# Neurocognitive Disorders: Differential Diagnosis and Workup

## Introduction

Neurocognitive disorders (NCDs) encompass a spectrum from **mild neurocognitive disorder** (formerly mild cognitive impairment) to **major neurocognitive disorder** (dementia). DSM-5 classifies these by etiology, including Alzheimer's disease, vascular disease, Lewy body disease, frontotemporal degeneration, and others. A systematic workup is essential to identify reversible causes, establish an etiological diagnosis, and guide management.

## DSM-5 Framework

### Mild Neurocognitive Disorder

Modest cognitive decline from a previous level of performance in one or more cognitive domains. Does **not** interfere with independence in everyday activities. Cognitive concerns reported by the individual, an informant, or clinician, supported by objective testing.

### Major Neurocognitive Disorder

Significant cognitive decline in one or more cognitive domains. **Interferes with independence** in everyday activities. Specify severity: mild, moderate, severe. Specify etiology and presence or absence of behavioral disturbance.

### Cognitive Domains

Complex attention. Executive function. Learning and memory. Language. Perceptual-motor function. Social cognition.

## Etiological Subtypes

| Subtype | Prevalence | Age of Onset | Early/Cardinal Features | Key Neuroimaging | Distinguishing Feature |
|---------|-----------|-------------|------------------------|-----------------|----------------------|
| Alzheimer's disease | 60-80% | >65 (typically) | Episodic memory loss | Hippocampal atrophy; amyloid/tau PET+ | Gradual onset; memory predominant |
| Vascular NCD | 15-20% | Variable | Executive dysfunction, processing speed | WMH, lacunar infarcts, strategic infarcts | Stepwise decline; CVD history |
| Lewy body disease | 5-15% | >60 | Fluctuating cognition, visual hallucinations, parkinsonism | May be normal; DaTscan positive | Neuroleptic sensitivity; RBD |
| Frontotemporal | 5-10% | 45-65 | Personality change, disinhibition OR language deficits | Frontal/temporal atrophy | Younger onset; memory preserved early |
| Parkinson's disease dementia | 3-5% | >65 | Subcortical pattern; >1 yr after motor onset | Cortical atrophy; DaTscan+ | Motor symptoms precede dementia |

### Alzheimer's Disease

**Most common cause** of dementia (60-80%) Insidious onset with progressive memory impairment as the hallmark. Early deficits in **episodic memory** (hippocampal involvement) Language, visuospatial, and executive deficits emerge later. Biomarkers: amyloid-beta reduction and tau elevation in CSF; amyloid and tau PET positivity.

### Vascular Neurocognitive Disorder

**Second most common cause**; often coexists with Alzheimer's disease (mixed dementia) Stepwise decline or temporal association with cerebrovascular events. Prominent **executive dysfunction** and processing speed impairment. MRI shows white matter hyperintensities, lacunar infarcts, or strategic infarcts.

### Lewy Body Disease

**Fluctuating cognition**, recurrent **visual hallucinations**, and **parkinsonism**. REM sleep behavior disorder often precedes cognitive decline. Severe **neuroleptic sensitivity** (contraindication to typical antipsychotics) DaTscan (dopamine transporter imaging) is a supportive diagnostic tool.

### Frontotemporal Degeneration

Younger onset (typically age 45-65) **Behavioral variant**: personality change, disinhibition, apathy, loss of empathy, compulsive behaviors. **Language variants**: progressive nonfluent aphasia and semantic dementia. Memory is relatively preserved early in the course.

### Other Etiologies

**Parkinson's disease dementia**: dementia developing at least 1 year after established motor parkinsonism. **Traumatic brain injury**: history of significant head trauma. **HIV-associated NCD**: subcortical pattern with psychomotor slowing. **Prion disease (CJD)**: rapid progression, myoclonus, characteristic MRI and EEG findings. **Normal pressure hydrocephalus**: triad of gait disturbance, urinary incontinence, dementia (potentially reversible) **Substance/medication-induced**: alcohol, anticholinergics, sedatives.

![Comparative features of major neurocognitive disorder subtypes](images/ncd-etiological-comparison.png)

## Diagnostic Workup

### Clinical Assessment

Detailed history from patient and **reliable informant** (essential) Assess functional status: ADLs and IADLs. Neurological examination: gait, motor signs, reflexes, cranial nerves. Cognitive screening: **MoCA** (more sensitive than MMSE for mild impairment)

### Laboratory Studies (Recommended Baseline)

Complete blood count. Comprehensive metabolic panel (including calcium, glucose, renal and hepatic function) Thyroid-stimulating hormone (TSH) Vitamin B12 and folate. Consider: RPR/VDRL, HIV, ESR, urinalysis. Consider ceruloplasmin (if age < 50), heavy metals, or autoimmune panels based on clinical suspicion.

### Neuroimaging

**MRI brain without contrast** is preferred: evaluates atrophy patterns, vascular changes, masses, hydrocephalus. CT head is acceptable if MRI is contraindicated. Functional imaging (FDG-PET, amyloid PET, tau PET, DaTscan) may be indicated when the clinical picture is ambiguous.

### Neuropsychological Testing

Formal testing clarifies the pattern and severity of cognitive deficits. Helps distinguish between NCD subtypes and between NCD and psychiatric conditions. Establishes baseline for longitudinal monitoring.

### Lumbar Puncture

Indicated when infection, inflammation, or prion disease is suspected. Alzheimer's biomarkers: low amyloid-beta-42, elevated total tau and phospho-tau.

![Systematic diagnostic workup algorithm for neurocognitive disorders](images/ncd-workup-algorithm.png)

## Reversible Causes to Exclude

A commonly used mnemonic is **DEMENTIA**:
**D**rugs (anticholinergics, benzodiazepines, opioids) **E**motional (depression/pseudodementia) **M**etabolic (thyroid, B12, hepatic or renal failure, electrolytes) **E**yes and ears (sensory deficits mimicking cognitive decline) **N**ormal pressure hydrocephalus. **T**umors and trauma. **I**nfections (HIV, syphilis, Whipple's, prion) **A**lcohol and autoimmune.

![Reversible causes of cognitive impairment using the DEMENTIA mnemonic](images/reversible-dementia-causes.png)

## Key Clinical Pearls

Collateral history from a reliable informant is indispensable; patients with early dementia often lack insight. Rapidly progressive dementia (weeks to months) is a medical emergency: consider CJD, autoimmune encephalitis, malignancy, or infection. Always screen for depression and delirium before diagnosing a neurocognitive disorder. The MoCA is superior to the MMSE for detecting mild cognitive impairment and frontal/executive deficits. Mixed pathology (e.g., Alzheimer's plus vascular disease) is the rule, not the exception, in elderly patients.

## References

1. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups. *Alzheimers Dement*. 2011;7(3):263-269.
2. McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report. *Neurology*. 2017;89(1):88-100.
3. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. *Brain*. 2011;134(Pt 9):2456-2477.
4. Petersen RC. Mild cognitive impairment as a diagnostic entity. *J Intern Med*. 2004;256(3):183-194.