Alzheimer disease
Due to world population ageing, degenerative disorders, mostly represented by the Alzheimer Disease (AD), are becoming an extremely challenging burden for our health system but also for our entire society. The number of AD patients is estimated around 1 million in France with an incidence around 200,000 new patients/year. Worldwide, between 2010 and 2015, 10 million patients have been identified with AD, that is roughly 1 new patient identified every 4 seconds!
The usual form of AD is observed in over 65 years-old patients and progress relatively slowly. The symptoms include cognitive disorders such as short-term memory loss, disorientation in time and space, reduction of executive functions (action planning…), speech and motion disorders… Such symptoms induce a progressive loss of patient autonomy. Another form of AD (5% of patients) is found in young patients (under 65 years-old) but is characterized by a quicker progression even if the patients can survive longer. Last, other diseases are associated to AD such as Frontal Temporal Dementia (FTD), dementia with Lewy bodies, cognitive disorders of vascular origin, Progressive Supranuclear Palsy (PSP)…) and will impair different brain areas inducing predominance of various symptoms (visual spatial, speech or behavioral disorders…) Those symptoms can be a very heavy burden for the patient and his/her relatives. Such patient will need special cares and sometime need to enter into specialized institutions.
AD’s symptoms appear very insidiously and in general, the disease is only suspected when the brain lesion are already well spread. The precise diagnosis of the cognitive disorders can be very difficult for medical doctors and a high degree of expertise is required, associating clinical & neuropsychological observations, MRI and PET imaging, biomarkers, genetic analyses… Some biomarkers (Beta amyloid, Tau protein) allow detection of brain lesions several years before any cognitive symptom appears. This delay vary depending on the patient cognitive reserve (the more, the better) and on the presence of other lesions (such as vascular lesions) which will accelerate the disorder progression. MRI imaging allows detection of brain tissue atrophy or neuronal network disruption while PET scan imaging can detect synapses and neurons dysfunctions (reduction of “FDG” glucose consumption). New biomarkers are currently tested in clinical research to detect β amyloid plaques or neurofibrillar tangles (β amyloid and Tau markers respectively).
At the brain tissue level, two different lesions are observed: on the one hand, amyloid plaques made of amyloid peptide aggregates and found outside the neurons and on the other hand, neurofibrillar tangles observed inside the neurons and made of hyper-phosphorylated Tau proteins. It is suspected that the amyloid peptides aggregate before the Tau proteins and would be one of the factors inducing or amplifying their spreading in the brain. Such toxic protein deposits will be lethal for the cells and a prion-like propagation of abnormal Tau proteins is under investigation. Other AD-related diseases are also linked to the Tau protein dysfunctions (FTD, PSP…) and are named “Tauopathies”
Genes play an important role in AD and related diseases. There are some rare hereditary dominant forms related to mutation of one gene. However, in most cases, some combinations of genomic variants are found to increase the risk to develop AD. In addition to the genetic factors, other factors (neurovascular disorders, diabetes, obesity, tobacco, other toxics…) increase the risk to develop AD and may accelerate it progression.
First symptoms
For two third of AD patients, the disease starts with memory loss symptoms. But remaining patients, there are no predominant memory disorders but rather atypical symptoms such as speech disorders (loss of words, comprehension difficulties …), motor skill disabilities not related to motor disorders (apraxy), difficulties to organize; to planify or to perform complex tasks (dysexecutive syndrome), object/face recognition disorders, visual-spatial disorders.
More rarely, patients can present unusual clinical symptoms such as secondary gait disturbance to lower limb motor disabilities (paraparesis), equilibrium disturbance (cerebellar ataxia), epileptic seizure, abnormal movement (myoclonus), neurovascular lesions (hemorrhages) and Parkinson-like symptoms.
Some psychological and behavioral symptoms (depression, anxiety, irritability, delirious thought and hallucinations) are observed. Generally speaking, young patients are usually well aware of their difficulties. Such AD symptoms can be wrongly attributed to psychological or psychiatric diseases inducing a consistent delay before a correct diagnosis can be established.
Genetic forms of AD
For 0.1% of patients, there is a hereditary transmission of AD. The first symptoms appear always before the age of 65 (even sometime before 50) in every generation of a family (autosomal dominant disease). Three different genes have been identified: PSEN1, PSEN2 and APP.
Differential diagnosis
In addition to AD in old patients, cognitive disorders can have numerous causes: other neurodegenerative diseases (frontal temporal dementia, dementia with Lewy bodies…), diseases of metabolic, genetic, autoimmune, inflammatory, cerebral vascular origins. The correct diagnosis of cognitive disorders is extremely important as some diseases have very specific therapies and care pathways.
For young patients (under the age of 60), AD is the most frequent cause of cognitive disorders. Considering their particularities, AD diagnosis for young patients requires specific clinical and para-clinical investigations and patients must be provided with an adapted care pathway in center of expertise for rare diseases.
The Alzheimer disease is defined by internationally recognized criteria.
AD is a dementia, a medical term signifying that cognitive disorders in minimum two domains (memory disorders, disorientation in time and space, gesture production, Object and face recognition, reasoning and judgment skills, task initiation and planning, speech) must be observed and be strong enough to disturb the patients’ work or social activities. There is a significant impact on everyday life and the patient must be helped or supervised to perform complex activities. Those disorders evolve progressively on several months. To be considered as symptoms, the disorders must be significant considering the anterior cognitive skills of the patient.
As the disease progress, some patient activities are impaired such as meal preparation, budget management, drug intake, car driving, use of public transport, phone and communication with people.
For Young patients with AD, considering the disease rarity and possible other causes, some specific analyses are required to confirm the AD diagnosis.
Diagnostic process for young patients with AD
The patient clinical history is discussed with the medical doctor and the family. Collection of personal and familial anterior medical disorders is essential to build the family tree of disease risk.
The clinical examination is usually normal but some neurological signs can be observed, especially if the clinical symptoms are atypical (motor or sensorial disorders, Parkinson syndrome, visual disorders…) Such abnormalities can orient the diagnoses toward other pathologies.
Neuropsychological assessment of cognitive functions is crucial in order to objectively assess the patient difficulties and remaining skills.
A typical biological check-up (glycemia, kidney, hematologic and thyroid status…) is made to detect any other possible causes of cognitive impairments (vitamin deficit, thyroidal abnormalities…). Considering the clinical situation, some more complex analyses can be required (metabolic check-up…)
A molecular diagnosis (genetic mutation screening) is made when a young patient has a close family member (parents, sister/brother) who was affected by AD before 65 years-old or when the first symptoms appeared before 50. This diagnosis required an informed consent signed by the patient. If the patient is under guardianship, it is mandatory to receive his/her guardian’s consent.
Brain morphological imaging : brain MRI imaging can pinpoint morphological abnormalities suggesting an Alzheimer disease. Abnormalities found in old AD patient such as hippocampus atrophy, are not systematically found in young patients inducing sometime a delay of diagnosis. For young patienst wit AD, the most frequent MRI sign is posterior cortex atrophy (parietal). MRI imaging can also eliminate other possible diagnoses (ex tumors)
Brain functional imaging (PET, SPECT): Single-photon emission computed tomography using FDG (fluorodesoxyglucose) can detect abnormalities specific of cerebral metabolism defects in the temporoparietal and occipital brain cortex of young AD patients. Such defects can be found also in older AD patients.
Lumbar puncture with dosage of Alzheimer disease biomarkers: Analyses of cerebrospinal fluid show a decrease of Aβ42 peptide and increase of tau and phosphorylated Tau proteins. Such anomalies are also observed in older patients.
Pharmaceutical treatments
Current treatments available are symptomatic treatments. Those drugs aim to increase the acetylcholine level inside the brain (neurotransmitter which level is decreased in AD) by inhibiting the acetylcholinesterase enzyme or by regulating the glutamate excessive level thanks to antiglutamate agents (memantine).
Acetylcholinesterase inhibitors are used for the symptomatic treatment of AD and dementia with Lewy bodies. The objective is to slow down the cognitive degradation and to improve some of the behavioral disorders such as apathy or hallucinations. Three molecules are approved in France: Donepezil, Rivastigmine and Galantamine. Drug prescription (first and renewed) is handled by experts (neurologists, geriatrists and psychiatrists). Most frequent secondary effects are transitory digestive disorders (diarrhea, nausea, loss of apetite) that can be handled easily. Drug tolerance monitoring is recommended one month after the start of the treatment. A disruption of the treatment is not recommended except in case of long term persistent intolerance or in case of AD high severity.
Memantine drug is prescribed for moderate to severe forms of AD. It can be used alone and in association with acetylcholinesterase inhibitors, amplifying it effect on cognitive decline and psycho behavioral disorders
Moreover, whatever is the type of dementia; treatments of cardiovascular risk factors are extremely important, especially arterial hypertension, diabetes and dyslipemia in order to prevent a rapid disease progression.
It is also important to prevent or treat all chronic associated pathologies that could induce a state of confusion. Sensorial deficit correction and monitoring of the patient nutritional state is also requested.
Management of psycho-behavioral disorders
For each symptom observed, It must be considered possible causes of organic (pain, digestive disorders, infection…), environmental (modified or non-fitting environment, exhausted caregiver) or drug treatments (neuroleptic or anticholinergic drugs…) that could be easily dealt with.
Sedative drugs must be limited for short periods, avoiding badly tolerated drugs such as neuroleptics (reserved to very specific situations) or benzodiazepine drugs. Depression, anxiety, sleep disorders must also be analyzed carefully and can be treated specifically toward patients with dementia.
Last, numerous treatments that could induce worsening of cognitive and behavioral disorders, must be systematically scrutinized by the medical staff especially in case of state of confusion.
Non-pharmaceutical management of AD
Several non-pharmaceutical therapies are available: cognitive therapies (memory trainings, cognitive recovery exercises), non-cognitive therapies with psychosocial aspects (orientation rehabilitation, past event recalling, empathic therapy) and non-cognitive therapies with other approaches (behavioral stimulation, physical activities, music-therapy, light-therapy, sensorial and multi-sensorial stimulations, aromatherapy…) but validation data are not enough consistent to evaluate their efficacy.
Impact on daily life
Alzheimer disease affects the cognitive skills of patients, modifying sometimes their behavior and inducing a loss of autonomy in daily activities. This loss of autonomy is not necessarily severe, notably at the start of the disease and for many years, but the patient will need to be helped or supervised for more complex activities such as, financial matters.
Decline in cognitive skills, sometimes conscious for the patient at the disease onset, as well as the loss of autonomy, are difficult to accept for the patients and their family. The limitation of some activities, such as driving a car, is difficult to admit.
In every case, it is better to avoid any situation of failure and to praise the preserved skills in order to avoid feelings of frustration and self-depreciation. As the learning skills of the patients are limited, it is better to not propose unknown activities and to not stimulate them too much. On the contrary, it is recommended to continue the familiar daily activities and adapt them to the capacities and safety of the patients. The patient can be encouraged to continue his/her hobbies especially if they involve social interactions. Last, if the patient is healthy, an activity such as walking or a soft sport activity can be very positive and reduce his/her anxiety.
Impact on the patient’s couple
During the disease, the caregiver can be confronted with changes in his/her relationship with the patient, becoming sometime the main helper. This change is difficult especially due to the lack of recognition from the patient. Confronted by this change of role within the couple and the family, the care giver can wonder: How and why does he/she take the role of caregiver? for love, for duty, for social obligation? Is there any expectation from the patient, the family, and friends? Last, he/she can have a feeling of strangeness in front of the sick partner: the partner is the same but also completely somebody else.
Due to the disease, the couple will need to modify or give up some projects. This could lead to some feelings of resentment, frustration, angriness, hate and sorrow. In those difficult situations, the caregiver can find some help from specialized psychologists or from some talk groups sharing experiences and advice on how to manage the disease every day.
Last, Alzheimer disease can also affect more intimate aspect of the couple life such as sexuality. Indeed, some cognitive and psycho-behavioral modifications such as apathy or disinhibition can modify the way to express feelings and sexual desire.
As the disease progress, the caregiver partner can be confronted to indifference from the partner or can think that he/she is taking advantage from the patient. The caregiver can ask for advice to find the best solution for both the patient and the partner to express their feelings and desire and to adapt the disease progression.
Impact on the patient’s family
Young patient with AD (under 60 years) can be confronted to contextual, familial or professional particularities related to their young age, adding more consequences to the disease.
Young AD patients usually have a central role in the family (salary, financial and administrative management, education, daily logistic…) If the patient cannot perform those responsibilities, the burden of the partner will increase drastically especially if the family have children.
The occurrence of AD in a young patient creates numerous problems in a family and affects all it social environment. The close family members can react in a different way: adapt to the disease (prevent patient’s failures, research for help, create solutions) or overlook the impact of the AD (minimize the symptoms and difficulties, attribution of new behaviors to the context or mood, rejection of the provided helps…)
The chosen position is related to the family and couple history. This opens question such as “Why me?” “Why our family?” “What are the causes ?”, “What is the future? » The uncertainty in front of the disease can create a feeling of anger and frustration. The capacity to give a precise diagnosis allows to better understand the disease, it symptoms and anticipate it progression.
Children are very vulnerable to AD. They understand with great difficulties their parent’s disease and the change of behavior, sometime thinking that “he/she did that on purpose” or that the patient doesn’t love them anymore. They have also to understand the change of role within the family. Confronted to the cognitive and behavioral impairments of the patient and due to a lack of knowledge, children can choose one “side” or another, inducing more stress, a loss of reference, ambivalence and later on a feeling of guilt. Children must benefit from help to better understand the disease induced changes and the contradictory feelings that they feel such as pain, fear and frustration. It is also important to inform the teachers of the children in such situation.
Professional impact
Professional activity is sometimes the first impacted by the cognitive impairments of young AD patients. However, detection of cognitive disorders in young adults leads very rarely to a diagnostic of AD. One of the objectives of Young AD patients care pathway is to raise the public awareness of those pathologies, wrongly recognized as old patients’ diseases
At the disease onset, modification of the working environment can allow the patient to continue his/her activities. This adaptation based on the patient’s preserved skills, requires a close cooperation between neurologists and occupational health doctors to plan carefully the changes.
Last, when the cognitive and behavioral disorders are too severe to work efficiently, the patient and His/her family must be oriented quickly toward the social welfare services to avoid any dire financial situation related to job loss.
Impact on car driving
During the care pathway, patient can be advice to not drive a car. If the patients want to continue to drive, he must declare his/her situation to the car driving license services which will cancel or not the driving license. Some driving test can be proposed by doctors to evaluate the patient’s driving abilities but such tests are not sufficient to decide. A doctor cannot directly indicate the danger of a patient car driving. This must be performed by the family to the police services.
