Diagnosis and Assessment¶

Summary¶

This comprehensive chapter covers the diagnostic process for dementia, including cognitive assessments, brain imaging, laboratory tests, and differential diagnosis. You will learn about cognitive screening tools like the Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), and Clock Drawing Test. The chapter explains various brain imaging techniques (MRI, CT, PET, and SPECT scans), blood tests, cerebrospinal fluid analysis, genetic testing, and biomarkers. You will also understand how doctors distinguish dementia from other conditions like delirium and depression through differential diagnosis, and how functional assessments evaluate a person's ability to perform daily activities. This knowledge helps families understand what to expect during medical evaluations and how diagnostic information guides treatment planning.

Concepts Covered¶

This chapter covers the following 20 concepts from the learning graph:

Cognitive Assessment
Mini-Mental State Exam
Montreal Cognitive Assessment
Clock Drawing Test
Brain Imaging
MRI Scan
CT Scan
PET Scan
SPECT Scan
Blood Tests
Neurological Examination
Medical History
Differential Diagnosis
Delirium
Depression
Dementia Screening
Biomarkers
Cerebrospinal Fluid Analysis
Genetic Testing
Functional Assessment

Prerequisites¶

This chapter builds on concepts from:

The Diagnostic Journey: From Concern to Diagnosis¶

Receiving a dementia diagnosis is often the culmination of a long journey that begins with a family member noticing something isn't quite right. Perhaps Mom keeps forgetting recent conversations, or Dad got lost driving to a familiar location. These concerns prompt a visit to the doctor, which initiates a comprehensive evaluation process designed to determine whether cognitive changes represent normal aging, dementia, or something else entirely.

Understanding the diagnostic process serves multiple purposes:

Reduces anxiety - Knowing what to expect during evaluations reduces fear of the unknown
Enables preparation - Families can gather necessary information (medication lists, symptom histories) beforehand
Promotes accurate diagnosis - Understanding the purpose of each test helps patients and families participate effectively
Guides treatment decisions - Diagnosis determines which interventions and medications may be appropriate
Facilitates planning - Early diagnosis allows time for legal, financial, and care planning
Differentiates conditions - Many treatable conditions mimic dementia and must be ruled out

The diagnostic process for dementia is inherently complex because there's no single definitive test. Unlike diagnosing diabetes (where a blood sugar test provides a clear answer) or a broken bone (where an X-ray shows the fracture), dementia diagnosis requires synthesizing information from multiple sources: clinical history, cognitive testing, brain imaging, laboratory tests, and functional assessments.

This chapter will walk you through each component of the diagnostic process, explaining what happens, why it matters, and what the results mean. By the end, you'll understand how physicians piece together diverse information to arrive at a diagnosis and distinguish dementia from other conditions.

The Foundation: Medical History and Clinical Evaluation¶

The diagnostic process begins not with sophisticated technology but with conversation. A thorough medical history and clinical evaluation provide the foundation upon which all other assessments build.

Medical History: Telling the Story¶

Medical history refers to the comprehensive gathering of information about a person's health background, current symptoms, and functional changes. This seemingly simple interview provides crucial diagnostic clues and often points toward the correct diagnosis before any tests are performed.

A complete medical history for dementia evaluation includes:

Current symptoms and their timeline - When did cognitive changes first become noticeable? - How have symptoms progressed over time (gradual vs. sudden)? - Which cognitive domains are affected (memory, language, reasoning, etc.)? - Are symptoms constant or fluctuating?

Functional impact - What activities has the person stopped doing or had difficulty with? - Have there been changes in work performance or ability to manage finances? - Is the person still driving safely? - Can they manage medications independently?

Past medical history - Previous strokes, heart attacks, or cardiovascular disease - History of head injuries or concussions - Diabetes, hypertension, high cholesterol - Depression or other psychiatric conditions - Thyroid disease, vitamin deficiencies - Previous surgeries and hospitalizations

Current medications - All prescription medications (many can affect cognition) - Over-the-counter medications - Supplements and herbal remedies - Recent medication changes

Family history - Dementia in parents, siblings, or grandparents - Age of onset in affected family members - Pattern of inheritance (if known) - Other neurological conditions in the family

Social history - Education level (affects cognitive test interpretation) - Occupation and work history - Alcohol and substance use - Living situation and support system - Hobbies and activities

Behavioral and mood changes - Personality changes - Mood disturbances (depression, anxiety, apathy) - Hallucinations or delusions - Sleep changes

The timeline and pattern of symptom development provide particularly important clues. Alzheimer's disease typically develops gradually over years, while vascular dementia may show stepwise progression (sudden worsening, plateau, then another sudden worsening). Lewy body dementia often presents with fluctuating cognition and early visual hallucinations. Frontotemporal dementia frequently begins with personality and behavioral changes rather than memory problems.

Collateral history from family members is essential. People with dementia often lack insight into their deficits (anosognosia), underestimating problems that are obvious to family. A spouse's report that "he gets lost going to the grocery store he's shopped at for 30 years" provides more valuable information than the patient's report that "my memory is fine."

Neurological Examination: Assessing Brain Function¶

The neurological examination is a systematic evaluation of the nervous system's structure and function. While neurological exams are often associated with dramatic demonstrations (testing reflexes with a rubber hammer, checking pupils with a bright light), the exam for dementia evaluation focuses on detecting signs that suggest specific brain regions are affected or that point toward particular types of dementia.

A neurological examination for dementia typically includes:

Mental status assessment - Level of alertness and attention - Orientation to time, place, and person - Ability to follow commands and instructions - Language function (naming objects, repeating phrases, comprehension) - Brief memory testing

Cranial nerve examination - Vision and visual fields (parietal lobe function, vitamin deficiencies) - Pupil responses (certain medications, neurological conditions) - Facial movement and sensation - Hearing - Swallowing and tongue movement

Motor examination - Muscle strength in arms and legs (stroke, weakness from other causes) - Muscle tone (rigidity in Parkinson's or Lewy body dementia) - Tremors or involuntary movements - Coordination and rapid alternating movements

Sensory examination - Touch, pain, and temperature sensation - Position sense (knowing where limbs are in space) - Patterns of sensory loss (peripheral neuropathy, stroke)

Reflexes - Deep tendon reflexes (knee jerk, ankle jerk, etc.) - Plantar response (Babinski sign indicating upper motor neuron damage) - Frontal release signs (primitive reflexes that reemerge in dementia)

Gait and balance - Walking pattern (shuffling gait in Parkinson's-related dementias) - Balance and coordination - Ability to turn smoothly - Risk of falls

Parkinsonian signs - Rigidity, bradykinesia (slow movement), tremor - Especially important for identifying Lewy body dementia and Parkinson's disease dementia

The neurological exam helps differentiate types of dementia and identify comorbid conditions. For example, focal neurological signs (weakness on one side, visual field deficits) suggest vascular dementia from strokes. Parkinsonian features early in the course suggest Lewy body dementia or Parkinson's disease dementia. An unsteady, magnetic gait (feet seeming to stick to the floor) may indicate normal pressure hydrocephalus, a potentially treatable cause of cognitive impairment.

Cognitive Assessments: Measuring Mental Function¶

While medical history and neurological exam provide qualitative impressions, cognitive assessments provide standardized, quantitative measurements of mental function. These tests systematically evaluate different cognitive domains—memory, attention, language, visuospatial abilities, executive function—allowing doctors to identify specific patterns of impairment and track changes over time.

Dementia Screening: The First Step¶

Dementia screening refers to brief cognitive tests administered to determine whether more comprehensive evaluation is warranted. Screening tests are designed to be quick (5-15 minutes), easy to administer (even by non-specialists), and sensitive enough to detect cognitive impairment that might otherwise be missed.

Common dementia screening tools include:

Mini-Cog (3-5 minutes) - Three-word recall plus clock drawing - Quick, culture-neutral, no education adjustment needed - Often used in primary care settings

Six-Item Screener (2-3 minutes) - Three-word recall and temporal orientation questions - Very brief for busy primary care practices

General Practitioner Assessment of Cognition (GPCOG) (4-5 minutes) - Patient cognitive tasks plus informant questionnaire - Incorporates family input systematically

Memory Impairment Screen (MIS) (4 minutes) - Controlled learning (provides category cues) followed by delayed recall - Sensitive to early memory problems

Screening tests serve as gatekeepers—negative results may reassure patients and doctors that comprehensive evaluation isn't immediately necessary, while positive results indicate the need for thorough assessment. However, screening tests have limitations: they can miss early or subtle impairment, and they don't provide specific diagnostic information about the type of dementia.

When screening suggests cognitive impairment, more detailed cognitive assessments are performed.

Mini-Mental State Exam (MMSE): The Traditional Standard¶

The Mini-Mental State Exam (MMSE) is perhaps the most widely known cognitive assessment tool, used extensively since its development in 1975. The MMSE is a 30-point questionnaire taking 5-10 minutes to administer that provides a quick snapshot of global cognitive function.

The MMSE evaluates:

Orientation (10 points) - What is the year, season, date, day, and month? (5 points) - Where are we: state, county, town, building, floor? (5 points)

Registration (3 points) - Repeat three unrelated words (e.g., apple, table, penny)

Attention and calculation (5 points) - Serial sevens: Count backward from 100 by sevens (93, 86, 79, 72, 65) - Alternative: Spell "WORLD" backward

Recall (3 points) - Remember the three words from earlier (apple, table, penny)

Language (8 points) - Name two objects shown (e.g., watch, pencil) (2 points) - Repeat a phrase: "No ifs, ands, or buts" (1 point) - Follow a three-stage command: "Take this paper, fold it in half, place it on the floor" (3 points) - Read and obey: "Close your eyes" (1 point) - Write a complete sentence (1 point)

Visuospatial (1 point) - Copy a design of two intersecting pentagons

MMSE Score interpretation: - 24-30: Normal cognition (though early dementia can exist with scores in this range) - 20-23: Mild cognitive impairment or early dementia - 10-19: Moderate dementia - 0-9: Severe dementia

Important caveats about the MMSE:

Education effects - People with less formal education may score lower even without dementia, while highly educated individuals may score normally despite early impairment

Language and cultural bias - The test requires English language proficiency and cultural familiarity with certain concepts

Ceiling effects - The MMSE isn't sensitive to early or subtle changes in high-functioning individuals

Copyright restrictions - The MMSE is now copyrighted, requiring fees for use in many settings, which has led to increased use of alternatives

What the MMSE doesn't assess well: - Executive function (planning, problem-solving) - Judgment and insight - Visuospatial abilities (one simple copying task isn't comprehensive) - Semantic memory and knowledge

Despite limitations, the MMSE remains valuable for tracking progression over time. A person scoring 28 initially but scoring 22 six months later shows significant decline, regardless of whether both scores fall in "normal" or "abnormal" ranges.

Montreal Cognitive Assessment (MoCA): Enhanced Sensitivity¶

The Montreal Cognitive Assessment (MoCA) was developed in 1996 to address some of the MMSE's limitations, particularly its insensitivity to mild cognitive impairment and subtle executive function deficits. The MoCA is also scored out of 30 points but includes more challenging tasks and better evaluates executive function, visuospatial abilities, and attention.

The MoCA evaluates:

Visuospatial/Executive (5 points) - Trail Making Test (connect alternating numbers and letters: 1-A-2-B-3-C...) - Copy a three-dimensional cube - Draw a clock showing specific time (11:10)

Naming (3 points) - Name three animals (lion, rhinoceros, camel—more difficult than common objects)

Attention (6 points) - Digit span forward and backward - Tap when hearing the letter "A" in a sequence - Serial sevens (count backward from 100 by sevens)

Language (3 points) - Repeat two complex sentences - Verbal fluency (name as many words starting with "F" in one minute)

Abstraction (2 points) - Explain how two things are similar (e.g., train-bicycle, watch-ruler)

Delayed recall (5 points) - Remember five words presented earlier (face, velvet, church, daisy, red)

Orientation (6 points) - Date, month, year, day, place, city

Score adjustment: Add one point if the person has 12 or fewer years of formal education.

MoCA Score interpretation: - 26-30: Normal cognition - 18-25: Mild cognitive impairment - 10-17: Moderate cognitive impairment - <10: Severe cognitive impairment

Advantages of the MoCA over the MMSE:

More sensitive to mild cognitive impairment and early dementia
Better assessment of executive function (planning, problem-solving, mental flexibility)
More challenging visuospatial tasks
Publicly available without copyright restrictions
Available in multiple languages with cultural adaptations

The MoCA's enhanced difficulty means that even highly educated individuals with subtle deficits may show impairment, making it particularly useful for detecting early changes.

Clock Drawing Test: Simple but Informative¶

The Clock Drawing Test is a quick screening tool that assesses multiple cognitive domains simultaneously through a single simple task: drawing a clock showing a specific time (usually 11:10 or 3:00).

Administration is straightforward: 1. Give the person a blank piece of paper 2. Ask them to "Draw a clock, put in all the numbers, and set the time to 11:10" (or another specified time) 3. Allow them to complete the task without assistance

This seemingly simple task requires:

Executive function - Planning how to approach the task, organizing elements
Visuospatial abilities - Spatial layout, recognizing circular shape
Numerical knowledge - Remembering numbers 1-12 and their sequence
Abstract thinking - Understanding what "11:10" means and representing it with hands
Motor control - Physically drawing the clock

Scoring varies depending on which of several systems is used, but generally assesses: - Overall circular shape - Presence of all numbers 1-12 - Numbers in correct sequence and proper positions - Hour and minute hands present - Hands pointing to correct time

Common errors in dementia: - Missing numbers or wrong sequence - Numbers outside the circle or clustered in one area - Drawing hands incorrectly (both pointing to same number, no distinction between hour and minute hands) - Concrete interpretation (writing "11:10" instead of using hands) - Perseveration (repeating numbers or elements) - Complete inability to attempt the task

The clock drawing test is particularly sensitive to executive dysfunction and visuospatial impairment, making it useful for detecting non-Alzheimer's dementias like frontotemporal dementia or Lewy body dementia, which may present with prominent executive or visuospatial deficits before significant memory loss.

Example patterns: - Alzheimer's disease - May do reasonably well early on, then show progressive difficulty with spatial layout - Frontotemporal dementia - Often shows poor planning and organization despite preserved memory - Lewy body dementia - Significant visuospatial distortion even when memory is relatively preserved - Vascular dementia - Variable performance depending on which brain regions are affected by strokes

The clock drawing test's simplicity is its strength—it requires no special equipment, takes only 2-3 minutes, can be administered by any trained person, and isn't affected by language barriers as much as verbal tests.

Comprehensive Neuropsychological Testing¶

When screening tests and brief cognitive assessments suggest impairment, comprehensive neuropsychological testing may be recommended. This detailed evaluation, typically performed by a neuropsychologist, takes 2-4 hours and systematically assesses all major cognitive domains using validated, standardized tests.

Comprehensive testing evaluates:

Memory - Verbal and visual memory, immediate and delayed recall, recognition vs. recall
Attention and concentration - Sustained attention, divided attention, processing speed
Executive function - Planning, problem-solving, mental flexibility, inhibition, working memory
Language - Naming, comprehension, fluency, repetition, reading, writing
Visuospatial abilities - Spatial perception, construction, visual organization
Motor function - Speed, coordination, strength

This detailed assessment provides several benefits:

Early detection - Identifies subtle deficits not apparent on brief tests
Specific patterns - Cognitive "fingerprints" help distinguish between types of dementia
Baseline establishment - Provides detailed baseline for tracking future changes
Differential diagnosis - Helps distinguish dementia from depression, anxiety, or other conditions
Treatment planning - Identifies specific strengths and weaknesses to guide interventions

While comprehensive testing requires significant time and expense, it provides the most detailed picture of cognitive functioning available through non-invasive means.

Brain Imaging: Visualizing Brain Structure and Function¶

Brain imaging allows physicians to visualize the brain's structure and function, identifying patterns of atrophy, detecting strokes or tumors, and observing metabolic activity. Different imaging techniques provide complementary information, and the choice of which scans to perform depends on the clinical situation.

Structural Imaging: MRI and CT Scans¶

Structural imaging techniques create detailed pictures of brain anatomy, showing the size and shape of brain structures and identifying abnormalities like strokes, tumors, or bleeding.

MRI Scan: Detailed Structural Imaging¶

MRI (Magnetic Resonance Imaging) uses powerful magnetic fields and radio waves to create highly detailed images of the brain's structure. MRI is the preferred structural imaging technique for dementia evaluation because it provides superior detail compared to CT scans and doesn't involve radiation exposure.

How MRI works: - Strong magnetic fields temporarily align hydrogen atoms in the body - Radio waves cause these atoms to produce signals - Different tissues produce different signal patterns - Computers process these signals to create detailed cross-sectional images

What MRI shows in dementia evaluation:

Atrophy patterns - Hippocampal atrophy (shrinkage of memory structures) - characteristic of Alzheimer's disease - Temporal lobe atrophy - Alzheimer's disease - Frontal and temporal atrophy - frontotemporal dementia - Global atrophy (whole brain shrinkage) - advanced dementia of any type

Vascular changes - Small vessel disease (white matter hyperintensities) - Previous strokes (visible as areas of dead tissue) - Microbleeds (tiny areas of bleeding) - Patterns suggesting vascular dementia

Other structural abnormalities - Brain tumors (may mimic dementia symptoms) - Normal pressure hydrocephalus (enlarged ventricles with preserved brain tissue) - Subdural hematomas (blood collections from head injury) - Infections or inflammatory conditions

Types of MRI sequences provide different information: - T1-weighted images - Show brain anatomy clearly, good for measuring atrophy - T2-weighted images - Show fluid and pathology clearly - FLAIR (Fluid-Attenuated Inversion Recovery) - Highlights white matter disease - Diffusion-weighted imaging - Detects recent strokes - Susceptibility-weighted imaging - Detects microbleeds

Advantages of MRI: - No radiation exposure - Excellent soft tissue detail - Can detect subtle changes - Multiple imaging sequences provide complementary information

Limitations of MRI: - Expensive (\(1,000-\)3,000+) - Takes 30-60 minutes (patient must lie still) - Not suitable for people with certain metal implants (pacemakers, some aneurysm clips) - Claustrophobic (enclosed tube scanner) - Noisy (loud banging sounds) - Some patients require sedation

CT Scan: Quick Structural Imaging¶

CT (Computed Tomography) uses X-rays to create cross-sectional images of the brain. CT scans are faster and more widely available than MRI, making them useful when quick imaging is needed, though they provide less detail than MRI for brain tissue.

How CT works: - X-ray beam rotates around the head - Detectors measure how much radiation passes through different tissues - Computer processes measurements to create cross-sectional images

What CT shows in dementia evaluation:

CT scans can identify: - Significant atrophy (though less sensitive than MRI for early or subtle atrophy) - Large strokes - Brain tumors - Bleeding (hemorrhage or subdural hematoma) - Hydrocephalus (enlarged ventricles) - Skull fractures from head injury

When CT is preferred over MRI: - Emergency situations (faster, more available) - Acute bleeding suspected (CT shows blood very clearly) - Patient has metal implants incompatible with MRI - Patient cannot tolerate the long, enclosed MRI scan - MRI not available - Cost is prohibitive

Limitations of CT: - Radiation exposure - Less detailed than MRI for brain tissue - Poor visualization of posterior fossa (cerebellum, brainstem) - May miss small strokes or early atrophy - Cannot perform multiple tissue contrast sequences like MRI

In dementia evaluation, MRI is generally preferred when available and tolerated, as it provides superior information about brain structure and detects subtle changes that CT may miss.

Functional Imaging: PET and SPECT Scans¶

While structural imaging (MRI, CT) shows brain anatomy, functional imaging shows brain activity and metabolism, providing complementary diagnostic information.

PET Scan: Metabolic and Molecular Imaging¶

PET (Positron Emission Tomography) measures metabolic activity and can visualize specific molecular processes in the brain. Different radioactive tracers allow PET to measure different aspects of brain function.

How PET works: - Radioactive tracer is injected into the bloodstream - The tracer accumulates in active brain tissue - Radioactive decay emits positrons that produce gamma rays - Detectors measure gamma rays and computers create images showing tracer distribution

Types of PET scans in dementia:

FDG-PET (Fluorodeoxyglucose PET) - Measures glucose metabolism (energy use) in the brain - Active brain regions use more glucose; damaged regions use less - Shows characteristic patterns for different dementia types: - Alzheimer's disease: Reduced metabolism in temporal and parietal regions - Frontotemporal dementia: Reduced metabolism in frontal and/or temporal lobes - Lewy body dementia: Reduced metabolism in occipital regions (visual processing) - Helps distinguish between dementia types when diagnosis is uncertain

Amyloid PET - Uses tracers that bind to amyloid plaques (hallmark of Alzheimer's disease) - Shows whether significant amyloid buildup is present - Positive scan supports Alzheimer's diagnosis - Negative scan argues against Alzheimer's (though doesn't rule it out completely) - Common tracers: Florbetapir, Flutemetamol, Florbetaben

Tau PET - Uses tracers that bind to tau tangles (another Alzheimer's hallmark) - Still primarily research tool, not yet routine clinical use - Shows distribution and severity of tau pathology - May predict symptom progression

Advantages of PET: - Shows brain function, not just structure - Can detect changes before structural atrophy is visible - Amyloid PET definitively shows amyloid presence - Helps distinguish between dementia types

Limitations of PET: - Very expensive (\(3,000-\)6,000+) - Radiation exposure - Limited availability (requires cyclotron for some tracers) - Insurance coverage varies (FDG-PET often covered, amyloid PET less consistently) - Doesn't change management in many cases - Positive amyloid scan doesn't guarantee symptoms are from Alzheimer's (some cognitively normal people have amyloid)

SPECT Scan: Blood Flow Imaging¶

SPECT (Single-Photon Emission Computed Tomography) measures blood flow in the brain. Because active brain regions receive more blood flow, SPECT indirectly shows which areas are functioning normally and which are impaired.

How SPECT works: - Radioactive tracer injected into bloodstream - Tracer distributes according to blood flow - Gamma camera rotates around head, detecting radiation - Computer creates 3D images showing tracer distribution

What SPECT shows in dementia: - Alzheimer's disease: Reduced blood flow in temporal and parietal regions - Frontotemporal dementia: Reduced blood flow in frontal and/or temporal lobes - Lewy body dementia: Reduced blood flow in occipital regions - Vascular dementia: Patchy areas of reduced blood flow corresponding to stroke locations

SPECT compared to PET: - Less expensive than PET - More widely available (doesn't require cyclotron) - Lower resolution images than PET - Less specific tracer options than PET - Used less frequently as PET becomes more available

Clinical use of SPECT: - Distinguishing between types of dementia when clinical picture is unclear - Supporting diagnosis of Lewy body dementia (dopamine transporter SPECT) - Evaluating blood flow in specific clinical scenarios

In practice, FDG-PET has largely replaced SPECT for dementia evaluation in centers where PET is available, as it provides better image quality and more specific information.

Laboratory Tests: Ruling Out Treatable Causes¶

Blood tests are essential components of dementia evaluation, not because they diagnose dementia (they don't), but because they identify treatable medical conditions that can cause or worsen cognitive impairment. Many of these conditions mimic dementia but improve or resolve with treatment.

Standard Blood Tests in Dementia Workup¶

Complete blood count (CBC) - Detects anemia (low red blood cells reducing oxygen to brain) - Identifies infections that may cause confusion - Screens for blood disorders

Comprehensive metabolic panel (CMP) - Kidney function (kidney failure causes confusion) - Liver function (liver failure causes encephalopathy) - Electrolyte imbalances (sodium, calcium abnormalities affect cognition) - Glucose levels (high or low blood sugar impairs cognition)

Thyroid function tests (TSH, T4) - Hypothyroidism (underactive thyroid) causes cognitive slowing, depression, memory problems - Hyperthyroidism (overactive thyroid) causes anxiety, confusion - Thyroid disorders are common and highly treatable

Vitamin B12 level - B12 deficiency causes cognitive impairment, neurological problems - Common in elderly, especially with poor nutrition or stomach issues - Treatable with B12 supplementation

Vitamin D level - Deficiency associated with cognitive decline - Very common in elderly - Easily treated with supplementation

Folate level - Deficiency can impair cognition - Often checked alongside B12

Lipid panel (cholesterol) - High cholesterol is vascular risk factor - Informs cardiovascular disease management

HIV test - HIV can cause dementia (HIV-associated neurocognitive disorder) - Important to screen, especially in at-risk populations - Treatable with antiretroviral therapy

Syphilis test (RPR or VDRL) - Neurosyphilis can cause dementia - Rare but treatable - Part of standard dementia workup

Heavy metal screening (if indicated) - Lead, mercury, arsenic can cause cognitive impairment - Tested if exposure history suggests risk

When Blood Tests Change Diagnosis and Treatment¶

Blood tests identify reversible causes of cognitive impairment:

Example 1: A 72-year-old woman with progressive memory loss and fatigue. TSH (thyroid test) reveals severe hypothyroidism. After thyroid hormone replacement, her energy improves and cognitive function largely normalizes. What appeared to be dementia was actually thyroid disease.

Example 2: An 80-year-old man with confusion and difficulty concentrating. B12 level is severely low (120 pg/mL, normal >200). After B12 injections, his cognition significantly improves, though some deficits persist (suggesting both B12 deficiency and underlying dementia).

Example 3: A 68-year-old with cognitive decline. Comprehensive metabolic panel shows severe kidney failure causing uremia (waste buildup in blood). Treatment of kidney disease improves but doesn't completely resolve cognitive symptoms, revealing underlying vascular dementia.

These examples illustrate why blood tests are mandatory: treatable conditions must be identified and addressed before attributing cognitive impairment solely to irreversible dementia.

Advanced Diagnostic Tests: Biomarkers and Genetic Testing¶

Beyond routine blood tests, specialized tests can provide additional diagnostic information, particularly when diagnosis is uncertain or when genetic factors are suspected.

Biomarkers: Molecular Indicators of Disease¶

Biomarkers are measurable biological indicators of disease processes. In dementia, biomarkers can detect Alzheimer's pathology (amyloid and tau) even before symptoms develop or become severe.

Cerebrospinal Fluid Analysis¶

Cerebrospinal fluid (CSF) analysis involves collecting fluid that surrounds the brain and spinal cord through a lumbar puncture (spinal tap) and measuring specific proteins that indicate Alzheimer's pathology.

The lumbar puncture procedure: - Patient lies on side, back curved forward - Local anesthetic numbs the lower back - Needle inserted between lumbar vertebrae into spinal fluid space - Small amount of fluid collected (about 2 tablespoons) - Takes 15-30 minutes - Headache is most common side effect (10-30% of patients)

CSF biomarkers for Alzheimer's disease:

Amyloid-beta 42 (Aβ42) - Decreased in Alzheimer's disease - Amyloid depositing in plaques reduces the amount in CSF - Low Aβ42 indicates amyloid pathology

Total tau protein - Increased in Alzheimer's disease - Tau released from degenerating neurons - High tau indicates neuronal damage

Phosphorylated tau (p-tau) - Increased in Alzheimer's disease - More specific than total tau - High p-tau indicates tau tangle formation

The "Alzheimer's signature" in CSF: - Low Aβ42 - High total tau - High p-tau - This pattern strongly supports Alzheimer's diagnosis

Accuracy of CSF biomarkers: - 80-90% accuracy for detecting Alzheimer's pathology - Can detect changes years before symptoms - Helps distinguish Alzheimer's from other dementias

When CSF analysis is useful: - Atypical presentation (unusual age, symptoms, or progression) - Diagnostic uncertainty after standard evaluation - Distinguishing Alzheimer's from other dementias - Clinical trials requiring biomarker confirmation - Early-onset dementia evaluation

Limitations: - Requires lumbar puncture (invasive, some risk of headache) - Expensive (\(1,500-\)3,000) - Not widely available (requires specialized laboratory) - Insurance coverage variable - Presence of biomarkers doesn't always correlate with symptom severity

Genetic Testing¶

Genetic testing analyzes DNA to identify genetic variants that cause or increase dementia risk. Genetic testing in dementia serves different purposes depending on whether the person has symptoms or is at-risk family member.

Genetic Testing in Symptomatic Individuals¶

When someone already has dementia symptoms, genetic testing may identify:

Causative genes for early-onset Alzheimer's disease: - APP (Amyloid Precursor Protein) - PSEN1 (Presenilin 1) - PSEN2 (Presenilin 2) - Mutations in these genes cause autosomal dominant Alzheimer's (if you inherit the mutation, you will develop the disease) - Account for <1% of all Alzheimer's cases - Typically cause symptoms before age 65, often in 40s or 50s

Genes for other hereditary dementias: - Frontotemporal dementia genes (MAPT, GRN, C9orf72) - Huntington's disease gene (HTT) - CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) - Prion protein gene mutations (familial Creutzfeldt-Jakob disease)

When genetic testing is recommended: - Early-onset dementia (age <65) - Strong family history suggesting genetic cause - Atypical features suggesting specific genetic syndrome - Multiple family members with early-onset dementia - Patient requests testing for family planning

Genetic Testing in Asymptomatic Individuals¶

Testing asymptomatic at-risk individuals raises ethical complexities:

APOE (Apolipoprotein E) gene: - APOE ε4 variant increases Alzheimer's risk - Everyone has two APOE alleles (ε2, ε3, or ε4) - ε4/ε4 (two copies): ~15x increased risk; 50-60% lifetime risk of Alzheimer's - ε3/ε4 (one copy): ~3x increased risk; 20-25% lifetime risk - ε3/ε3 (no copies): Average risk; ~10-15% lifetime risk - ε2 allele: Protective, reduces risk

Important caveats about APOE testing: - APOE ε4 increases risk but doesn't guarantee Alzheimer's (many ε4 carriers never develop dementia) - Many people without ε4 develop Alzheimer's - No specific interventions prevent Alzheimer's in ε4 carriers - Testing can cause psychological distress without providing actionable information - Insurance discrimination concerns (genetic information may affect long-term care insurance)

Most genetic counselors and physicians do not recommend APOE testing in asymptomatic individuals because: - Risk information without prevention options may cause harm - Uncertainty (risk probabilities, not certainties) difficult to interpret - Psychological impact of knowing elevated risk - Limited clinical utility currently

Exceptions where APOE testing might be considered: - Research study participation (many trials stratify by APOE status) - Individual strongly desires information after genetic counseling - Family planning considerations

Genetic counseling is essential before any dementia-related genetic testing, to ensure individuals understand: - What the test can and cannot tell them - Psychological and practical implications of results - Insurance and discrimination considerations - Options available regardless of results

Differential Diagnosis: Distinguishing Dementia from Other Conditions¶

Differential diagnosis is the process of distinguishing dementia from other conditions that can cause cognitive impairment. Several conditions mimic dementia symptoms but have different causes, treatments, and prognoses. Accurate differential diagnosis is crucial because misdiagnosing a treatable condition as irreversible dementia deprives patients of effective treatment.

The Three D's: Dementia, Delirium, and Depression¶

Three conditions beginning with "D" commonly cause cognitive impairment and must be carefully distinguished:

Delirium: Acute Confusion¶

Delirium is an acute, fluctuating state of confusion caused by medical illness, medications, or other physiological disturbances. Delirium is a medical emergency requiring prompt identification and treatment of underlying causes.

Key features distinguishing delirium from dementia:

Feature	Delirium	Dementia
Onset	Sudden (hours to days)	Gradual (months to years)
Course	Fluctuating (worse at night)	Stable, slowly progressive
Duration	Days to weeks (resolves when cause treated)	Months to years (progressive)
Attention	Severely impaired (hallmark feature)	Relatively preserved until late stages
Consciousness	Altered (drowsy, stuporous, or hyperalert)	Normal until very late stages
Reversibility	Usually reversible when cause treated	Irreversible (though symptoms may be managed)
Hallucinations	Common, especially visual	Less common (except Lewy body dementia)

Common causes of delirium: - Infections (urinary tract infections, pneumonia, sepsis) - Medications (anticholinergics, benzodiazepines, opioids, many others) - Metabolic disturbances (electrolyte imbalances, kidney failure, liver failure) - Dehydration - Pain - Constipation or urinary retention - Hypoxia (low oxygen) - Substance intoxication or withdrawal (alcohol, drugs) - Surgery and anesthesia (postoperative delirium) - Hospitalization (ICU delirium, hospital delirium)

Why distinguishing delirium matters: - Delirium is often reversible if cause is identified and treated - Delirium in a person with dementia (delirium superimposed on dementia) requires treating the delirium - Mistaking delirium for dementia delays treatment of potentially life-threatening conditions - Delirium increases mortality risk and can accelerate dementia progression

Key clinical point: Sudden cognitive changes (developing over hours to days) suggest delirium, not dementia, and require urgent medical evaluation.

Depression: Pseudodementia¶

Depression can cause cognitive impairment that mimics dementia, sometimes called "pseudodementia" or "depression of cognitive impairment." Older adults with severe depression may exhibit memory problems, slowed thinking, poor concentration, and apathy that resemble dementia.

Key features distinguishing depression from dementia:

Feature	Depression	Dementia
Onset	Can be relatively sudden or insidious	Gradual
Cognitive pattern	Inconsistent performance; better with encouragement	Consistently poor performance
Effort	Often says "I don't know" without trying	Tries hard but fails
Awareness	Aware of and concerned about deficits	Often minimizes or unaware of deficits (anosognosia)
Mood	Prominent sadness, hopelessness, anhedonia	Mood changes less prominent (early stages)
Motivation	Low motivation, apathy	May try to engage despite difficulties
Diurnal variation	Often worse in morning, improves during day	Relatively stable across day (except sundowning)
Response to treatment	Cognitive improvement with antidepressant treatment	No cognitive improvement with antidepressants

The complicated relationship between depression and dementia:

Depression can cause cognitive impairment (pseudodementia) that improves with antidepressant treatment
Depression can be an early symptom of dementia (especially frontotemporal dementia or vascular dementia)
Depression commonly coexists with dementia (30-50% of people with dementia have depression)
History of depression increases dementia risk (depression may damage hippocampus over time)

These overlapping relationships make diagnosis challenging. Often, a trial of antidepressant treatment helps clarify: if cognitive symptoms substantially improve, depression was primary; if mood improves but cognition doesn't, dementia with comorbid depression is likely.

Why distinguishing depression matters: - Depression is highly treatable with medication, therapy, or both - Treating depression can restore cognitive function if depression is the primary cause - Even if dementia is present, treating comorbid depression improves quality of life

Other Conditions Mimicking Dementia¶

Mild Cognitive Impairment (MCI) - Cognitive decline beyond normal aging but not severe enough to interfere with daily function - Some cases progress to dementia; others remain stable - Not dementia (by definition, daily function is preserved)

Normal aging - Slower processing speed - Occasional forgetfulness (where did I put my keys?) - Word-finding difficulties - But daily function preserved, no progressive decline

Medication side effects - Anticholinergic medications (many common drugs) - Benzodiazepines (Valium, Ativan, etc.) - Opioid pain medications - Antihistamines (Benadryl) - Many others

Sleep disorders - Severe sleep apnea - Chronic insomnia - Restless leg syndrome

Vitamin deficiencies - B12, folate, thiamine deficiencies

Metabolic and endocrine disorders - Thyroid disease - Diabetes with frequent hypoglycemia - Kidney or liver disease

Normal pressure hydrocephalus - Classic triad: cognitive impairment, gait disturbance, urinary incontinence - Potentially treatable with shunt placement

Brain tumors - Especially slow-growing tumors or those in frontal regions

Thorough evaluation distinguishes between these possibilities and dementia.

Functional Assessment: How Dementia Affects Daily Life¶

While cognitive tests measure mental abilities, functional assessments evaluate how cognitive impairment affects real-world functioning—the ability to perform daily activities that are necessary for independent living.

Activities of Daily Living (ADLs)¶

Basic ADLs are fundamental self-care activities: - Bathing and showering - Dressing - Eating (getting food to mouth) - Toileting - Continence - Transferring (moving from bed to chair, standing)

Instrumental ADLs (IADLs) are more complex activities needed for independent living: - Managing finances (paying bills, balancing checkbook) - Managing medications (taking correct doses at correct times) - Shopping and meal preparation - Housework and laundry - Using telephone - Transportation (driving or using public transit) - Managing appointments and schedule

Stages of Functional Decline¶

Functional abilities decline in predictable patterns:

Early stage - IADLs affected first (finances, medications, complex cooking) - Basic ADLs preserved - Person may hide difficulties or family compensates without realizing

Middle stage - Increasing IADL impairment - Basic ADLs begin to be affected (needs reminders or assistance) - Safety concerns emerge (driving, wandering, medication errors)

Late stage - Severe IADL impairment (cannot perform any independently) - Basic ADL impairment (needs assistance with dressing, bathing, toileting) - Eventually needs total care

Measuring Functional Abilities¶

Standardized tools assess functional abilities:

Functional Activities Questionnaire (FAQ) - 10 questions about IADLs - Informant-based (family member answers) - Scores 0-30 (higher = more impairment) - Score ≥9 suggests dementia-level impairment

Lawton IADL Scale - Assesses 8 IADL domains - Widely used in research and clinical practice

Barthel Index / Katz ADL Index - Assesses basic ADLs - Used more in later dementia stages

Why functional assessment matters: - Diagnosis - Dementia requires functional impairment; cognitive deficits alone don't constitute dementia - Staging - Functional abilities define mild, moderate, severe stages - Safety - Identifies safety risks (driving, medication management, cooking) - Care planning - Determines what assistance is needed - Legal decisions - Functional capacity affects competency determinations - Tracking progression - Changes in function show disease progression

Putting It All Together: The Diagnostic Process¶

Dementia diagnosis involves synthesizing multiple sources of information:

Medical history - Timeline, symptoms, functional changes, risk factors
Neurological examination - Focal signs, Parkinsonism, gait
Cognitive assessment - MMSE, MoCA, clock drawing, neuropsychological testing
Brain imaging - MRI showing atrophy patterns, vascular changes
Laboratory tests - Rule out treatable causes (thyroid, B12, etc.)
Functional assessment - Impact on daily activities
Informant report - Family observations of changes

Physicians integrate this information to: - Confirm cognitive impairment is present (not just subjective concern) - Determine whether impairment affects daily function (dementia vs. MCI) - Identify the type of dementia (Alzheimer's, vascular, Lewy body, etc.) - Rule out treatable causes (thyroid, B12, depression, etc.) - Assess severity (mild, moderate, severe) - Develop treatment and care plan

Diagnostic Criteria for Dementia¶

Modern diagnostic criteria (DSM-5, NIA-AA) require:

Evidence of cognitive decline from previous level in one or more domains
Impairment in daily function due to cognitive deficits
Not explained by delirium or other mental disorder

Additional biomarker evidence (CSF, amyloid PET) increases diagnostic certainty but isn't required for clinical diagnosis.

Communicating the Diagnosis¶

Delivering a dementia diagnosis requires sensitivity and thoroughness:

Use clear, direct language ("Alzheimer's disease," not vague euphemisms)
Explain what the diagnosis means for prognosis and treatment
Provide both the person with dementia and family information
Address questions and emotions
Offer resources and support
Develop care plan addressing medical, legal, safety, and support needs
Schedule follow-up to monitor progression and adjust management

Conclusion: The Value of Accurate Diagnosis¶

Comprehensive dementia evaluation serves multiple essential purposes:

Identifies treatable causes - Thyroid disease, B12 deficiency, depression, normal pressure hydrocephalus, and other reversible conditions can masquerade as dementia. Blood tests and thorough evaluation prevent missing opportunities for treatment.

Establishes accurate diagnosis - Different dementias have different prognoses, treatments, and needs. Distinguishing Alzheimer's from Lewy body dementia, frontotemporal dementia, or vascular dementia allows tailored management.

Provides baseline for tracking - Initial cognitive testing and imaging establish baselines for monitoring progression, evaluating treatment effects, and making care decisions.

Enables planning - Early diagnosis provides time for legal planning (power of attorney, advance directives), financial planning, and care arrangements before capacity is lost.

Guides treatment - Accurate diagnosis determines which medications may help, which clinical trials might be appropriate, and which non-pharmacological interventions to prioritize.

Reduces uncertainty - Families living with unexplained cognitive changes experience tremendous anxiety. Even when the diagnosis is dementia, having a name for what's happening and a path forward reduces some of that distress.

The diagnostic process may seem lengthy and complex, involving multiple appointments, various tests, and patience. However, this thoroughness ensures accurate diagnosis, avoids missing treatable conditions, and provides the foundation for appropriate care. Understanding what to expect during evaluation helps families navigate the process and actively participate in care decisions.

Key Takeaways¶

Dementia diagnosis requires synthesizing medical history, neurological exam, cognitive testing, brain imaging, laboratory tests, and functional assessment—no single test diagnoses dementia
Medical history and informant reports are critical, as people with dementia often lack insight into their deficits
Cognitive assessment tools (MMSE, MoCA, clock drawing) provide standardized measurement but have limitations and must be interpreted in context
MRI is the preferred structural brain imaging technique, showing atrophy patterns and ruling out strokes, tumors, and other structural abnormalities
PET scans measure brain metabolism and can detect amyloid plaques, helping distinguish between dementia types
Blood tests don't diagnose dementia but identify treatable conditions (thyroid disease, B12 deficiency) that must be ruled out
Biomarkers (CSF analysis, amyloid PET) can detect Alzheimer's pathology with high accuracy but are expensive and not always covered by insurance
Genetic testing identifies causative mutations in early-onset dementia but APOE testing in asymptomatic individuals is generally not recommended
Differential diagnosis distinguishes dementia from delirium (acute, fluctuating confusion) and depression (potentially reversible cognitive impairment)
Functional assessment evaluates impact on daily activities and is required for dementia diagnosis—cognitive impairment alone isn't sufficient
Comprehensive evaluation enables accurate diagnosis, identifies treatable conditions, establishes progression baseline, and guides treatment planning

Review Questions¶

Why is collateral history from family members essential in dementia evaluation, and what might patients themselves underreport?
Compare and contrast the MMSE and MoCA. What are the advantages of the MoCA over the MMSE?
Why is the clock drawing test useful despite its simplicity? What cognitive domains does it assess?
What are the main advantages of MRI over CT scan for dementia evaluation? When might CT be preferred?
Explain how FDG-PET and amyloid PET provide different types of information in dementia diagnosis.
Why are blood tests essential in dementia workup if they can't diagnose dementia? Give three examples of treatable conditions they can identify.
What is the "Alzheimer's signature" in cerebrospinal fluid analysis? What three biomarkers are measured?
Why do most experts not recommend APOE genetic testing in asymptomatic individuals, even if they have family history of Alzheimer's disease?
How do you distinguish delirium from dementia? Why is this distinction critical?
Explain why functional assessment is required for dementia diagnosis. Can someone have cognitive impairment on testing without having dementia?

Additional Resources¶

Alzheimer's Association: Diagnosis of Alzheimer's Disease and Dementia
National Institute on Aging: How Is Alzheimer's Disease Diagnosed?
American Academy of Neurology: Practice Guidelines for Dementia
Alzheimer's Association: Brain Tour - Interactive overview of brain changes in Alzheimer's

Next: Chapter 9: Medical Treatments and Medications explores pharmacological treatments for dementia, including cholinesterase inhibitors, memantine, and medications for managing behavioral symptoms.