Prepared by: Dr. James Rini, MD, MPH | Section Head, Ochsner Neurocognitive Program

This article provides a structured approach for evaluating patients with cognitive concerns. It emphasizes accurate diagnosis and appropriate referral pathways, covering comprehensive history-taking and advanced biomarker analysis to differentiate between neurodegenerative, reversible, and rapidly progressive conditions.

Step 1: Comprehensive Initial Assessment

Begin with a full clinical assessment for patients presenting with cognitive concerns:

• History:
  • Onset and Progression of Symptoms: Determine if cognitive decline is sudden, fluctuating, gradual, rapid (<1-2 years), or stepwise.
  • Functional Impact: Assess the patient's ability to perform activities of daily living (ADLs) and instrumental activities of daily living (IADLs). Early impairment in IADLs may indicate dementia onset.
  • Comorbidities: Identify vascular risk factors (e.g., hypertension, diabetes), psychiatric conditions (e.g., depression, anxiety), and other neurological disorders contributing to cognitive impairment.
  • Medications: Review current and recent medications for agents affecting cognition, such as anticholinergics, benzodiazepines, or opioids.
  • Family History: Inquire about a history of dementia or neurodegenerative diseases in family members, suggesting a genetic predisposition.
  • Behavioral and Psychiatric Symptoms: Note changes in behavior, mood, or personality, such as apathy, disinhibition, or hallucinations, to help differentiate between dementia subtypes.
• Neurologic Examination:
  • Motor Signs:
    • Parkinsonism: Bradykinesia, rigidity, and resting tremor are characteristic of Parkinson's disease dementia and dementia with Lewy bodies (DLB).
    • Axial Rigidity and Postural Instability: Early falls and axial rigidity are hallmark features of progressive supranuclear palsy (PSP).
    • Limb Apraxia and Cortical Sensory Loss: Suggestive of corticobasal syndrome (CBS).
    • Vertical Supranuclear Gaze Palsy: A classic sign of PSP.
    • Saccadic Intrusions: May be observed in DLB and PSP.
  • Language and Speech:
    • Nonfluent/Agrammatic Speech: Characteristic of nonfluent/agrammatic variant primary progressive aphasia (nfvPPA).
    • Semantic Deficits: Impaired object naming and comprehension suggest semantic variant PPA (svPPA).
    • Word-Finding Difficulties: Prominent in logopenic variant PPA (lvPPA).
  • Behavioral Changes:
    • Disinhibition, Apathy, and Compulsive Behaviors: Common in behavioral variant frontotemporal dementia (bvFTD).
  • Upper Motor Neuron (UMN) Signs:
    • Spasticity and Hyperreflexia: May be present in CBS and PSP.
  • Visual-Spatial Deficits:
    • Difficulty with Depth Perception and Object Recognition: Indicative of posterior cortical atrophy (PCA).
• Cognitive Screening:
  • MMSE:
    • 26-30: Normal to Questionable cognitive impairment
    • 21-25: Mild cognitive impairment
    • 11-20: Moderate cognitive impairment
    • 0-10: Severe cognitive impairment
  • MoCA:
    • 26-30: Normal to Questionable cognitive impairment
    • 18-25: Mild cognitive impairment
    • 10-17: Moderate cognitive impairment
    • <10: Severe cognitive impairment

Source: Perneczky R, Wagenpfeil S, Komossa K, Grimmer T, Diehl J, Kurz A. "Mini-mental state examination and clinical dementia rating scale: predictive validity for Alzheimer disease in clinical practice." Am J Geriatr Psychiatry. 2006 Feb;14(2):139-46. Nasreddine ZS, Phillips NA, Bedirian V, et al. "The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment." J Am Geriatr Soc. 2005 Apr;53(4):695-9.

Disclaimer: MMSE and MoCA are screening tools. Scores within the "normal" or "questionable" ranges do not definitively exclude cognitive impairment. Clinical judgment should guide further evaluation.

Step 2: Core Diagnostic Workup

Recommended for all patients with cognitive concerns:

• Laboratory Tests:
  • Standard Screening Labs:
    • TSH, Vitamin B12, Methylmalonic Acid (MMA), Homocysteine, Folate (B9), Thiamine (B1), CBC, CMP, Glucose, Albumin, Treponemal antibody
  • Serum Biomarkers:
    • pTau181 or Amyloid-Tau-Neurodegeneration (ATN) Profile
    • pTau217 or pTau217/A beta 42 ratio
    • Neurofilament light chain (NfL) or Amyloid-Tau-Neurodegeneration (ATN) Profile

Disclaimer: While pTau181, pTau217, and the pTau217/A beta 42 ratio are promising biomarkers, their clinical utility is still being established. Interpret results in the context of the clinical presentation.

• MRI Brain (without contrast):
  • SWI/SWAN (assess microbleeds)
  • Thin-slice hippocampal imaging
  • Axial FLAIR
  • 3D volumetric T1-weighted imaging

Source: UCSF Memory and Aging Center MRI Protocol: UCSF Protocol PDF Alzheimer's Disease Neuroimaging Initiative (ADNI) MRI Protocol: ADNI MRI Protocol

Step 3: Interpretation and Further Evaluation

• If pTau217 or pTau181 is elevated, or pTau217/A beta 42 ratio is abnormal:
  • Interpretation: Suggests hippocampal/parahippocampal degeneration consistent with Alzheimer's-type pathology (T+)
  • If symptoms are mild (MMSE >21 or MoCA >17):
    • Consider eligibility for anti-amyloid therapy (ATM)
    • Counsel on therapy risks, benefits, and goals

Disclaimer: Coverage criteria for anti-amyloid therapies may vary by payer. While newer agents such as donanemab are approved for patients with MMSE >20, clinical trials consistently show these therapies are most effective when initiated at the earliest symptomatic stages-ideally when cognitive impairment is minimal. Clinical judgment should guide both timing and appropriateness of treatment.

• Proceed with confirmatory testing to establish AT(N) profile and assess treatment readiness:
  • CSF Panel:
    • CBC, Protein, Glucose, Albumin
    • NSE
    • A beta 42/40 Ratio (e.g., Mayo AMYR)
    • pTau181 and Total tau (t-tau) (e.g., Mayo ADEVL)
  • Amyloid-PET: Approved by CMS for treatment eligibility

Disclaimer: CMS currently requires only amyloid PET to confirm eligibility for anti-amyloid therapy. However, pTau and total tau levels are highly valuable for prognostication, disease staging, and identifying likely responders to disease-modifying therapy.

• If NfL or NSE is elevated:
  • Indicates neuronal injury or degeneration (N+), not specific to Alzheimer's disease
• If biomarker levels are borderline but phenotype is concerning:
  • Especially in early-onset, rapid progression, or strong family history:
  • Proceed with a full CSF panel (as above)
  • Consider Amyloid-PET for confirmation if CSF is declined or inconclusive
• If results are normal:
  • Reassuring against Alzheimer's disease
  • Still consider:
  • Lewy body dementia
  • Frontotemporal degeneration
  • Functional or psychiatric cognitive syndromes
  • Reassess in 6-12 months:
    • Repeat MoCA
    • Repeat MRI
    • Serial pTau217 and NfL levels
• If RPD Trigger Workup:
  • Clinical history suggests rapid decline (symptom onset to dementia within 1-2 years) and elevated NfL or pTau
  • Proceed directly to Rapidly Progressive Dementia evaluation

Step 4: Rapidly Progressive Dementia (RPD) Workup

Rapidly Progressive Dementia (RPD) refers to cognitive disorders characterized by a swift and significant decline in cognitive abilities, typically progressing from symptom onset to dementia within less than 24 months-and often within 12 months. Unlike typical neurodegenerative diseases such as Alzheimer's, which progress over years, RPD requires urgent evaluation due to its broad differential diagnosis, including:

• Autoimmune encephalitis
• Infectious etiologies (e.g., prion diseases, viral encephalitis)
• Neoplastic/paraneoplastic syndromes
• Toxic-metabolic and vascular causes
• Atypical presentations of neurodegeneration

Because many causes of RPD are treatable or reversible, early recognition and expedited workup are critical.

• Laboratory Tests:
  • ESR, CRP
  • ANA, ANCA, Anti-thyroid antibodies
  • HIV, Syphilis serology
  • Vitamins B1, B12, E
  • Paraneoplastic and autoimmune encephalitis panels
• CSF Analysis:
  • Cell count, Glucose, Protein
  • A beta 42/40, pTau, Total tau, NSE
  • 14-3-3 protein, RT-QuIC
  • Oligoclonal bands
  • Autoimmune encephalitis markers
• Neuroimaging:
  • MRI Brain with diffusion-weighted imaging (DWI)
  • FDG-PET if frontotemporal degeneration suspected
• Additional Evaluations:
  • EEG (encephalopathy, seizure activity)
  • Syn-One skin biopsy (if synucleinopathy suspected)

Source: Geschwind MD. Rapidly Progressive Dementia. Continuum (Minneap Minn). 2016 Apr;22(2):510-537.

Step 5: Follow-Up and Monitoring

• If diagnosis remains uncertain:
  • Reassess every 6-12 months
  • MoCA or MMSE
  • MRI brain
  • Serum biomarkers (pTau217, NfL)
• If diagnosis is confirmed:
  • Initiate appropriate management
  • Educate and support patient and caregivers

Step 6: Questions remain?

If you're ever unsure, refer to your friendly neighborhood Ochsner Neurocognitive Program. We're here to help.