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Guide de pratique clinique pluridisciplinaire relatif à la collaboration dans la dispense de soins aux personnes âgées démentes résidant à domicile et leurs aidants prochesPublished by: Groupe de Travail Développement de recommmandations de première ligneLast published: 2017Multidisciplinaire richtlijn voor thuiswonende oudere personen met dementie en hun mantelzorgersPublished by: Werkgroep Ontwikkeling Richtlijnen Eerste Lijn (Worel)Last published: 2017

The clinical hallmarks of Alzheimer's disease (AD) are cognitive deficits, identified either by the patient or by a family member or carer. Disease onset is insidious and there is gradual progression of symptoms.

The diagnosis of AD is made clinically. The average sensitivity for clinical diagnosis of probable AD is 81% and specificity is 70%, using post-mortem brain histopathology as the standard.[91][92]

Work-up for AD includes a complete history, physical examination, and cognitive screening. Neuropsychiatric testing may be necessary in some cases. Reversible causes of cerebral impairment should be excluded with initial laboratory testing and brain imaging.

In large prospective cohort studies, the greatest risk factors for dementia were: age; the presence of one or more APOE e4 alleles; high number of additional risk alleles; diabetes; mid-life smoking; less than secondary school education; black race; hypertension; and pre-hypertension.[54] Some of these are modifiable risk factors and should be investigated and targeted with appropriate interventions.[72]

History from patient and carer

Accurate diagnosis requires a collateral history from an informant familiar with the patient’s daily function.

The presenting symptom is usually loss of recent memory first, and often difficulty with executive function and/or nominal dysphasia (difficulties in word finding and naming).

Patients also experience loss of episodic memory that is marked by, for example, loss of recall of the names of recent visitors, and may exhibit confabulation, confusion, and marked distortions of memory.

There is a loss of executive function with difficulty in reasoning, abstraction, and judgement. Performing tasks such as planning activities, organising events, and managing money becomes more challenging.

Cognitive deficits may include aphasia (language deficits), apraxia (inability to do tasks), and agnosia (inability to recognise using the senses).

Later in the disease progression, language difficulties are often marked by non-fluent speech, paraphrasing, and conveying information inappropriately.

The Alzheimer's Association has prepared a list of 10 common presenting features that may be helpful in forming a diagnosis. Alzheimer's Association: 10 early signs and symptoms of Alzheimer's and dementia Opens in new window

With progression of disease

Deficits in visuo-spatial function (seen as impaired performance in tasks such as clock-drawing, which is also an executive function task) and problems with driving become evident. Features such as prosopagnosia (not recognising familiar faces) and autoprosopagnosia (not recognising oneself in the mirror) tend to develop later in AD.

Progression of disease variably leads to changes in personality and affect. Behavioural and mood abnormalities such as aggression, apathy, disinhibition, paranoia, delusions, hallucinations, sundowning (behaviour change at dusk) and depression may become evident.[93][94]​​ Wandering, loss of spontaneous speech, incontinence, and the effects of institutionalisation tend to characterise the terminal stages of the illness. As cognitive function declines further, daily activities become so impaired that 24-hour assistance is required.

Cognitive testing

A screening tool is used for cognitive testing for all older people who present with memory impairment, decline in functional status, mood disorders, or behavioural abnormalities.

Commonly used tools include the Mini-Mental State Examination (MMSE) and the Blessed Dementia Scale.[95][96]​ Several other tools are available, such as the Saint Louis University Mental Status (SLUMS) examination and Mini-Cog.[95][97][98][99]​​​ Saint Louis University School of Medicine: SLUMS Examination Opens in new window​​​ Mini-Cog© Opens in new window​ The Montreal Cognitive Assessment (MoCA) test can be used to detect mild cognitive impairment.[95][100]​​​​ Montreal Cognitive Assessment Opens in new window

Impaired recall, nominal dysphasia, disorientation (to time, place, and eventually person), constructional dyspraxia, and impaired executive functioning are common. The Geriatric Depression Scale should be used to screen for comorbid depression.[101] [ Geriatric Depression Scale Opens in new window ]

Remote cognitive assessment is increasingly used, but evidence on accuracy is limited and more research is needed.[102]​ There is insufficient evidence to recommend the use of self-administered cognitive assessment tools.[103]

See Screening.

Physical examination

Physical examination is mostly unremarkable in the early stages. In advanced disease, patients may appear sloppily dressed, confused, apathetic, and/or disorientated, with a slow, shuffling gait and stooped posture. Findings such as focal neurological deficits, a stepwise course, skin and hair changes, or postural instability point to alternative diagnoses.

Terminal disease is marked by rigidity, and inability to walk and speak. The focus should shift to identifying complications such as infections, complications of dysphagia, risk of falls, and complications of immobility.

Laboratory investigations

Reversible causes of cerebral impairment should be excluded during initial laboratory testing.

Routine laboratory investigations include:

  • Full blood count

  • Basic metabolic panel including liver function tests and serum calcium

  • Thyroid-stimulating hormone

  • Vitamin B12

  • Urine drug screen (as appropriate)

  • Serological testing for syphilis (rapid plasma reagin/Venereal Disease Research Laboratory [VDRL]) in people at risk

  • HIV testing in people at risk

Cerebrospinal fluid (CSF) analysis should be considered when clinical features suggest disorders such as HIV, Lyme disease, herpes infection, or prion disease.

Imaging studies

Structural imaging is recommended at least once during the work-up.[104][105]

Computed tomography (CT) and magnetic resonance imaging (MRI)

Radiographical imaging with non-contrast CT or MRI of the brain can exclude structural causes of dementia and may be used to assess hippocampal atrophy to support a diagnosis of AD.​​ MRI shows greater sensitivity than CT for identifying lesions.​[105]​​[106]​ Disproportionate atrophy on structural MRI in the medial, basal, and lateral temporal lobes, and medial parietal cortex, constitutes one of the clinical criteria for the diagnosis of AD.[107][108]

Positron emission tomography (PET)

Amyloid PET has been used to detect in vivo ABeta protein deposition in patients with AD. Amyloid imaging with fluorine 18-labelled tracers (18F-florbetapir, 18F-florbetaben, and 18F-flutemetamol) can distinguish people with AD from people without AD, and may be able to identify people with mild cognitive impairment who are at greater risk of developing AD.[105][109][110][111]​ 

Fluorodeoxyglucose-PET (FDG-PET) can distinguish patients with AD from people without AD, and shows characteristic reductions of regional glucose metabolic rates in patients with probable and definite AD.[112]​ It is particularly useful for early diagnosis, as it can show characteristic patterns of AD neurodegeneration earlier than MRI in individuals with mild cognitive impairment who will go on to develop Alzheimer’s dementia. It is also helpful in atypical presentations, when the diagnosis is uncertain and AD is a possibility, and therefore imaging results are likely to impact patient care.[105][113]​​[114][115][116]

Neuropsychological testing

Formal neuropsychological testing may be helpful in differentiating between normal ageing, mild cognitive impairment, and early AD, as well as differentiating other neurodegenerative dementias such as dementia with Lewy bodies or frontotemporal dementia.[117] Batteries include: Wechsler tests for intellectual functioning; Boston Naming Test for language processing; semantic and category fluency (FAS and animal naming); Rey-Osterrieth Complex Figure test for visuospatial processing; digit span and reverse/Trail Making Test for attention and memory; Wisconsin card sorting test and trails B for executive functioning.

Genetic testing

Genetic testing is offered to patients with early onset dementia or when a strong family history is present.[118]

Biomarkers

There are several potential biomarkers that could play a role in the diagnosis of AD; the US Food and Drug Administration (FDA) is evaluating several emerging blood biomarker tests, some of which have reasonable correlations to amyloid positivity, and there are already FDA-approved laboratory tests to assess amyloid ratio in cerebrospinal fluid.[119]​​ The utility from both an individual and population perspective is under investigation.[120]

CSF biomarkers

CSF biomarkers include amyloid beta (ABeta)-1-42, ABeta-1-40, phosphorylated tau (p-tau), and total tau (t-tau).[121]​ Cochrane reviews concluded that measuring ABeta42 levels in CSF may help differentiate AD from other dementia subtypes, but that there is some uncertainty regarding the value of CSF biomarker measurement (t-tau, p‐tau, or p‐tau/ABeta ratio) for identifying which people with mild cognitive impairment will develop AD within a specified period.[122]​ However, a combination of low ABeta-1-42 and elevated tau or p-tau shows high diagnostic specificity in the context of cognitive changes.[123]​ Consensus guidelines recommend using CSF biomarkers as an adjunct to clinical evaluation, for predicting functional decline or progression to AD among people with minor cognitive impairment.[124]​ Appropriate pre- and post-biomarker counselling is required.[124]​ CSF biomarker testing may be of some benefit in the differential diagnosis of AD and other dementias.[125][126]

Additional potential CSF biomarkers include synaptic proteins such as neurogranin, SNAP-25, and GAP-43.[127]

Blood biomarkers

Potential blood-based biomarkers include the core pathological biomarkers ABeta, t-tau, and p-tau, and blood markers of neurodegeneration such as neurofilament light chain (NfL).[128][129]​ Companies have created chemiluminescent immunoassay certified tests that are becoming available and have good correlation with amyloid imaging results.

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