Physiology of Behavior
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NeurologicalDisordersAlzheimersandDementiasSpring20231.pptxDifferential Diagnosis of Dementias (Alzheimer’s Focus)
Nathaniel W. Nelson, Ph.D., LP, ABPP
Licensed Psychologist
Board Certified in Clinical Neuropsychology
Overview
Anatomical Considerations of Alzheimer’s Dementia (AD)
Risk Factors and Epidemiological Trends
Diagnostic/Treatment Considerations
Neuropsychological Considerations
First, what is “Dementia”?
The term ‘dementia’ is no longer used in DSM-5-TR (now Major Neurocognitive Disorder), but the term continues to be used regularly in clinical and research settings
Dementia (Loring, 1999): (Latin: “De” – signifying separation or cessation, and “mens” (mentia), mind)
Dementia can be defined as a clinical syndrome of acquired cognitive impairment that is associated with a number of potential disease processes (Nyenhuis & Gorelick, 1998)
Alzheimer’s disease (AD) is only one of several causes of Dementia (Major Neurocognitive Disorder)
Pronounced, generalized cortical atrophy of the brain is common in patients with AD
Hence, AD is often considered the prototypical “cortical” dementia
Image from: http://medlib.med.utah.edu/WebPath/TUTORIAL/CNS/CNSDG002.html
Anatomy of AD
Anatomy of AD
AD typically involves degeneration of mesial temporal structures
Particular involvement of the hippocampus and entorhinal cortex accounts for memory difficulties in AD patients (Caselli & Boeve, 2003)
Enlargement of the cerebral ventricles due to atrophy or loss of adjacent tissues (hydrocephalus ex vacuo) can also eventually result
Image from: http://www.ahaf.org/alzdis/about/BrainAlzheimer.htm
http://www.alz.org – Your Brain
Anatomy of AD
Widespread, cortical neuritic plaques are pathological characteristics of AD (Caselli & Boeve, 2003)
Neurofibrillary tangles (NFT’s) are also prominent in AD: “no patient with Alzheimer’s Disease has ever been reported without NFT’s in the entorhinal and hippocampal regions…” (Boller & Duyckaerts, 2004, p. 521)
Images from: http://www.rnw.nl/health/html/brain.html
Risk Factors of AD
Age (mainly after ages 60 to 65)
Apolipoprotein E ε4 allele: it’s presence nearly doubles one’s risk of developing AD (Bennett, 1999)
Down’s Syndrome (Trisomy 21)
Female Gender
AD is the most common form of dementia in Western Hemisphere
Head trauma? HTN? Al exposure?
Alzheimer’s Disease: One of several neurodegenerative processes
Frontal
dementia
AD
Pick’s
Disease
Semantic
dementia
PD
DLB
HD
PSP
CBD
PPA
Comportmental
Linguistic
Amnestic
Movement
Tauopathies
Amyloidopathies
Synucleinopathies
Adapted from Relkin & Caporaso (2004)
Proteins associated with formation of pathological lesions in degenerative diseases of the brain
Disease Lesion Protein
-----------------------------------------------------------------------------------------------
AD Senile Plaque (extracellular) AB
NFTs (intracellular) Tau
FTD Pick bodies Tau
CBD Intraneuronal inclusions Tau
PSP NFTs Tau
DLB Lewy bodies a-Synuclein
PD Lewy bodies a-Synuclein
HD Intranuclear inclusions Huntingtin
CJD Plaques Prion (PrP)
Adapted from Relkin & Caporaso (2004)
Alzheimer’s Association (2023). 2023 Alzheimer’s disease facts and figures. Alzheimers Dement, 19, 1-128.
Alzheimer’s disease: Epidemiological Considerations
Alzheimer’s disease (AD) is by far the most common cause of major neurocognitive disorder (dementia) among individuals
Prevalence varies by age (Alzheimer’s Association, 2023):
Ages 65-74: 26.7%
Ages 75-84: 37.9%
Ages 85+: 35.4%
Incidence: New AD cases will increase considerably in the next decade:
In the State of Minnesota alone, the number of AD cases is projected to rise from 99,000 in 2020, to 120,000 in the year 2025, a relative increase of 21.2%.
Alzheimer’s Association (2023). 2023 Alzheimer’s disease facts and figures. Alzheimers Dement, 19, 1-128.
Alzheimer’s disease: Epidemiological Considerations
Alzheimer’s Association (2023). 2023 Alzheimer’s disease facts and figures. Alzheimers Dement, 19, 1-128.
Alzheimer’s disease: Epidemiological Considerations
Alzheimer’s Association (2023). 2023 Alzheimer’s disease facts and figures. Alzheimers Dement, 19, 1-128.
Alzheimer’s disease: Epidemiological Considerations
Alzheimer’s Association (2023). 2023 Alzheimer’s disease facts and figures. Alzheimers Dement, 19, 1-128.
Alzheimer’s disease: Epidemiological Considerations
Deaths associated with complications of AD are also much higher than other common causes of death in aging communities.
Whereas deaths associated with stroke, prostate cancer, and heart disease either declined or remained stable between the years 2000 and 2019, deaths associated with AD increased by approximately 145% over that same timeframe (U.S. Department of Health & Human Services, 2020, as cited by Alzheimer’s Association, 2010).
Alzheimer’s disease: Epidemiological Considerations
Alzheimer’s Association (2023). 2023 Alzheimer’s disease facts and figures. Alzheimers Dement, 19, 1-128.
Genetic Associations in AD
Gene Chromosome Background Onset
-------------------------------------------------------------------------
APP 21 Familial Early
PS1 14 Familial Early
PS2 1 Familial Early
APOE 19 Sporadic Late
Adapted from Relkin & Caporaso (2004)
Progression of Disease
Alzheimer’s Association (2022). 2022 Alzheimer’s disease facts and figures. Alzheimers Dement, 18, 1-120.
MCI
NORMAL
AD
Alzheimer’s disease (AD): Neurodegenerative Progression
Adapted from Petersen (2003)
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Alzheimer’s disease (AD): Neurocognitive Impairment
General profile characterized by deficits in:
Learning/memory (anterograde amnesia)***
Language (e.g., verbal fluency)
Abstract reasoning and other ‘executive functions’,
Visuospatial/constructional abilities
Smith, G. E., & Bondi, M. W. (2013). Mild cognitive impairment and dementia: Definitions, diagnosis, and treatment. Oxford University Press.
Alzheimer’s disease: Hallmark Symptoms and Impairments
Associated Clinical Features
Patients with AD may have limited insight into the extent of their impairment (which speaks to the importance of collateral interview with a loved one).
Psychosis (ranging from 22 to 56%; Rabins, 1999)
Alzheimer’s disease: Diagnosis
Ideally, diagnosis of probable AD is the product of multidisciplinary approach
Consultation with physician (ideally a neurologist)
Brain neuroimaging study (which may or may not confirm signs of cortical atrophy in key brain regions)
Neuropsychological evaluation (formal, psychometric assessment of learning/memory and other cognitive domains)
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).
Selected Disorders:
Neurodevelopmental
(e.g., Autism, ADHD, Learning)
Schizophrenia, Psychosis, Bipolar and Related
Major Depression
Anxiety Disorders
Trauma-Related
(e.g., PTSD)
Mild and Major Neurocognitive Disorders
(e.g., Alzheimer’s, Vascular, other conditions)
Essential to consider/rule out alternate causes of impairments, such as:
Other neurodegenerative condition (e.g., FTD)?
Toxic/Metabolic process?
Vascular Dementia (VaD)?
AD Differential Diagnosis (e.g., Vascular Dementia, VaD)
VaD can be the result of cerebrovascular events such as strokes
Strokes may be classified as either ischemic (most common) or hemorrhagic
Ischemic strokes include thrombosis and embolism
Hemorrhagic strokes involve blood leakages from a weakened vessel (may be the result of aneurysms or vascular malformations)
Abrupt onset of symptoms/signs associated with stroke is distinct from what is typical in AD
However, small vessel ischemic change, or Leukoaraiosis (Hachinski et al, 1987), is sometimes observed in VaD and has been associated with cognitive decline
Anatomy of VaD: Thrombus
A thrombus may contribute to brain ischemia (lack of blood flow) and eventual infarction (tissue death) by impeding distal blood flow to the brain
Localized thrombus occurs on an atherosclerotic arterial narrowing (Chung & Caplan, 2003)
Anatomy of VaD: Embolus
Brain embolism involves arterial blockage by a thrombus fragment or any other intra-arterial/intracardiac material
Most common embolic source is the heart
Emboli tend to lodge at bifurcations, branchings, and curvatures (e.g., ICA, MCA)
Anatomy of VaD: Hemorrhage
Bleeding injures surround tissues by:
1. cutting vital pathways
2. exerting pressure on local structures
3. causing ischemia of adjacent tissues
(Chung & Caplan, 2003)
Copyright © Allyn & Bacon 2007
Distribution of the Major Cerebral Arteries
ACA: dorsal and medial
MCA: lateral
PCA: ventral and posterior
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Anatomy of VaD: Site of Infarction and Clinical Manifestations
Carotid Artery Vertebral Artery
ACA - Lateral medullary (Wallenberg’s) syndrome
Contralateral lower extremity paresis
Mutism, apathy, pseudobulbar palsy
MCA
Contralateral hemiparesis
Hemisensory loss
Aphasia
Hemi-inattention
PCA
Contralateral homonymous hemianopsia
Alexia without agraphia
Vertebrobasilar System
Basilar Artery
Total Occlusion
Coma
Locked-in Syndrome
Occlusion of branch
Cranial Nerve Palsy with contralateral hemiparesis (Adapted from Kaufman, 2001)
Internuclear ophthalmoplegia
Anatomy of VaD: Leukoaraiosis
Refers to either changes in the periventricular white matter (along the lateral ventricles), or deep white matter changes occurring in tissues adjacent to the lateral ventricles (Cosentino et al., 2004)
Associated with multiple ischemic lesions, but can also occur in AD as well as normal aging (Loring, 1999)
There is evidence that even a minor degree of leukoaraiosis can have subtle effects on cognition (Bowler & Hachinski, 2004)
Image from: http://www.amershamhealth.com/medcyclopaedia/medical/Volume%20VI%201/LEUKOARAIOSIS.ASP
Risk Factors of VaD
Age
Male Gender
Hypertension
Heart Disease
Hypercholesteremia
Diabetes Mellitus
Smoking
Drug Treatments*
Cholinesterase Inhibitors (e.g., Aricept, Excelon)
NMDA Inhibitor (Namenda)
Anti-amyloids (e.g., Aducanumab, Lecanemab)+
Alzheimer’s disease (AD): Treatment Considerations
Non-pharmacologic interventions
Computerized Memory Training?
Music Therapy?
Aerobic Exercise?
*Note. “None of the pharmacologic treatments (medications) available today for Alzheimer’s dementia slow or stop the damage and destruction of neurons that cause Alzheimer’s symptoms and make the disease fatal” (Alzheimer’s Association, 2019, p. 10).
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From: Yu, Vock, Zhang, Salisbury, Nelson, Chow, Smith, Barclay, Dysken & Wyman (2021). Cognitive effects of aerobic exercise in Alzheimer’s disease. A pilot randomized controlled trial. Journal of Alzheimer’s Disease, 80, 233-244.
Alzheimer’s disease (AD): Treatment Considerations
No differences in cognitive performances between aerobic exercise (cycling) and comparison (stretching) conditions at 6 and 12 months.
Conclusion: “Exercise may reduce decline in global cognition in older adults with mild-to-moderate AD dementia”.
Both groups (cycling, stretching) showed significantly less cognitive impairment than what is observed naturally with disease progression
Groot et al. (2016). The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials. Ageing Research Reviews, 25, 13-23.
Overall effect size = .42
“These findings indicate that physical activity interventions may serve as a cost-effective and feasible alternative/add-on to pharmacological treatment for patients with dementia” (p. 18).
Alzheimer’s disease (AD): Treatment Considerations
Major Neurocognitive Disorder
Cognitive decline (>1 domain) based on:
Concern of individual and/or others
Impaired cognitive performance, preferably documented by standardized neuropsychological testing
Cognitive deficits interfere with daily activities
Cognitive deficits do not occur exclusively in context of delirium
Cognitive decline not better explained by another condition (e.g., Major Depression, Schizophrenia, other)
Specifiers (e.g., Alzheimer’s, Other)
Mild and Major Neurocognitive Disorder
Adapted from DSM-5 (APA, 2013).
Mild Neurocognitive Disorder
Modest cognitive decline based on:
Concern of decline (individual and/or others)
Modest cognitive impairment, preferably documented by standardized neuropsychological testing
Cognitive deficits do not interfere with daily activities
Cognitive deficits do not occur exclusively in context of delirium
Cognitive decline not better explained by another condition (e.g., Major Depression, Schizophrenia, other)
Specifiers (e.g., Alzheimer’s, Other)
Vignette #1
Background
75-year-old, HS-educated man
Referral by Neurologist: MMSE = 17/30; Neurodegenerative dementia?
Patient: no concerns. (“my memory is as good as yours”).
Spouse: 3-year course of progressive memory decline
Daily activities: difficulties with medication management, finances (per spouse)
Relevant Medical Records:
Brain MRI: Diffuse cortical atrophy, of moderate progression relative to patient’s age.
Behavioral observations:
Interpersonally pleasant
Frequently repeats self in conversation
Difficulty representing aspects of recent background information (turns to spouse)
Diagnostic Impression (DSM-5):
????????
Recommendations:
?????????
| Test Domain | Findings |
| Orientation | Impaired (unable to reorient to month/year) |
| Attention/Concentration | Intact |
| Language | Variable |
| Visual-Spatial | Variable |
| Executive | Impaired |
| Learning/Memory | Impaired (0% retention) |
| Psychological/Emotional | Minimal |
Vignette #2
Background
60-year-old, college-educated woman, self-referred, presents with self-reported memory difficulties in last 5 years
Patient: Marked memory concerns
(“I am not myself; something is wrong”)
Son: No concerns about her memory abilities; concerned that she may be depressed (“so down on herself; she cries a lot”).
Daily activities: No concerns from either; works full-time, usual effectiveness.
Relevant Medical Records:
Primary care physician: Mini Mental State Examination (MMSE) = 29/30.
Behavioral observations:
Excellent historian; articulate.
Mood is “blah”; affect is restricted.
Tearful while discussing memory concerns.
Diagnostic Impression (DSM-5):
??????????
Recommendations:
????????????
| Test Results | Findings |
| Orientation | Intact |
| Intellectual | FSIQ = 123 (superior) |
| Attention/Concentration | Intact |
| Language | Intact |
| Visual-Spatial | Intact |
| Executive | Variable (processing speed) |
| Learning/Memory | Intact (superior) |
| Psychological/Emotional | Marked distress (moderate depressive symptoms) |
Thoughts?
Alzheimer’s Association (2023). 2023 Alzheimer’s disease facts and figures. Alzheimers Dement, 19, 1-128.
