Approach
The diagnosis of dementia is first considered by comparing the patient's current level of cognitive and functional capabilities with their premorbid or 'baseline' level.[1] If a significant decline is noted, then a diagnosis of dementia can be considered by means of history, cognitive examination, physical examination, laboratory tests, and neuroimaging.[40] It is also important to include a review of medication, as some medicines may adversely affect cognitive function.[9]
History
The patient, family, carers, and other knowledgeable sources should be interviewed to discover changes in cognition, function, personality, language skills, and behaviour. An insidious onset with a slow (months to years) progressive course is consistent with a degenerative process.[41] An abrupt change, stepwise decline, or a gradual cognitive decline after one or more clinical events such as stroke is suggestive of a vascular-type cause.[41] However, minor strokes are often unrecognised. An acute (days to weeks) or subacute (weeks to months) course may suggest the presence of an infection, a metabolic disorder, an expanding brain lesion, the effects of medications, stroke, or hydrocephalus. Creutzfeldt-Jakob disease can also be considered.[15] Rapid (hours to days) deterioration in function suggests an acute confusional state or delirium.[41]
Any changes in the ability to manage activities of daily living (eating, bathing, dressing, toileting, transferring [i.e., walking], and continence) or instrumental activities of daily living (doing housework, cooking, cleaning, shopping, managing funds, managing medications, use of telephone, and transportation) provide important clues in diagnosing and classifying the illness.[42] An overall deterioration in all areas may point to a diffuse degenerative process such as Alzheimer's disease, whereas a disproportionate decline in one area may suggest a more focal cause such as a tumour, stroke, or frontal dementias.
Family history, drug use, past medical history of systemic illness, or risk factors for stroke (previous history of stroke, transient ischaemic attacks, hypertension, coronary artery disease, and atrial fibrillation) may be present. Systolic blood pressure ≥130 mmHg at age 50, below the conventional ≥140 mmHg threshold used to define hypertension, is associated with an increased risk of dementia, independent of cardiovascular disease.[43] A detailed assessment of alcohol use is important, particularly in older patients with mild cognitive impairment.[44]
An inquiry into a history of Parkinson's disease is important as dementia is not uncommon in these patients, with a prevalence rate of about 80% after a disease duration of 10 years or longer.[45]
Some patients with vascular dementia have transient neurological symptoms, a history of gait abnormalities, and incontinence at the time of initial assessment.
Patients with normal-pressure hydrocephalus (NPH) may describe pronounced gait disturbances accompanied by urinary incontinence and cognitive decline.[46][47][48]
Cognitive examination
Cognitive screening is recommended for older people with history of delirium, depression, diabetes, Parkinson's disease, or recent unexplained functional losses.[12][49] The US Preventive Services Task Force found insufficient evidence to assess the balance of benefit versus harm for asymptomatic, community-dwelling adults ≥65 years.[50]
Folstein Mini-Mental State Examination (MMSE) is still the most widely used cognitive screening test.[51] A score of <24 out of a possible 30 points is widely accepted to indicate an abnormal result. However, others have suggested that a cut-off of <21 indicates an increased probability of cognitive impairment, whereas a score of ≥25 reduces the probability of cognitive impairment. Intermediate scores between 21 and 25 are less useful in determining the probability of the disease.[6] Patients with scores between 21 and 25 can be considered for re-evaluation in 3 to 6 months.
MMSE is sometimes not sensitive enough to detect mild cognitive impairment (MCI).[52] These patients are often younger and have a high educational level. In addition, the MMSE lacks the ability to capture progressive decline fully in severe dementias, as well as impairments caused by focal neurological lesions.[53][54] For these reasons cognitive examination should always be correlated with history and decline from baseline level of functioning.[55][56][57] The visual association test (VAT) has shown substantial incremental value for identifying those at increased risk for developing dementia, in patients with a small decline on the MMSE over a 2-year period.[58]
Although many other scales, such as the Alzheimer’s Disease Assessment Scale-Cognitive Section (ADAS-Cog), the Mattis Dementia Rating Scale (MDRS), the Montreal Cognitive Assessment (MoCA), or the AD-8 questionnaire have been developed as screening tools for patients with cognitive impairment, a review indicates that no one scale is superior to the others in terms of diagnostic accuracy.[59] A Cochrane review found that there is insufficient evidence to recommend the Mini-Cog as a screening tool for dementia in the secondary care settings.[60][61]
[ 
]
In the UK, alternative cognitive tests include the 6-item cognitive impairment test and the General Practitioner Assessment of Cognition (GPCOG) test.[9][62]
The use of standardised functional assessment questionnaires to augment cognitive testing will help differentiate patients with early dementia from patients with MCI.[63]
The diagnostic process may be complemented with neuropsychological testing. If the patient has experienced a cognitive decline by history with functional activities largely preserved, then the patient can be described as having MCI.[11]
During the diagnosis process and at follow-up, the patient should also be assessed for medical and psychological comorbidities.[9]
Physical examination
Neurological examination findings can be helpful in the differential diagnosis of dementia. However, findings may be non-specific, even in the presence of a brain tumour or other focal and structural lesions.
Cranial nerve examination: patients with vascular dementia can present with visual field deficits. Evidence of ataxia, nystagmus, and lateral gaze palsy may suggest underlying alcohol-related dementia. In advanced cases of dementia, pseudobulbar palsy (involuntary laughing or crying) may be present.
Motor examination: patients with vascular dementia can present with hemiparesis. Although isolated extrapyramidal signs occur in both Alzheimer's disease and normal ageing (e.g., masked face, resting tremor), rigidity, bradykinesia, and abnormal speech and posture (especially in combination) are much less common in healthy older people.[64]
Sensory examination: sensory findings (such as a peripheral neuropathy) may implicate an underlying nutritional deficiency, or metabolic or toxic condition.
Co-ordination and gait: some patients with vascular dementia have transient gait abnormalities. Gait abnormalities, impaired vibration or position sense, spasticity, and paraesthesias may be found in patients with vitamin B12 deficiency. Patients with normal pressure hydrocephalus (NPH) can have pronounced gait disturbance.[46][47][48]
Reflexes: the findings on examination are usually normal in early Alzheimer's disease, although primitive reflexes (glabellar, grasp, and snout) may be present.[65] Patients with vascular dementia may demonstrate asymmetric deep tendon reflexes, a unilateral extensor plantar response, or visual field deficits. Creutzfeldt-Jakob disease is suggested when generalised myoclonus (with a prominent startle response) and motor disorders are present.[15]
Hearing test: hearing loss from central auditory dysfunction (i.e., sentence identification in a background of competing speech) reflects abnormal cortical processing and is more common with even mild cases of dementia than presbycusis, a form of hearing loss common in healthy older people.[66]
Cardiovascular examination: in patients with vascular dementia there may be hypertension, dysrhythmias (e.g., atrial fibrillation), peripheral vascular disease (such as carotid bruits), valvular disease, or congestive heart failure.
Psychiatric evaluation
Mood, affect, thought process, and thought content should be evaluated because depression and other psychiatric disorders can impair cognitive function. Social withdrawal, paranoia, and anxiety are frequent and early signs of Alzheimer's disease.[67]
Depression and delusions are common in patients with vascular dementia, and "emotional incontinence" such as extensive mood lability can be found in advanced stages.[68]
Personality changes, disinhibited behaviours, social withdrawal, and lack of insight are often found in the early stages of Pick's disease.
Mood and psychotic symptoms are not uncommon in patients with Parkinson's disease who are developing a dementing illness.[45]
When psychiatric and/or behavioural symptoms are suspected, standardised scales like the behavioural pathology in Alzheimer’s disease rating scale (Behave-AD), the neuropsychiatric inventory (NPI), and the Cohen Mansfield agitation inventory (CMAI) can be used. Instruments developed specifically for the measurement of depressive symptoms and the apathy syndrome in the patient with dementia include the Cornell scale for depression in dementia, the EURO-D scale for depression, and the apathy inventory.
Assessment of patients with behavioural disturbances includes not only an objective evaluation of their cognitive and behavioural profile, but also of their global functional status.[69] The use of standardised neurobehavioural scales will assist in qualifying and quantifying these symptoms and behaviours based on the type of dementia, leading to optimised treatment plans.[70]
Neuropsychological testing
Neuropsychological testing is recommended when dementia is suspected clinically, but the results of the initial evaluation are equivocal or the diagnosis is unclear. It can also be useful in distinguishing depression from dementia and a diffuse process from a focal one. In some cases, neuropsychological testing may offer a detailed report to consolidate symptoms of the thought disorder seen in dementias and can point to a specific region of the brain affected by the process (e.g., the frontal lobe).
Testing can provide additional data when decisions about driving, occupation, safety, and competence must be made.[71]
Baseline studies are important in determining prognosis and in assessing response to medications.
In many cases, these more exhaustive evaluations are unnecessary. When they do become necessary, normative data on commonly used neuropsychological tests have become available to assess performance in older patients (up to 100 years of age).[72]
Laboratory evaluation
There is no laboratory test to prove the presence of dementia. Laboratory testing is performed to find partially reversible or reversible causes of dementia.
In one published series, 5% of older outpatients with suspected dementia had underlying metabolic abnormalities (hypothyroidism - in 3%, hyperparathyroidism, hyponatraemia, or hypoglycaemia) that were thought to have produced or contributed to the cognitive impairment.[73]
The following are initial tests in all patients:
Blood chemistry profiles (including glucose, sodium, potassium, chloride, bicarbonate, urea, and creatinine)
FBC with differential
Thyroid stimulating hormone
Cobalamin level
Folate level
Erythrocyte sedimentation rate (abnormal is >25 mm/hour or age in years + 10 [if female] divided by 2)
C-reactive protein
Urinalysis
Urine microscopy and culture
Chest x-ray.
The following tests should also be considered:
Fasting blood glucose (if random blood glucose is abnormal or equivocal)
HIV testing in those considered at risk
Urine toxicology panel (for opiates, benzodiazepines, cannabinoids, and cocaine)
Collagen vascular profile (if there is evidence of systemic vascular involvement)
Urinalysis for heavy metals for patients who are considered at risk by history (i.e., suspicion of poisoning, social exposure to lead)
Cerebrospinal fluid Venereal Disease Research Laboratory (CSF-VDRL) followed by fluorescent treponemal antibody absorption test, if indicated, for suspected neurosyphilis.[74]
Neuroimaging
Despite the relative rarity of intracerebral conditions such as tumour, haematoma, or hydrocephalus, structural imaging studies should be performed because these lesions are easily detected and often treatable.[75] Neuroimaging can also be used to improve positive or negative predictive value in the diagnosis of more common causes of dementia.[75]
To assess progression and identify patients with progressive mild cognitive impairment (MCI), several non-invasive imaging methods are available; however, there is no consensus on the ideal one. Head computed tomography (CT) or head magnetic resonance imaging (MRI) are the main modalities.[75] MRI is more sensitive than CT for evaluating atrophy, vascular lesions, and lesions adjacent to bone, but the clinical utility of these findings in the evaluation of most cases of dementia is unclear.
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is a useful supplement to current surveillance techniques, with a predictive accuracy better than that of single-photon emission tomography or MRI.[76]
Amyloid PET scan has shown promise in making an earlier and more accurate diagnosis of Alzheimer's dementia.[77]
Cerebrospinal fluid (CSF) analysis
Biochemical, immunological, microbiological, or cytological analysis of the cerebrospinal fluid (CSF) can be considered in the following situations:
Dementing illnesses of acute or subacute onset (especially in patients with fever or nuchal rigidity)
Atypical or rapidly progressive initial manifestations
Dementia in people <55 years of age
Suspected syphilis
Suspected infection or malignant lesion of the CNS[15]
Patients with evidence of hydrocephalus[78]
Creutzfeldt-Jakob disease[79]
Immunosuppression
Demyelinating disease
Vasculitis (e.g., in the presence of connective tissue disease).
Patients should be evaluated for raised intracranial pressure before performing a lumbar puncture.
Electroencephalogram (EEG)
Overall, EEG has limited utility in the initial evaluation of dementia. Generalised slowing of the background rhythm on EEG is a frequent finding in Alzheimer's dementia and Lewy body dementia, and may be helpful in distinguishing such patients from those with depression.
The EEG can be used in cases of dementia in which a high clinical suspicion exists for an atypical disorder (e.g., Creutzfeldt-Jakob disease) where a characteristic EEG finding can aid in the diagnosis.
Speciality consultations
Timely referral to a dementia or neurodegenerative disease specialist facilitates classification of dementia and pharmacological treatment if appropriate. Available data indicate that primary care physicians correctly identify those patients with mild cognitive impairment (MCI) and mild dementia less than half of the time.[80]
Neurology speciality evaluation may also be considered in patients who have cognitive impairment of recent onset (<12 months), when atypical manifestations (e.g., strokes, seizures, or focal neurological findings) are present, when memory loss or dementia is suspected clinically but cognitive testing shows normal findings, or when there is an unclear diagnosis.
The use of guidelines such as the European Federation of Neurological Societies (EFNS) guideline for the diagnosis of Alzheimer’s disease improves the diagnostic accuracy.[81] Practical guidelines can help primary care physicians, who are often the first clinicians to evaluate individuals with cognitive issues, to correctly diagnose individuals with dementia.[8]
Genetic testing
Genetic testing is appropriate in patients with cognitive dysfunction who have a documented family history of dementia and who request such testing.[82]
Confirmation of diagnosis
The diagnosis of dementia is confirmed by post mortem neuropathological assessment of the brain. The National Institute on Aging-Alzheimer’s Association has published updated guidelines for the neuropathological assessment of Alzheimer’s disease.[83]
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