Memory loss and cognitive decline

Memory loss and cognitive decline describe a reduction in memory, thinking, language, visuospatial function or executive function compared with the patient's previous level.

Definitions. Mild cognitive impairment is objective impairment in one or more domains with preserved independence in daily activities. Dementia (major neurocognitive disorder) is impairment in one or more domains that interferes with independence in daily activities and is not explained by delirium.

Mechanisms. Neurodegeneration (amyloid and tau in Alzheimer disease, alpha synuclein in Lewy body disease, tau or TDP-43 in frontotemporal disease), cerebrovascular injury, structural lesions, infection, inflammation, toxic and metabolic disturbance, and psychiatric illness.

Classification by domain pattern. Amnestic (early episodic memory loss), dysexecutive and behavioural, language led, visuospatial or posterior, and parkinsonian with fluctuation.

Temporal patterns. Gradual over years (neurodegenerative), stepwise (vascular), subacute over weeks to months (infective, autoimmune, neoplastic, prion), and onset under age 65 (young onset), each with a different approach.

Key distinctions. An informant history, the first affected domain and the speed of progression point to the cause. Rapid progression over weeks to months needs urgent investigation.

History from the patient and an informant. First symptoms and date, course, domains affected (repeating questions, getting lost, word finding difficulty, misplacing items, personality change, poor judgement), functional decline (managing money, medicines, cooking, driving, self care), hallucinations, delusions, sleep (acting out dreams), mood, falls, gait, incontinence, headache, seizures, weight loss, and effect on safety.

Background. Vascular risk factors, stroke, head injury, alcohol, depression, sleep apnoea, thyroid disease, B12 deficiency, HIV and syphilis risk, cancer, family history of dementia (age at onset), education level, hearing and vision, and occupational or environmental exposures.

Drug history. Anticholinergics, benzodiazepines, antiepileptics, opioids, antihistamines, tricyclic antidepressants, and recent drug changes.

Cognitive testing

• Montreal Cognitive Assessment (MoCA): maximum 30; below 26 suggests impairment (add 1 point when education is 12 years or less). Sensitive for mild impairment.
• Mini-Cog (3 word recall and clock drawing): scored 0 to 5; under 3 suggests impairment.
• Addenbrooke Cognitive Examination III: maximum 100; under 88 suggests impairment.
• Mini Mental State Examination: maximum 30; 23 or less suggests impairment (adjust for education).
• 6 item cognitive impairment test: score over 7 suggests impairment.

These tools screen and do not establish a cause. Depression screening with PHQ-9 or a geriatric depression scale is part of every assessment.

Examination. Blood pressure, pulse (atrial fibrillation), BMI, hydration, hearing and vision, focal signs, gait (magnetic gait, shuffling, ataxia), parkinsonism (rigidity, bradykinesia, tremor), vertical gaze palsy, frontal release signs, myoclonus, neuropathy, thyroid, signs of alcohol or liver disease, and fundi.

Red flags

• Rapid decline over weeks to months
• Onset under age 65
• Focal deficit, headache, seizures, myoclonus or ataxia
• Early gait disturbance with incontinence
• Fever, weight loss, cancer, HIV, or immunosuppression
• New psychosis or severe behavioural change
• Recent head injury, especially on anticoagulants
• Visual hallucinations with fluctuating alertness
• Family history of early onset dementia

Special groups. Young onset: wider genetic, inflammatory and metabolic causes. Region specific: HIV associated neurocognitive disorder and neurosyphilis are important in many settings. Note capacity, driving, firearm and medicine safety, finances, and carer strain.

Neurodegenerative

• Alzheimer disease
• Dementia with Lewy bodies and Parkinson disease dementia
• Frontotemporal dementia (behavioural variant, semantic variant, non-fluent variant)
• Progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy
• Huntington disease
• Creutzfeldt Jakob disease and other prion disease

Vascular

• Vascular dementia (large vessel, small vessel disease, strategic infarct)
• Cerebral amyloid angiopathy, CADASIL
• Mixed Alzheimer and vascular disease

Potentially reversible or treatable

• Depression, delirium, drug effect
• Hypothyroidism, vitamin B12 deficiency, folate deficiency, thiamine deficiency (Wernicke Korsakoff syndrome)
• Hypercalcaemia, hyponatraemia, uraemia, hepatic encephalopathy, chronic hypoxia, obstructive sleep apnoea
• Alcohol related brain damage
• Normal pressure hydrocephalus
• Chronic subdural haematoma, brain tumour
• Neurosyphilis, HIV associated neurocognitive disorder, chronic meningitis (tuberculous, cryptococcal), progressive multifocal leukoencephalopathy
• Autoimmune and paraneoplastic limbic encephalitis, CNS vasculitis, neurosarcoidosis
• Wilson disease, heavy metal exposure
• Hearing and visual impairment

Other memory disorders

• Amnestic stroke (thalamic or hippocampal), transient epileptic amnesia, transient global amnesia
• Traumatic brain injury and repeated head injury
• Mild cognitive impairment, benign forgetfulness of ageing
• Late onset psychosis

Reasoning. First confirm impairment and function with an informant, exclude delirium and depression, find reversible contributors, characterise the syndrome from the domain pattern, tempo and associated features, then image.

Blood tests. Full blood count, urea, electrolytes, creatinine, calcium, glucose and HbA1c, liver function, thyroid stimulating hormone, vitamin B12 and folate, C reactive protein or ESR, lipids. Add HIV test, syphilis serology, and ammonia when risk or features suggest. Urine dipstick, ECG.

Neuroimaging. MRI brain (with FLAIR and diffusion weighted sequences) is preferred, to show the pattern of atrophy (hippocampal in Alzheimer disease, frontotemporal, posterior cortical), small vessel disease burden, infarcts, subdural haematoma, tumour and ventriculomegaly. CT head is an alternative when MRI is not available or tolerated and still excludes mass lesions, hydrocephalus and subdural haematoma.

Further tests, usually by specialists

• CSF: amyloid beta 42, total tau and phosphorylated tau, with cells, protein and oligoclonal bands, in atypical, young onset or rapidly progressive cases. Real time quaking induced conversion testing has high specificity for prion disease.
• EEG for suspected prion disease, seizures or encephalitis.
• Amyloid PET or FDG PET for diagnostic uncertainty; dopamine transporter imaging to separate dementia with Lewy bodies from Alzheimer disease.
• Autoimmune and paraneoplastic antibody panels for subacute onset with seizures or psychiatric features.
• Neuropsychological assessment for mild or unclear impairment.
• Genetic testing with counselling for young onset or strong family history.
• CT chest, abdomen and pelvis for paraneoplastic disease.

Limitations. Cognitive scores are affected by education, language, depression and hearing loss. Normal screening does not exclude early dementia. Biomarkers can be positive in cognitively normal older adults.

Treat reversible causes. Stop or reduce anticholinergics, benzodiazepines and other culprit drugs. Replace thyroid hormone for hypothyroidism. Vitamin B12 deficiency with neurological signs: hydroxocobalamin 1 mg IM on alternate days until no further improvement (up to 3 weeks), then 1 mg every 2 months.

Treat depression, correct hearing and vision, treat sleep apnoea, stop alcohol and replace thiamine (500 mg IV every 8 hours for 3 days in suspected Wernicke encephalopathy, then 100 mg orally three times daily). Refer normal pressure hydrocephalus to neurosurgery for shunt assessment. Neurosyphilis, tuberculous and cryptococcal meningitis need specialist infectious disease treatment.

Vascular risk control. Blood pressure under 140/90 mmHg (lower if tolerated and safe), statin and antiplatelet therapy when indicated, anticoagulation for atrial fibrillation, glucose control, smoking cessation, exercise and cognitive activity.

Alzheimer disease, dementia with Lewy bodies and Parkinson disease dementia

• Donepezil 5 mg orally at night for 4 to 6 weeks, then 10 mg at night; maximum 10 mg daily in usual practice. Rivastigmine 1.5 mg orally twice daily, increased every 2 weeks by 1.5 mg twice daily to a usual 3 to 6 mg twice daily (maximum 12 mg daily), or patch 4.6 mg/24 hours daily for at least 4 weeks then 9.5 mg/24 hours (maximum 13.3 mg/24 hours). Use for mild to moderate Alzheimer disease, and for dementia with Lewy bodies and Parkinson disease dementia. Monitor pulse, weight, nausea, sleep and syncope. Avoid or use cautiously in bradycardia, heart block, sick sinus syndrome, QT prolongation, active peptic ulcer, and asthma or chronic obstructive pulmonary disease. Review benefit at 3 to 6 months, then every 6 months. Do not stop abruptly without review.
• Memantine 5 mg orally daily for 1 week, then 10 mg daily, then 15 mg daily, then 20 mg daily at weekly steps; maximum 20 mg daily. Creatinine clearance 5 to 29 mL/min: maximum 10 mg daily; 30 to 49 mL/min: 10 mg daily, increased to 20 mg if tolerated. Use for moderate to severe Alzheimer disease, or when cholinesterase inhibitors are not tolerated.
• Monoclonal antibodies against amyloid (lecanemab 10 mg/kg IV every 2 weeks) are used in selected patients with early Alzheimer disease and confirmed amyloid, with baseline MRI and repeat MRI before the 5th, 7th and 14th infusions for amyloid related imaging abnormalities. Benefit is modest, risk is greater with ApoE e4 homozygosity and with anticoagulants, and access is limited. Specialist only.

Behavioural and psychological symptoms. Look for pain, infection, constipation, retention and drug effects first, with non-drug measures. Antipsychotics increase the risk of stroke and death in dementia; use only for severe distress or risk of harm: risperidone 0.25 mg orally twice daily, usual 0.5 mg twice daily, maximum 2 mg daily, for up to 6 weeks with review. Avoid in dementia with Lewy bodies because of severe sensitivity reactions; quetiapine 12.5 to 25 mg at night is the usual alternative in Lewy body disease.

Supportive care and safety. Capacity assessment, driving review, medicine supervision, financial and legal planning (lasting power of attorney), advance care planning, home safety, falls prevention, carer support, and community or day care services.

Monitoring. Cognition and function every 6 to 12 months, weight, mood, blood pressure, drug adverse effects, carer wellbeing.

Referral and escalation. Memory clinic or neurology for mild cognitive impairment, young onset dementia, atypical features or diagnostic uncertainty. Urgent neurology for rapid progression, focal deficit, seizures, myoclonus or suspected prion or autoimmune disease. Neurosurgery for hydrocephalus, subdural haematoma or tumour.

Admission criteria. Rapid decline, new delirium, unsafe self care, risk to self or others, or suspected CNS infection or encephalitis. Others can be managed as outpatients.

Safety netting. Relatives should return for sudden change, new weakness, falls, fever, severe behavioural disturbance, or weight loss.