It is important, as a first step, to make the diagnosis of Dementia and afterwards try to determine its cause. Some cases of Dementia can be linked to metabolic or infectious diseases and are potentially treatable. It is important to keep in mind that different types of Dementia can co-exist in the same patient (overlapped) – for example it is very common the association between Alzheimer’s Disease and Vascular Dementia.
Oftentimes, the diagnosis of Alzheimer-Dementia is then largely based on exclusion diagnosis, i.e., exams are made to investigate treatable causes and when no of them are found, there is a strong probability to be a case of Alzheimer’s disease..
The diagnosis of dementia is made through:
- A detailed anamnesis (symptoms, family history, mental or cognitive changes);
- Neurological tests (vision and speech, senses and reflexes, writing and drawing, walking and motor skills),
- Cognitive tests (memory, concentration, feeling for time and space) – Mini exam of Mental State, Clock drawing test, etc…
- Psychiatric evaluation (depression, anxiety, confusion, hallucination)
- Psychometric tests (ability to make decisions, use of language, attention, planning and organisation, problem solving strategies)
- Laboratory examination – extensive blood test, should include dosage of vitamin B12, evaluation for anemia, thyroid hormones, HIV, metabolic evaluation.
- Electroencephalogram– to exclude epilepsy. It can also show some changes commonly signs found in dementia
- Structural brain magnetic– resonance imaging (MRI): provides information about the shape, position or volume of brain tissue. Can show structural changes as brain tumor or atrophy of specific areas (For example, frontotemporal dementia is often associated with reduced volume in the frontal and/or temporal lobes.
- Functional brain imaging – reveals how well cells in various brain regions are working by showing how actively the cells use sugar or oxygen. Functional techniques include positron emission tomography (PET) and functional MRI (fMRI). The technique currently most commonly used in dementia is fluorodeoxyglucose (FDG)-PET, which measures the use of glucose by the brain. FDG-PET studies indicate, for example, that AD is often associated with reduced use of glucose in brain areas important for memory, learning and problem solving.
- Molecular brain imaging-Radiotracers that bind to beta-amyloid in the brain have been developed for use with PET scans, so that for the first time the presence of AD pathology can be detected in the living brain. Pittsburgh compound B (PIB) was the first radiotracer capable of highlighting deposits of beta-amyloid. Other radiotracers that bind to different chemicals in the brain may be used to assist in the diagnosis of other types of dementia. For example, PET scans that detect receptors for dopamine may be used to show the reductions in this chemical in Lewy body disease.
- Cerebrospinal fluid exam– Research suggests that AD causes changes in CSF levels of tau and beta-amyloid, two proteins that form abnormal brain deposits in this disease. In the early stages of AD, beta-amyloid levels in the CSF fall and levels of phosphorylated tau rise. This technique can detect early changes indicating AD is under way before any symptoms are noticeable and is less expensive than amyloid brain imaging.
- Plasma biomarkers– Although CSF biomarkers can be an early (and ongoing) indicator of amyloid deposits progression, the procedure required to obtain such data (lumbar puncture) is an invasive procedure with some restrictions for routine clinical use. To overcome these challenges, a strong focus has been placed on the development of blood-based biomarkers that can reduce costs and detect the early signs of AD. Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression. Serum NfL rate of change peaked in patients converting from the pre-symptomatic to the symptomatic stage and was associated with cortical thinning. Two blood tests have been developed recently: one measures the level of Aβ42/Aβ40 (amyloidβ) and the other the level of p-Tau 181 (phosphorylated tau protein. Both tests have the advantage to be done in a blood sample, and were able to predict the risk of developing cognitive decline and its progression. They are not yet available in the market, but have the potential to be incorporated into clinical practice as a rapid screening test to rule out AD and to guide therapy in patients with dementia (read more in our newsfeed).
- Blood tests: Currently two new tests have been developed: The first test measures the concentrations of the pathological amyloid β fragments Aβ42 and Aβ40 in the plasma and calculates the quotient Aβ40. The second is an ultrasensitive blood test for an AD-specific tau protein which is hyperphosphorylated at the position threonine 181 and is therefore also called ‘p-tau 181’. Both tests are not yet available on the market, but due to their specificity compared to previous blood tests, they have a great potential to be adopted into clinical practice as a screening test for AD and also as a marker for disease progression. Further information can be found in our newsfeed.
- Genetic tests – in cases of familiar AD, mutation on the usual genes involved (APP, PSEN1, PSEN2) can be identified by genetic tests. These tests can confirm the diagnosis and also determine whether a member of the next generation carries the mutation. A blood test can also identify the individual APOE allele (see section about AD genetic), but results cannot predict who will develop Alzheimer’s disease or not. It measures a genetic risk (or protection) factor to AD.
If no other diseases of the brain, such as tumours, infections or metabolic diseases, are present and drug-induced dementia is excluded, then the diagnosis of “Alzheimer’s disease” comes into focus.The presence of plaques can substantiate the suspicion, but the connection between plaque formation and Alzheimer’s is compelling.
The diagnosis of AD is always made in a probability basis. The more suggestive signs of the disease are present (and fewer signs of other etiologies), the more likely the diagnosis is.
Clock drawing Test
Hane, F. T. et al. (2017) ‘Recent Progress in Alzheimer’s Disease Research, Part 3: Diagnosis and Treatment’, Journal of Alzheimer’s Disease, 57(3), pp. 645–665. doi: 10.3233/JAD-160907. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389048/pdf/jad-57-jad160907.pdf
Weston, P. S. J. et al. (2017) ‘Serum neurofilament light in familial Alzheimer disease’, Neurology, 89(21), pp. 2167–2175. doi: 10.1212/WNL.0000000000004667. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696646/pdf/NEUROLOGY2017815514.pdf
Preische, O. et al. (2019) ‘Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease’, Nature Medicine, 25(2), pp. 277–283. doi: 10.1038/s41591-018-0304-3. https://www.ncbi.nlm.nih.gov/pubmed/30664784
Karikari TK, Pascoal TA, Ashton NJ, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020;19(5):422-433. https://pubmed.ncbi.nlm.nih.gov/32333900/
Schindler SE, Bollinger JG, Ovod V, et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019;93(17):e1647-e1659.https://pubmed.ncbi.nlm.nih.gov/31371569/