Lecture 8: Vascular dementia

Question 1

Criteria dementia/major neurocognitive disorders (DSM V):

Answer 1

1. Evidence significant cognitive decline based on report patient or informant AND objective deficits (>2 SD below appropriate norms)
2. Cognitive deficits sufficient to interfere with independence
3. Cognitive deficits not exclusively in context delirium
4. Cognitive deficits not attributed to Axis 1 disorder (e.g. depression or schizophrenia)

Question 2

¨Vascular dementia (VaD) – dementia caused by cerebrovascular disease

Answer 2

• Cerebrovascular disease (CVD) – diseases of blood vessels in brain affect blood supply
  
  • Cerebrovascular pathology associated with reduction in blood flow
  • Until 1960s cerebrovascular disease regarded main cause dementia in older adults

Question 3

Prevalence

• Vascular dementia:

Answer 3

Vascular dementia:

• second most common form of dementia, after AD
  
  • Netherlands: 16% of dementia cases are vascular dementia (Alzheimer Nederland)
  • UK: 17% vascular (Alzheimer Society)

Question 4

Vascular cognitive impairment (VCI):

• all forms cognitive impairment caused by cerebrovascular disease (Gorelick et al., 2011)

Answer 4

• Ranging from Very mild to severe
• Milder forms: VCI no dementia (VCIND) or vascular MCI (VaMCI)
• More severe forms: consequences for daily functioning, vascular dementia (VaD)

Question 5

VaD result from 2 main forms cerebrovascular disease:

Answer 5

1. white matter lesions, lacunar infarcts, small vessel stroke
2. cerebral arteries stroke/large vessel stroke

• or combination of 1 and 2

Question 6

white matter lesions, lacunar infarcts, small vessel stroke:

Answer 6

• problem with blood supply, hence not enough oxygen
• vessel disease - hypoperfusion brain tissue - degeneration white matter (white matter lesions)
• vessel disease - microbleeds in brain tissue - tissue death
• diffuse

Picture: White matter lesions visible as hyperintensities on MRI scans: minor (L) and extensive (R)

Question 7

VaD result 2 main forms cerebrovascular disease

1. white matter lesions, lacunar infarcts, small vessel stroke
   * Atherosclerosis:

Lacunar refers to small blood vessels deep inside the brain.

Answer 7

Atherosclerosis:

• build up plaque inside arteries
• hardens and narrows the arteries
• limits flow blood to tissues
• risk rupture
• Narrowed arteries or high blood pressure increase risk lacunar infarct/lacunar stroke.
• Lacunar infarct/lacunar stroke most common type of ischaemic stroke
  • Lacunar infarct: narrowed arteries blocked more easily.
  • Leads to lack of oxygen and blood in the area.
• Microbleeds: occurs when small bloos vessels rupture, hence, damage.

Question 8

VaD result 2 main forms cerebrovascular disease

2. cerebral arteries stroke/large vessel stroke:
   * Picture: Likelihood of stroke for particullar areas*

Answer 8

• Ischemic (meaning occlusion/blockage) or hemorrhagic (rupture)
• More localised
• Strategic location or volume
• VaD and large vessel disease. Areas medial cerebral artery & carotid artery

Question 9

Clinical features

Clinical presentation VaD diverse:

(Vascular dementia)

Answer 9

• Clinical presentation VaD diverse – “heterogeneity is the rule”
  
  • variety cerebrovascular events can lead to symptoms
  • damage can occur in variety locations
  • criteria for diagnosis revised number of times

Question 10

VaD result 2 main forms cerebrovascular disease (percentages/relative frequencies):

1. white matter lesions, lacunar infarcts, small vessel stroke
2. cerebral arteries stroke/large vessel stroke

Answer 10

Question 11

Clinical features

• Earlier criteria (e.g. DSM 4)

Vascular dementia

Answer 11

• Memory prominent impairment.
  
  • Memory critical impairment (from AD)
  • memory not always most prominent impairment in VaD
  • pathology may not include medial temporal areas (as AD)
• stepwise deterioration (abrupt deterioration and stable intervals)
  • Cognitive decline in steps: rapid decline and stable periods
  • Further stroke - rapid decline
  • Unlike gradual decline AD

Question 12

Clinical features (nowadays)

Vascular dementia

Answer 12

Diagnosis VCI/VaD based on 2 factors

• Presence cognitive impairment (dementia/MCI) on neuropsychological tests
• Presence cerebrovascular disorder (CVD) on neuroimaging
  
  • Regardless of cause, e.g. atherosclerosis, ischemic, hemorrhagic.

Plus a third and most difficult condition:

• Establish relationship cognitive impairment and CVD.
  
  • Location of lesions in line cognitive impairments observed
  • Cognitive impairments appear shortly after onset CVD

Question 13

VCI

Clinical features

• Most recent criteria for diagnosis (Gorelick et al., 2011)

Answer 13

Question 14

Most recent criteria for diagnosis (Gorelick et al., 2011)

• Vasular dementia:

Clinical features

Answer 14

• see picture: so a single isolated cognitive impairment (as sometimes occurs due to strok) is not sufficient
• if there is hemianopia (which is usually caused by a stroke) that would disqualify for dementia….

Original table: https://www.ahajournals.org/doi/full/10.1161/STR.0b013e3182299496

Question 15

Most recent criteria for diagnosis (Gorelick et al., 2011)

• Probable Dementia

Answer 15

Question 16

Most recent criteria for diagnosis (Gorelick et al., 2011)

• “possible dementia”

Answer 16

Possible VaD

• cognitive impairment and CVD
• no clear relationship
• Insufficient evidence, information missing
• Aphasia too severe to assess cognition
• Indications neurodegenerative or other diseases

Question 17

Clinical features

Most recent criteria for diagnosis (Gorelick et al., 2011)

• VaMCI

Answer 17

VaMCI

• cognitive impairment at least 1 domain
• Instrumental activities daily living intact/only mildly impaired.
• Relationship moment and severity cerebrovascular event and onset cognitive deficit

Question 18

Clinical features

• VCIND/VaMCI:

Answer 18

• Functions affected vary, can include memory, executive function, attention, visuospatial functions
• can be precursor/prodromal stage VaD
  
  • Conversion rates vary (up to 50%)
• Persons with VCIND may revert back normal performance

Question 19

Clinical features

• Definitive diagnosis VaD confirmed post-mortem:

Answer 19

Definitive diagnosis VaD confirmed post-mortem:

• Evidence cerebrovascular disease in brain
• Absence of AD pathology or other disease that can cause dementia

Question 20

Risk factors VCI same as for stroke:

Answer 20

• Age biggest risk factor.
• Other unmodifiable risk factors:
  
  • male sex
  • low birth weight
  • genetic factors
    
    • Notch 3 gene – causative gene for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) – hereditary form of VaD.
• Modifiable risk factors include: hypertension, smoking, diabetes, obesity (same as for stroke)

Question 21

Difficulties diagnosis VaD:

Answer 21

• common occurrence mixed dementia: cerebrovascular pathology and AD pathology
  
  • mixed dementia at least as common as pure VaD or pure AD
    
    • Schneider et al . (2009): mixed pathology nearly as common as pure AD.
  • large proportion AD cases also CVD (up to 80%)
• overlap in clinical features VaD and AD

Question 22

Difficulties diagnosis VaD

• Stepwise course uncommon in VaD (Gorelick et al., 2011) -> believed to be defining feature decades ago
• Demonstration link CVD and cognitive deficits

Answer 22

• Stepwise course uncommon in VaD (Gorelick et al., 2011)
  
  • Insidious onset and gradual decline more common in VaD
  • so it can’t be used as a distinguising factor anymore
• Demonstration link CVD and cognitive deficits
  • No stepwise decline
  • “silent” or asymptomatic infarcts

Question 23

Cognitive impairments present in Vascular dementia:

• stepwise vs gradual decline
• subcortical vs cortical

Answer 23

• VaD often consequence additive effect of cerebrovascular disorders
  
  • progressive decline in cognitive functions
• Brain areas affected influence pattern of cognitive decline
  
  • Lacunar infarcts and white matter lesions often in subcortical (“deep”) areas
• VaD referred to as “subcortical” or “frontal-subcortical” dementia
  • AD referred to as “cortical” dementia
• Not all VaD caused by subcortical pathology
  
  • Neuropathology cortical or subcortical.
  • Emphasis research on subcortical VaD
    
    • includes infarcts white matter, subcortical grey matter (e.g. basal ganglia)

Question 24

Cognitive impairments

• subcortical VaD (Binswanger’s disease)

Answer 24

• subcortical VaD (Binswanger’s disease)
  
  • EF relatively more impaired than in AD
  • interruption frontal subcortical circuits
  • episodic memory relatively less impaired than in AD

Question 25

Cognitive imairments: * Subcortical – cortical dementia (table 6.2 Smith and Bondi, 2013):

Answer 25

* cortical dementia referred to AD * subcortical dementia referred to VaD

Question 26

Cognitive impairments VaD * Amount white matter abnormalities (WMA) in persons with VaD associated with EF (Price et al., 2005)

Answer 26

Amount white matter abnormalities (WMA) in persons with VaD associated with EF (Price et al., 2005) * more WMA, poorer performance EF task (WMS – mental control subtest ± WM task) * No association WMA severity and memory performance

Question 27

Cognitive impairments * Limitation studies comparing VaD and AD cognitive profile: **diagnosis not confirmed in autopsy**

Answer 27

Limitation studies comparing VaD and AD cognitive profile: diagnosis not confirmed in autopsy * Clinical diagnosis – possibility of misclassifications * Difficult to compare neuropsychological profiles, if uncertain who has AD and who has VaD

Question 28

Cognitive impairments * Reed et al. (2007) autopsy diagnosis confirmed: * neuropsychological profiles in autopsy confirmed AD (n=23) and CVD (n=11) * AD - plaques and tangles * CVD - infarcts: subcortical (including hippocampus, internal capsule, white matter, subcortical grey matter (e.g. basal ganglia), brain stem and cerebellum) and cortical (cortical grey matter) * only small lesions - lacunar infarct, microinfarct Classification (profiles): * Cases substantial ischemic pathology and little AD pathology - VaD * Cases substantial AD pathology, little vascular pathology - AD * Mixed cases

Answer 28

Cognitive impairments Reed et al. (2007) autopsy diagnosis confirmed * AD: memory poorer than EF * CVD/VaD: EF poorer than memory In cases with cognitive impairments: * Low Memory score: 79% AD, 0% CVD * Low EF score: 5% AD, 67% CVD * 45% CVD cases and 4% AD cases no cognitive impairments during life

Question 29

Differential diagnosis VaD and AD * How does diagnosis based on neuropsychological profiles compare to autopsy-confirmed diagnosis? * ¨Reed et al. (2004), from same sample as Reed et al. (2007):* * diagnosis on based neuropsychological test: * AD – prominent episodic memory impairment (rapid forgetting), no prominent impairments EF * Ischemic vascular dementia (ILVD) – impaired EF (poor initiation, poor switching, poor WM, perseverations), impaired memory (poor learning, but relatively good recognition) * Mixed – features of both AD and IVD

Answer 29

¨Reed et al. (2004), from same sample as Reed et al. (2007) * Diagnosis AD mostly correct. * Diagnosis IVD and mixed less likely to be correct, but correctly distinguished form AD * no IVD/ Mixed incorrectly diagnosed as AD * Episodic memory impairment useful key cognitive impairments to distinguish AD from VaD * impairment EF less useful as clinical feature to identify VaD McGuiness et al. (2010). No difference EF in VaD (46) & AD (76)

Question 30

Differential diagnosis VaD and AD * How does diagnosis based on neuropsychological profiles compare to autopsy-confirmed diagnosis? * **Naming:**

Answer 30

* BNT: VaD better than AD, worse than matched HC * Overall VaD group less impaired than AD group (Lukatela et al 1998) * Fewer semantic errors suggests semantic memory relatively intact

Question 31

Differential diagnosis VaD and AD * How does diagnosis based on neuropsychological profiles compare to autopsy-confirmed diagnosis? * **Language:**

Answer 31

* Similar pattern language impairments in VaD and AD (Vuorinen et al. 2000). * Naming, comprehension, production narrative * Preserved word repetition, reading out words – require no semantic processing

Question 32

How does diagnosis based on neuropsychological profiles compare to autopsy-confirmed diagnosis? Other cognitive impairments * **Visuospatial deficits** * IVD – white matter abnormalities probable IVD * AD – without cortical or subcortical infarction on MRI

Answer 32

Rey complex figure test (Freeman et al., 2000) * Copying: AD more accurate than IVD, HC more accurate than AD and IVD. Recognition after 20 min delay * IVD higher scores than AD, IVD worse score than HC * Visuospatial abilities more impaired in VaD than AD, * Visual memory less impaired in VaD than AD Clock drawing: * Patients diagnosed VaD and severe WMA, more errors on CDT than those with mild WMA (Price et al. 2005)

Question 33

Cognitive impairments VaD versus AD * **Meta-analysis (Mathias & Burke, 2009)** * 81 studies comparing cognitive performance in persons diagnosed with AD and VaD

Answer 33

* Episodic memory more impaired in AD than VaD: confirmed * EF more impaired in VaD than AD: not confirmed * NB. no distinction between different subgroups, e.g. subcortical or cortical VaD * Very few tests discriminated between 2 groups, exceptions were * Emotional recognition test: VaD worse than AD * Delayed Story Recall: VaD better than AD

Question 34

**Neuropsychiatric symptoms (NPS)/behavioural disturbances:** * Common in VaD and mixed AD/VaD

Answer 34

* Overall prevalence NPS similar in AD and VaD groups (69.7% vs. 69.4%). AD (n=166) higher frequency agitation/aggression and irritability/lability than VaD (n=136) (D’Onofrio et al., 2012) * Postmorten confirmed AD (n = 40) or VaD (n = 40). Most prevalent agitation (57.0%), depression (41.2%) , anxiety (35.4%). No difference AD and VaD (Echavarri et al., 2013) * VaD patients (n=34) significantly more agitation (40 vs. 14%) and sleep disturbances (57 vs. 32%) than AD patients (n=92) (Anor et al., 2017). (-\> contrary to the study above by D’Onofrio et al., 2012) * overall it seems that there are no large differences in NPS

Question 35

Assessment * (differential) diagnosis of VaD * Interview and history * Neuropsychological assessment * Neuroimaging, corroborating MRI essential

Answer 35

Interview and history: * patient and informant, (early) signs and symptoms * stepwise course not critical sign VaD Neuropsychological assessment * sufficient breadth: memory, language, speed, attention, visuospatial, EF * include learning across trials, delayed retention and recognition * AD poor all indices, VaD better recognition Neuroimaging, corroborating MRI essential * Lacunar infarcts and white matter hyperintensities * Amount of CVD sufficient to account for the cognitive difficulties

Question 36

¨Vascular dementia * pharmacological intervention * Current treatments aimed at (modifiable) risk factors VaD

Answer 36

* ¨No pharmacological intervention specifically for VaD * Acetylcholinesterase inhibitors, glutamate antagonists * mixed reports effect on cognition (Tuokko & Smart, 2018) * Frequent severe side-effects * hypertension, diabetes, obesity - medication or life style changes * Reducing risk factors could prevent VaD * Importance diagnosis - different interventions VaD and AD

Question 37

Intervention VaD: * Non-pharmacological interventions

Answer 37

Non-pharmacological interventions * Same approaches as used in AD (very little differences) * Similar effects