Diagnosis

Diagnosis

Diagnostic Approach

This is a diagnostic approach based not only on the presence of negative arguments, but above all on the collection of positive arguments.

• Diagnosis during the patient’s lifetime is a diagnosis of probability. A definitive diagnosis relies on neuropathological examination (post-mortem).
• The probability of making an accurate diagnosis depends on a combination of positive and negative findings. The greater the concordance between these arguments, the higher the diagnostic probability.
• Diagnosis is based on five types of arguments:

1. Positive clinical arguments: the profile of cognitive impairment.
2. Neuroimaging arguments: negative findings (absence of other lesions) and positive findings (hippocampal atrophy).
3. Negative arguments from blood tests, used to rule out differential diagnoses, particularly so-called reversible dementias.
4. Positive metabolic imaging arguments (hypometabolism and/or hypoperfusion of associative cortices).
5. Positive arguments from cerebrospinal fluid (CSF) biomarkers, showing a characteristic profile of intrathecal phosphorylated tau proteins.

• In the vast majority of cases, the combination of clinical examination (including detailed cognitive assessment), brain MRI, and biological testing is sufficient to establish a diagnosis with high probability. Metabolic imaging and CSF biomarker analysis are not currently performed routinely.

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Natural History of the Disease

Three progressive phases must be distinguished:

• The pre-dementia or prodromal phase, marking the beginning of the symptomatic stage;
• The dementia phase (mild to severe);
• The very severe dementia phase.

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a. Pre-dementia or Prodromal Phase

• At this stage, patients remain autonomous for most activities of daily living.
• The most frequent abnormality is a deficit in episodic memory consolidation:
  • This reflects severe involvement of the internal temporal regions (hippocampus and adjacent cortex).
  • Memory complaints are by far the most common symptom leading to suspicion of the diagnosis. This typically involves rapid forgetting (e.g., repeatedly asking the same questions), reflecting an inability to form lasting memories from lived events. Patients often minimize these complaints (anosognosia), while relatives are concerned.
• During the five-word test, patients with episodic memory consolidation impairment are unable to recall the five words after a few minutes. Importantly, they are not helped by semantic cues, suggesting that the words were not encoded.
• Neuropsychological memory assessment complements the evaluation, confirming impaired recall abilities (e.g., using the Free and Cued Selective Reminding Test – 16 items) and consolidation deficits. Patients may introduce intrusions (words not belonging to the original list).
• This memory profile differs from memory impairments secondary to attention or executive dysfunction, which affect encoding or retrieval but not consolidation. In such cases, patients benefit from cues. This profile is commonly seen in depression, sleep disorders, anxiety, or excessive use of psychotropic medications.

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b. Dementia Phase

• Autonomy is significantly impaired in instrumental activities of daily living, such as using the telephone, transportation, managing medications, or handling finances.
• In addition to memory impairment, other cognitive domains are affected to varying degrees, including aphasia, apraxia, agnosia, and executive dysfunction.
• These deficits reflect the spread of lesions to associative cortical areas (prefrontal, parietal, and lateral temporal cortices).

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c. Advanced Stage of the Disease (Severe Dementia)

• Loss of autonomy is total due to impairment of basic activities of daily living (personal hygiene, dressing, mobility, feeding). Patients are often institutionalized. This phase precedes end of life and typically occurs 7 to 8 years after the first symptoms appear.
• In addition to global cognitive impairment (which may include failure to recognize relatives), patients may present with psychological and behavioral disturbances (agitation or apathy, hallucinations, delusions, wandering, sleep and appetite disorders, sphincter control disorders), sleep–wake rhythm disturbances, malnutrition, and other neurological signs (gait and posture disorders with falls, epilepsy, myoclonus).
• Death usually occurs due to general complications related to bedridden status (bronchopulmonary infections, complications following falls and prolonged immobilization) or sudden death.

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Differential Diagnosis

1. Acute Confusional State (Delirium)

Important:
In older adults, delirium may reveal an underlying dementia or occur during its progression. Delirium does not rule out dementia; on the contrary, it should prompt further evaluation after recovery (approximately 6 months later) with a clinical and cognitive assessment.

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2. Functional Causes of Neurocognitive Disorders

• Depression, sleep disorders (insomnia and sleep apnea), chronic anxiety, and psychotropic medications (benzodiazepines, antidepressants, hypnotics, etc.) may cause attention and executive dysfunction impacting memory (“pseudo-amnesia”).
• If cognitive impairment occurs in a depressive context, a full-dose antidepressant trial for a minimum of 3 monthsshould be considered.

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3. Organic Causes

a. Secondary and Potentially Reversible Dementias

• Hypothyroidism, vitamin B12 and/or folate deficiency, syphilis, progression of HIV infection, and certain brain tumors (e.g., frontal meningiomas).
• Normal pressure hydrocephalus: characterized by gait disturbances (small-step gait), frontal-type cognitive impairment with apathy, and urinary incontinence. Brain CT or MRI shows tetraventricular enlargement without mass effect and periventricular fluid transudation. Diagnostic and therapeutic lumbar punctures may be performed, and ventriculo-peritoneal shunting is considered when diagnostic probability is high.
• Chronic subdural hematoma: a frequent cause of cognitive impairment in the elderly, often detected long after minor head trauma. Risk factors include dehydration, chronic alcoholism, and anticoagulant therapy. CT or MRI reveals a crescent-shaped extra-axial fluid collection, often bilateral. Surgical evacuation or monitoring is considered on a case-by-case basis.
• Vascular lesions due to small-vessel disease (hypertension, diabetes) include lacunes, white-matter hyperintensities, microbleeds, and small subcortical infarcts. Their accumulation may lead to vascular dementia or mixed dementia (vascular and Alzheimer’s).

If dementia progresses rapidly within less than one year, subacute encephalopathies should be considered, such as Creutzfeldt-Jakob disease or inflammatory/autoimmune encephalitis (including paraneoplastic syndromes).