Physiology of Behavior

Differential 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/CN S/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.

MCINORMAL AD

Alzheimer’s disease (AD): Neurodegenerative Progression

Adapted from Petersen (2003)

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

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/m edical/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).

  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: (a) Concern of individual and/or others (b) 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: (a) Concern of decline (individual and/or

others) (b) 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.