Methylphenidate and Cognitive Training in Elderly

Currently, there is no available drug to treat the symptoms of neurodegenerative and vascular cognitive disorders that affect millions of people worldwide.

Methylphenidate is indicated at high dose (1 mg/kg/day) in children having attention deficit and hyperactivity disorder (ADHD) and remains the best cognitive enhancer drug at lower dose. However, there is no proof of efficacy with chronic administration, outside ADHD, and concern remains about long-term cardiac and vascular risks in elderly and particularly in population with vascular risk factors and drug abuse in young people. Moreover, the effect appears to be very limited at the very advanced stage of dementia, for which the neuronal plasticity is too reduced to expect a benefit of training.

Taken all together, we sought to develop a new paradigm of association of both pharmacological and non-pharmacological procedure to enhance the neuronal plasticity in order to expect a persistent effect on slight to mild cognitive disorders with benefit on ecological test (i.e. driving). Finally, short-term treatment would reduce the safety concerns.

The concept will be to prove that low dose of methylphenidate associated with active cognitive training during 6 weeks can improve the cognitive function in healthy aged volunteers with a persistent effect at 3 months.


Eligibility Criteria:
Inclusion Criteria:

* Without severe chronic neurological or mental or psychiatric pathology
* Absence of cognitive impairment affecting autonomy (scores on the dementia scale of Mattis\> 130 and the IADL = 4)
* Right-handed participant
* Subjects holding driving license B and continuing a driving activity
* Affiliate or beneficiary of a social security scheme
* Subject having signed informed consent
* Subject having agreed to be registered on the National File of Healthy Volunteers
* Patient willing to comply with all procedures of the study and its duration
* No planned changes in lifestyle (nutritional and physical, social interactions) during the life of the protocol

Exclusion Criteria:

* Administrative reasons: impossibility of receiving informed information, inability to participate in the whole study, absence of coverage by the social security system, refusal to sign consent.
* Subject simultaneously participating in another clinical trial or in an exclusion period.
* Subject under tutelage or curatelle.
* Subject during breastfeeding or pregnancy.
* Subject not sufficiently fluent in the French language to understand the instructions necessary to carry out the cognitive tests.
* Subject with uncorrected visual pathology or motor pathology (orthopedic example) likely to interfere with the passing of tests.
* Subject with dependencies pre-existing to medicines, drugs or alcohol.
* Presence of contraindications to MRI: Claustrophobia, Anxiety crisis, Morphotype not allowing access to MRI, metal implant (eg a pacemaker), surgical clips Ferromagnetic, orbital or brain metallic foreign bodies).
* Hypersensitivity to methylphenidate or any other constituents of the product.
* Subject with a personal and / or family history of motor tics and Gilles de la Tourette syndrome.
* Subjects with a previous psychiatric history (based on the semi-structured psychiatric interview with the MINI of DSM IV adapted to DSM V): state, severe depression, severe generalized anxiety, anorexia nervosa or anorexic disorders, suicidal tendencies, psychotic symptoms, severe mood disorders, mania, schizophrenia, psychopathic personality disorder or borderline disorder. Dysthymia and an isolated history of depression do not constitute an exclusion criterion.
* Subjects consuming one or more psychotropic drugs or related products (antidepressants, antipsychotics, antiepileptic drugs, daily use of benzodiazepine anxiolytics or other anxiolytics, vesperal hypnotic intake). A history of taking point hypnotics is not a criterion of exclusion. However, there should be no regular and regular intake in the previous 3 months and less than once a week (ideally, lack of intake would be desirable but would considerably limit the potential for inclusion). They will be asked not to change their habits during the study period.
* Subjects with dysthyroidism or thyrotoxicosis
* Subjects with pre-existing cardiovascular disorders including severe hypertension, heart failure, occlusive arterial disease, angina pectoris, congenital heart disease with hemodynamic repercussions, cardiomyopathy, myocardial infarction, arrhythmias and channelopathies
* Subject with angle-closure glaucoma.
* Significant abnormalities on MRI and EEG according to the investigator's judgment
* Presence of untreated hypertension discovered during screening
* Subject with pheochromocytoma
* Pre-existing cerebrovascular disorders, cerebral aneurysm, vascular abnormalities, including vasculitis or stroke in the subject
* Subjects with hepatic and renal insufficiency
* Obese subject according to WHO classification (BMI\> 30)
* Presence of one of the following treatments that cannot be stopped for a period corresponding to 5 half-lives before inclusion: selective and non-selective MAOIs (nialamide and iproniazide, selegiline), other indirect sympathomimetics (phenylpropanolamine, pseudoephedrine, Phenylephrine), halogenated volatile anesthetics, guanethidine and related compounds.
* Treatment with alpha sympathomimetics (oral and / or nasal route) (etilefrin, midodrine, naphazoline, oxymetazoline, tetryzoline, tuaminoheptane, tymazoline), opiates and morphine derivatives. These concomitant treatments are contraindicated at baseline and throughout the study period.
* Subject with leukopathy classified ≥2 on the Fazekas scale