tauopathy in other major neurodegenerative diseases ncludes subtypes of FTLD, such as:
* progressive supranuclear palsy (PSP)
* corticobasal degeneration (CBD)
* FTD
* FTD with parkinsonism due to MAPT mutations

Question 12

Neurofibrillary tangles accumulation in the brain in AD

Answer 12

In aging and AD, neurofibrillary tangles typically begin to accumulate in the mesial temporal lobe, specifically the entorhinal and hippocampal cortices.
Neurofibrillary tangle accumulation in aging and AD has been described by Braak in six stages.
The progression as described by Braak shows stages 1 through 4 are largely restricted to the mesial temporal lobe, whereas stages 5 and 6 are widespread in the neocortex

Question 13

Autosomal dominant forms of AD
1) percentage
2) genes
3) mechanism

Answer 13

1) about 5% to 10% of early-onset cases (younger than 65 years old) (and less than 1% of all AD cases)

2) are most commonly caused by highly penetrant mutations in presenilin 1 (PSEN1) but may also be caused by mutations in amyloid precursor protein gene (APP) and presenilin 2 (PSEN2).
Such mutations are highly penetrant, meaning that carriers have a nearly 100 percent chance of developing the disease in their lifetime.

3) The pathogenic mutations either result in overproduction of the Aβ protein or cause a greater ratio of Aβ42 to Aβ40.
Interestingly, both PSEN1 and PSEN2 are proteins of the γ-secretase complex.
These proteins are involved in the proteolytic cleavage of amyloid precursor protein into Aβ.

Question 14

APOE gene:
1) what is it
2) main variants
3) risk for AD

Answer 14

1) a cholesterol transport protein secreted primarily from astrocytes and affecting neurons mostly through the low-density lipoprotein family of receptors.

2) Human APOE has three main variants, ε2, ε3, and ε4. Most people have two copies of the ε3 variant, but about 25% of population have at least one copy of the ε4 allele

3) The most firmly established genetic risk factor for late-onset AD is APOE.
ε4 increases the risk of AD
Pathologically, people with the ε4 allele have a greater accumulation of brain amyloid than those with other alleles, and people with the less common ε2 allele have less Aβ than those with the ε3 allele.

Carriers of one e4 allele are at two- to threefold increased odds of developing AD compared with noncarriers, and those with two e4 alleles are at approximately 8- to 12-fold increased odds.

The ε2 allele is protective for AD, decreasing risk of developing the disorder.

Question 15

Alzheimer disease:
1) Prevalence
2) Incidence

Answer 15

1) 3% of people between the ages 65-74
32% of people age 85 and older

2) 2 per 1000 in 65-74
11 per 1000 in 75-84
37 per 1000 in 85 and older

Question 16

Alzheimer disease: Acquired risk factors

Answer 16

Vascular factors (increase the risk of dementia and may impact AD)
1) Hypertension
2) Dyslipidemia
3) Cerebrovascular disease
4) Peripheral and cardiovascular atherosclerosis
5) Type 2 diabetes and obesity
6) Activity

7) Brain trauma (not confirmed)
8) Medications (mostly anticholinergics, probably but not proven benzos and PPIs)
9) Smoking
10) Anemia (?)

Question 17

Is family history for dementia a risk factor for Alzheimer disease?

Answer 17

• Family history of dementia is a risk factor for the development of AD
• patients with a first-degree relative with dementia have a 10 to 30 percent increased risk of developing the disorder.
• Individuals in families with two or more affected siblings with late-onset AD have a threefold increased risk of AD compared with the general population

Question 18

Alzheimer disease diagnostic criteria
(NIA 2011)

Answer 18

Question 19

Περιορισμοί βιολογικής μόνο διάγνωσης Alzheimer

Answer 19

1) Κάποια άτομα μπορεί να έχουν παθολογία Alzheimer αλλά να μην αναπτύξουν ποτέ συμπτώματα
Ως εκ τούτου δεν έχει καλή προγνωστική αξία
2) Μπορεί η παθολογία Alzheimer να είναι συννοσηρότητα σε άλλου τύπου άνοια

ΑΝΟΙΑ 2023

Question 20

Κλινικές εκδηλώσεις νόσου Alzheimer

Answer 20

Τυπική αμνησική άνοια ιπποκάμπειου τύπου
Οπίσθια φλοιική ατροφία
Λογοπενική πρωτοπαθώς προϊούσα αφασία > svPPA > nfaPPA
Μετωπιαία παραλλαγή
Φλοιοβασικό σύνδρομο

ΑΝΟΙΑ 2023

Question 21

How is memory affected in Alzheimer disease

Answer 21

• Declarative episodic memory (memory of events occurring at a particular time and place) is usually profoundly affected in AD. This type of memory depends heavily on the hippocampus and other medial temporal lobe structures.
• Memory for facts such as vocabulary and concepts (semantic memory) often becomes impaired somewhat later.
  Semantic memory is supported by neocortical temporal regions, particularly in the anterior temporal lobe.
  Subtler impairments of semantic memory may be a relatively early feature given early temporal lobe pathology
• Memory deficits develop insidiously and progress slowly over time, evolving to include deficits of semantic memory and immediate recall.
• Impairments of procedural memory appear only in late stages of AD.

Question 22

Mental status scales to evaluate cognition and cutoffs

Answer 22

MMSE: scores ≤23 are most commonly regarded as abnormal and indicative of cognitive impairment
However, age, education, and race/ethnicity each appear to have significant effects on overall MMSE scores, suggesting that these demographic variables should be taken into account when evaluating individual patient performance.

MoCA: In the original publication describing the MoCA, scores ≤25/30 indicated the presence of significant cognitive impairment.
Subsequent versions of the test have added a cutoff point of ≤24/30 for patients with ≤12 years of formal education, but in broader patient populations, a cutoff point of ≤22/30 for cognitive impairment may be more optimal and reduce the frequency of false-positive results

Question 23

Role of lumbar puncture in Alzheimer disease diagnosis

Answer 23

1) to rule out inflammatory, infectious, or neoplastic central nervous system disorders

2) biomarkers may allow confirmation or refutation of a clinical diagnosis of AD.
Cerebrospinal fluid (CSF) β-amyloid-42 (AB42) levels are typically low, whereas total tau and phosphorylated tau levels are usually elevated, even in the earliest stages of AD

Question 24

Biomarkers in Alzheimer disease

Answer 24

Molecular biomarkers of Aβ protein deposition include:

● Low cerebrospinal fluid (CSF) Aβ42 (or Aβ42:Aβ40 ratio)
● Positive amyloid PET imaging using one of the amyloid PET tracers

Biomarkers of tau deposition (a key component of neurofibrillary tangles) include:

● Increased CSF total tau and phospho-tau
● Tau PET imaging using flortaucipir F-18

** In Alzheimer’s disease, the Aβ42/40 ratio is typically lower than in healthy individuals.
This is because the concentration of Aβ42 decreases in the CSF of AD patients due to its deposition in amyloid plaques in the brain.

Question 25

Neuroimaging in Alzheimer disease

Answer 25

● MRI – Structural MRI findings in AD include both generalized and focal atrophy, as well as white matter lesions. In general, these findings are nonspecific.
The most characteristic focal finding in AD is reduced hippocampal volume or medial temporal lobe atrophy.
Because hippocampal volumes decline in normal aging, however, age-specific criteria are needed.

● FDG-PET and SPECT – Functional brain imaging with 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) or single-photon emission computed tomography (SPECT) reveals distinct regions of hypometabolism (PET) and hypoperfusion (SPECT) in AD.
These areas include:
1) the hippocampus
2) the mesial parietal lobes and
3) the lateral parietal and posterior temporal cortex
In practice, FDG-PET may be most useful in distinguishing AD from FTD in patients with atypical presentations, as well as discriminating from non-neurodegenerative conditions, such as depression. FDG-PET and SPECT are the only functional neuroimaging methods that are currently reasonably widely available for clinical use.

● Amyloid PET imaging – Amyloid PET tracers (florbetapir F-18, flutemetamol F-18, florbetaben F-18) measure amyloid lesion burden in the brain; these aid in the diagnosis of AD, differentiating AD from other causes of dementia.

the US FDA approval specifies that an amyloid PET scan that is negative decreases the likelihood that a patient with dementia has AD.
In a symptomatic dementia patient, a positive scan indicates that the person has amyloid plaque pathology, but such a finding does not rule out a coexisting pathology.

● Tau PET imaging

Question 26

Seizures in Alzheimer disease

Answer 26

• Seizures occur in 10 to 20 percent of patients with AD, usually in the later stages of disease
• Younger patients, including those with autosomal-dominant forms of AD, may be at higher risk for seizures, which may occur early in the course of disease
• The predominant seizure type is focal nonmotor with impaired awareness, with symptoms often suggestive of medial temporal lobe onset (eg, amnestic spells, unexplained emotions, metallic taste, rising epigastric sensation)

Question 27

Posterior cortical atrophy syndrome: pathology

Answer 27

• In most patients, neuropathologic examination reveals Alzheimer pathology with a greater predominance of pathology involving visual association areas and even primary visual cortex compared with more typical presentations
• A minority of patients with this syndrome have alternative pathologies, such as dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), prion disease, or frontotemporal lobar degeneration (FTLD)

Question 28

Posterior cortical atrophy diagnostic criteria

Answer 28

Question 29

Logopenic Primary progressive aphasia: 1) clinical findings 2) imaging

Answer 29

1) frequent word-finding pauses and paraphasic speech errors without major grammar or comprehension deficits

2) structural imaging often shows predominant left posterior perisylvian or parietal atrophy

Question 30

Alzheimer disease treatment

Answer 30

1) Cholinesterase inhibitors –
For patients with newly diagnosed Alzheimer disease dementia a trial of a cholinesterase inhibitor is suggested

Patients with dementia of mild to moderate severity (eg, MMSE 10 to 26) may be the most likely to derive clinical benefit, which is typically modest and must be balanced with the risk of adverse effects.
Decisions should be individualized in patients with very advanced dementia (eg, MMSE <5) at the time of diagnosis.

2) Memantine –
In patients with moderate to advanced dementia (eg, MMSE ≤18), adding memantine (10 mg twice daily) to a cholinesterase inhibitor, or using memantine alone in patients who do not tolerate or benefit from a cholinesterase inhibitor is suggested

In patients with severe dementia (MMSE <10), continuing memantine is suggested, given the possibility that memantine may be disease modifying.
However, in some patients with advanced dementia, it may make sense to discontinue administration of medications to maximize quality of life and patient comfort.

3) Aducanumab –
Aducanumab is approved by the US FDA for the treatment of mild AD.
While aducanumab appears highly effective in reducing brain amyloid levels, it is uncertain that patients benefit clinically from treatment.
In addition, aducanumab has known risks that require close monitoring with clinical and imaging assessments
At present, the routine use of aducanumab for patients with AD is not suggested.

4) Vitamin E – It is reasonable to offer treatment with vitamin E (1000 international units twice daily) to patients with mild to moderate AD after discussing risks and benefits.
Experts do not consistently use vitamin E in patients with AD.
Vitamin E may provide a benefit in regard to slowing progression of disease; however, the benefit is likely to be small, and some studies suggest that there are risks in patients with cardiovascular disease

Question 31

Rivastigmine: 1) Mechanism of action, 2) dosing, 3) monitoring

Answer 31

1) rivastigmine increases acetylcholine in the central nervous system through reversible inhibition of its hydrolysis by cholinesterase

2)
Oral: Initial: 1.5 mg twice daily; may increase by 3 mg daily (1.5 mg/dose) every 2 weeks based on tolerability (maximum recommended dose: 6 mg twice daily).
Transdermal patch:
Initial: 4.6 mg per 24 hours patch applied once daily; after a minimum of 4 weeks, increase as tolerated to 9.5 mg per 24 hours; continue as long as therapeutically beneficial. After a minimum of 4 weeks, may increase as tolerated to a maximum dose of 13.3 mg per 24 hours.

3)
Cognitive function at periodic intervals, symptoms of GI intolerance, decreased weight, signs of cutaneous reactions.

Question 32

Rivastigmine: 1) adverse effects, 2) contraindications

Answer 32

1)
i) Cardiac effects
Acetylcholinesterase inhibitors, including rivastigmine, have been associated with cardiac effects, such as conduction abnormalities (eg, bradycardia, atrioventricular block, arrhythmias) and hypertension.
Syncope has also been reported

ii) Dermatologic reactions

iii) GI effects and weight loss
Symptoms may include nausea, vomiting, diarrhea, and abdominal pain.

2)
* Severe hepatic impairment;
* history of severe skin reactions (eg, allergic dermatitis, Stevens-Johnson syndrome) with oral or transdermal rivastigmine
* history of QT prolongation and/or torsades de pointes, including congenital long QT syndromes
* history of cardiac arrhythmias

Question 33

Donepezil: 1) Mechanism of action, 2) dosing, 3) monitoring

Answer 33

1) donepezil reversibly and noncompetitively inhibits centrally active acetylcholinesterase, the enzyme responsible for hydrolysis of acetylcholine. This appears to result in increased concentrations of acetylcholine available for synaptic transmission in the CNS.

2) Oral:
Mild to moderate: Initial: 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks.
Moderate to severe: Initial: 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks; (may increase further to 23 mg once daily if stable on 10 mg daily for ≥3 months)

3) Mental status, weight, symptoms of GI intolerance, symptoms of active or occult GI bleeding.

Question 34

Donepezil: 1) adverse effects, 2) contraindications

Answer 34

1)
cardiac effects
such as conduction abnormalities (eg, atrioventricular block, arrhythmias [including prolonged QT interval on ECG and torsades de pointes], bradycardia) and hypertension.
Syncope has also been reported
GI effects and weight loss
Symptoms may include nausea, vomiting, and diarrhea
Insomnia

2) none

Question 35

Memantine: 1) Mechanism of action, 2) dosing

Answer 35

1) Η μεμαντίνη είναι ένας εξαρτώμενος από την τάση, μη ανταγωνιστικός ανταγωνιστής υποδοχέος NMDA μέτριας συγγένειας. Ρυθμίζει τη δράση των παθολογικά αυξημένων τονικών επιπέδων γλουταμινικού που μπορούν να οδηγήσουν σε νευρωνική δυσλειτουργία

2) Oral:
Immediate release: Initial: 5 mg once daily; increase daily dose by 5 mg every week as tolerated to a target maximum dose of 20 mg/day.
Note: Dose may be administered once daily or in 2 divided doses

Question 36

Memantine: 1) adverse effects, 2) contraindications

Answer 36

1) Neuropsychiatric effects
confusion, dizziness, drowsiness, and headache, are the most commonly reported adverse reactions with memantine.
Ataxia, impaired consciousness, loss of consciousness, sleep disturbance, falling, and seizures are among other CNS effects that have also been reported
Agitation, delusion, and hallucination have also occurred

2) none

Question 37

Aducanumab: 1) Mechanism of action, 2) dosing, 3) monitoring

Answer 37

1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta.
Aducanumab reduces amyloid beta plaques, the accumulation of which is a defining pathophysiological feature of Alzheimer disease.

2) Alzheimer disease: IV: Initial: Dosing based on actual body weight: 1 mg/kg once every 4 weeks for infusions 1 and 2; 3 mg/kg once every 4 weeks for infusions 3 and 4; 6 mg/kg once every 4 weeks for infusions 5 and 6; maintenance dose: 10 mg/kg once every 4 weeks starting with infusion 7. Administer infusions at least 21 days apart.

3) PET or lumbar puncture to confirm presence of amyloid beta pathology (prior to initiation);
brain MRI (prior to initiation [within 1 year], prior to infusion 5 [first dose of 6 mg/kg], infusion 7 [first dose of 10 mg/kg], infusion 9 [third dose of 10 mg/kg], and infusion 12 [sixth dose of 10 mg/kg]);
monitor closely for clinical and MRI changes;
monitor for symptoms suggestive of amyloid-related imaging abnormalities (ARIA) (eg, headache, altered mental status, dizziness, visual disturbance, seizure, nausea); MRI as indicated if ARIA symptoms present or asymptomatic ARIA observed

Question 38

Aducanumab: 1) adverse effects, 2) contraindications

Answer 38

1) Amyloid-related imaging abnormalities
Amyloid-related imaging abnormalities-edema (ARIA-E) consistent with vasogenic edema and/or sulcal effusions or amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H) characterized by superficial siderosis and microhemorrhages
Patients may develop ARIA-H with concomitant ARIA-E.
Clinical symptoms suggesting ARIA (-E and/or -H) may include altered mental status, abnormal gait, confusion, delirium, disorientation, dizziness, focal neurologic deficits, headache, nausea, seizure, and visual disturbance.
Resolution of ARIA (-E and/or -H) occurred within 12 to 20 weeks in the majority of cases in clinical trials.

2) none

Question 39

Lecanemab: Mechanism of action, indications, Dosing

Answer 39

humanized monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. Lecanemab reduces amyloid beta plaques, the accumulation of which is a defining pathophysiological feature of Alzheimer disease.

patients with mild cognitive impairment or mild dementia (MMSE >21) due to Alzheimer disease

IV: 10 mg/kg once every 2 weeks

Question 40

Lecanemab: major adverse effect and monitoring

Answer 40

ARIA (risk factor: Apolipoprotein E ε4 carriers; specifically ApoE ε4 homozygotes)

Monitoring:

• PET or lumbar puncture to confirm presence of amyloid beta pathology (prior to initiation)
• apolipoprotein E ε4 (ApoE ε4) status testing (prior to initiation)
• brain MRI (prior to initiation [within 1 year]; prior to 5th, 7th, 14th infusions; periodically as appropriate in the setting of amyloid-related imaging abnormalities (ARIA); monitor closely for clinical and MRI changes
• monitor for symptoms suggestive of ARIA (eg, headache, altered mental status, visual changes, dizziness, nausea, gait difficulty, focal neurologic deficits, seizure)

Question 41

core clinical features of MCI

Answer 41

● Cognitive concern reflecting a change in cognition reported by patient or informant or observed by clinician

● Objective evidence of impairment in one or more cognitive domains, typically including memory

● Preservation of independence in functional abilities

● Not demented

Question 42

Mild cognitive impairment prognosis

Answer 42

Patients with MCI typically progressively worsen and develop a dementia disorder—most commonly AD—but sometimes FTD, PSP, dementia with Lewy bodies, or another disease.
Occasionally patients may “revert,” becoming normal, particularly those with a medical or psychiatric etiology.
Overall, there is a “conversion” rate from MCI to dementia, of between 10% and 25% per year

Question 43

Which is the second most common cause for dementia after AD

Answer 43

Vascular dementia

Question 44

Which is the most common neuropathologic correlate of both vascular dementia and multiple-etiology (“mixed”) dementia with a vascular component

Answer 44

cerebral small vessel disease

Question 45

Main causes of cerebral small vessel disease

Answer 45

1) Arteriolosclerosis – Arteriolosclerosis due to aging, hypertension, and conventional stroke-related vascular risk factors is the most common type of cerebral small vessel disease. The walls of small arteries and arterioles exhibit changes such as thickening, hyalinization, lipohyalinosis, microaneurysm formation, and loss of vascular integrity with cracking and perivascular hemosiderin deposits

Arteriolosclerotic cerebral small vessel disease prominently affects subcortical brain regions including the basal ganglia and corona radiata.
Patients with arteriolosclerotic cerebral small vessel disease typically have multiple lacunes or extensive, confluent white matter lesions as the pathogenic basis for their symptoms.

2) Cerebral amyloid angiopathy –
CAA is the second most common type of cerebral small vessel disease. CAA is usually caused by deposition of beta-amyloid in small arteries and arterioles in the leptomeninges and cerebral cortex.

One of the most prominent changes in CAA is a loss of vascular integrity resulting in both large, symptomatic and small, asymptomatic brain hemorrhages. Hemorrhages are restricted to typical locations in the cortex or subcortical white matter (also called “lobar” locations) with sparing of the basal ganglia and brainstem.

3) Others – There are many other less common or rare causes of cerebral small vessel disease, including genetic disorders such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), small vessel vasculitides and other inflammatory disorders, and venous collagenosis

Question 46

Main syndromes of vascular dementia

Answer 46

A) Poststroke dementia
- stepwise cognitive decline following a clinically diagnosed stroke
- prominent impairment of executive functions, sometimes with relative sparing of episodic memory
- It may be accompanied by other cortical signs of stroke including aphasia and apraxia

(Not all patients exhibit the classic syndrome of disproportionate executive function impairment. For example, anterior thalamic infarction can cause isolated memory impairment with preservation of other domains, which could mimic the cognitive profile of Alzheimer disease)

B) Vascular dementia without recent stroke
- imaging evidence of clinically unrecognized cerebrovascular disease.
- prominent impairment in executive function and processing speed!!
Impairment is not exclusive to these domains, however, and more global impairments in memory and other functions can occur.

Question 47

Categories of cerebrovascular disease that can cause dementia

Answer 47

Multi-infarct (or multi-hemorrhage) dementia
Damage to multiple brain regions has the cumulative effect of disrupting brain function, resulting in clinically significant cognitive impairment.
Strategic infarction (or hemorrhage)
Damage to a single brain location can be sufficient to cause clinically significant cognitive impairment. Examples include the medial frontal lobes (anterior cerebral artery territory), language cortices, thalamus, and medial temporal lobes.
Small vessel ischemic disease
(eg, multiple lacunae in the basal ganglia or in subcortical or periventricular white matter)
Hypoperfusion (eg, global, due to cardiac arrest or hypotension)
Hemorrhagic cerebrovascular disease
(eg, intracerebral or subdural hematomas or subarachnoid hemorrhage)

Question 48

Clinical differences between AD and vascular dementia

Answer 48

Compared with patients with AD, patients with vascular cognitive impairment tend to have better verbal learning and recall, on average, and worse executive function

Question 49

Non-cognitive symptoms of vascular dementia

Answer 49

Neuropsychiatric:
depression, abulia, apathy, and psychosis with delusions or hallucinations.
Patients may exhibit pathologic laughing or crying, a phenomenon known as pseudobulbar affect

Motor:
Slowing of gait is common in patients with cerebral small vessel disease and may lead to a syndrome described as lower body parkinsonism.

Other:
Increased urinary frequency may be seen
Symptoms and signs related to past history of stroke may also be present, including aphasia, motor weakness, and sensory impairments

Question 50

Vascular dementia differential diagnosis

Answer 50

● Alzheimer disease

● Parkinson disease and other related dementias

● Normal pressure hydrocephalus

● Depression

Question 51

Vascular dementia and AD differential diagnosis

Answer 51

Alzheimer disease produces a gradual, progressive decline that can be mimicked by progressive cerebral small vessel disease.
However, the typical cognitive profile of AD differs from vascular dementia in that there is usually more prominent impairment in episodic memory.
Atypical presentations of AD, such as the frontal variant, can make it difficult to distinguish from vascular dementia.

In most cases, clinical history and routine neuroimaging are probably sufficient to make a clinical diagnosis of vascular dementia, AD, or multiple-etiology dementia due to vascular dementia and AD.

** Amyloid PET or measurements of beta-amyloid and phosphorylated tau in the cerebrospinal fluid determine the presence or absence of AD pathology with high sensitivity and specificity
** On 18- FDG PET, a typical pattern of parietal and temporal hypometabolism suggests the presence of AD pathology, whereas the pattern of hypometabolism is more patchy and heterogeneous in patients with vascular dementia

Question 52

Vascular dementia and Lewy body disease differential diagnosis

Answer 52

Lewy body diseases (eg, Parkinson disease, dementia with Lewy bodies) produce a gradual, progressive decline with symptoms of gait-slowing that can mimic the progressive cognitive and gait impairment seen in cerebral small vessel disease.

Vascular parkinsonism differs from Parkinson disease and other Lewy body diseases in that bradykinesia affects the legs more than the arms (“lower-body parkinsonism”) and, in contrast to Parkinson disease, there is no resting tremor.

The presence of REM sleep behavior disorder, fluctuations in level of alertness, and prominent visuospatial dysfunction favor dementia with Lewy bodies as the cause of or contributor to the dementia

Question 53

Hachinski ischemic score

Answer 53

If present, each of the following features is assigned two points:

● Abrupt onset
● Fluctuating course
● History of stroke
● Focal neurologic symptoms
● Focal neurologic signs

The remaining features are each assigned one point:

● Stepwise deterioration
● Nocturnal confusion
● Preservation of personality
● Depression
● Somatic complaints
● Emotional incontinence (pseudobulbar affect)
● Hypertension
● Associated atherosclerosis

A score of 7 or greater indicates that a vascular contribution is likely.
The score has been validated against autopsy data and accurately discriminates pure or mixed vascular dementia from pure Alzheimer disease dementia.

Question 54

Pattern of cognitive dysfunction in vascular dementia

Answer 54

patients with VCI on average have the greatest impairments in
* speed
* praxis
* executive function (δυσεπιτελικό σύνδρομο - δυσχέρεια στο σύνθετο νοητικό έργο)
* visual memory
++ διαταραχή προσοχής και συγκέντρωσης

with less prominent impairment in verbal episodic memory

Το MMSE μπορεί να διατηρείται ψηλά για τον βαθμό της έκπτωσης

ΙΑΕΕ 2023

Question 55

Vascular dementia diagnostic criteria (VAS-COG Society)

Answer 55

ΙΑΕΕ 2023

Question 56

Vascular dementia management

Answer 56

1) Vascular risk modification

2) Antithrombotic therapy
Patients with vascular dementia who have had a clinical ischemic stroke or TIA should be treated with the appropriate antithrombotic therapy according to their stroke subtype in order to prevent recurrent ischemic stroke

A decision to initiate antiplatelet therapy in patients with VaD who have not had a clinical ischemic stroke or TIA should be individualized
(treat patients with aspirin 50 to 100 mg daily when brain imaging demonstrates an infarction but not when there are only white matter lesions)

3) Cholinesterase inhibitor therapy
Initiation of cholinesterase inhibitor therapy (donepezil or galantamine) is suggested in patients with VaD who have progressive cognitive decline that is not directly attributable to a clinical stroke

Initiation of cholinesterase inhibitor therapy in patients with dementia diagnosed after a stroke if there is not progressive cognitive decline is not suggested