New Therapeutical Target in Alzheimer’s Disease

Alzheimer’s disease is characterized by the overproduction of plaques formed by beta-amyloid, which can be contrasted through the use of proteins belonging to the family of alpha-secretase. In a trial performed by MIT, some rats with an overproduction of beta-amyloid (with consequent behavioural and cognitive alterations very similar to the ones in Alzheimer’s disease) have been matched with some rats with an overproduction of SIRT1 (a molecule stimulating the production of alpha-secretase and slowing oxidative processes and ageing). Children have presented less plaques of beta-amyloid than their parents and have resulted protected against memory deficiency and against the loss of cognitive capability. On the contrary, when sick mice were matched with mice without SIRT1 overproduction, it was seen that the offspring presented more plaques of beta-amyloid and more cognitive damages than their parents.

A new path for the struggle against Alzheimer’s dementia is open: the stimulation of SIRT1 production. It is not the case of easy enthusiasm: we neither know the negative effects of SIRT1, nor whether in humans it is a practicable way. But the first step has been done.

Cerebral Biopsies and Dementia

In the cases where it is not possible to explain the occurrence of a rapid and progressive cognitive decline through usual non-invasive examinations, the use of cerebral biopsy has been proposed. In a trial performed by Emory University in Atlanta, some neurosurgeons have re-examined the medical records of 51 adults undergoing cerebral biopsy between 1999 and 2008 to determine the causes of an acute or sub-acute cognitive decline. Subjects with mass cerebral lesions, with malignant tumours or HIV infection have been excluded. The commonest pre-operative diagnoses have been: vasculitis (24 cases), encephalitis (8 cases), Creutzfeld-Jakob’s disease (7 cases). Cerebral biopsy has established diagnosis in 18 cases: Creutzfeld-Jakob’s disease (8), amyloidosis (3), lymphoma (2), encephalitis (2), demyelination (2) and infarction (1). The other biopsies have only identified a non-specific inflammation (20) or they have resulted completely normal (13). Biopsy results have implied a new therapeutical approach only in 4 cases and, only in 2 cases, subjects with lymphoma have shown a benefit from the new treatment. In two subjects, there have been post-biopsy cerebral bleedings.

It is true that cerebral biopsy has established a sure diagnosis in about 1/3 of cases, but it is also true that only 2 patients have had a benefit from that procedure, apart from the risks linked to the procedure. Cerebral biopsy remains a procedure to be used only in particular cases and with all possible precautions: it cannot certainly become a routine procedure. A little note: vasculitis, diagnosed in about half of the patients, has been confirmed in no cases by biopsy: a mistaken diagnosis? An overestimation of a little frequent disease?

New Drugs For Migraine

Migraine is generally managed with triptans, which however present the disadvantage of being poorly tolerated (precordial pain, dizziness, pharyngeal constriction) and of being contraindicated in patients with coronary artery disease. A new product has been recently experimented, telcagepant, which seems to be promising for this invalidating disease. In a randomized, case-control, double-blind trial, sponsored by pharmaceutical industry, telcagepant (a calcitonin gene-related peptide receptor antagonist) was experimented on 1380 adults (averagely 42; 85% women) affected by events of acute migraine in a design implying the use of these drugs: telcagepant 160-300 mg, zolmitriptan 5 mg or placebo. The trial was performed in 81 centers of primary care and in centers for the study of headache, in Europe and USA. Patients with heart disease or non-controlled hypertension or under SSRIs, anti-MAOs or propanolol treatment for at least one month were excluded from the trial. All the subjects were invited to keep a migraine diary, recording pain intensity (absent, mild, moderate, severe) and the presence or the lack of associated symptoms (phonophobia, photophobia, nausea). The recording had to be made at the beginning of the painful event, then every 30 minutes for the first three hours. Afterwards, after 4, 6, 8 and 24 hours. 300-mg telcagepant and 5-mg zolmitriptan showed themselves to be equally effective and both better than 150-mg telcagepant and placebo in reducing pain and related symptoms. The only severe side effect occurred in a subject taking placebo. Moderate side effects were much more frequent with zolmitriptan than in the other three groups.

In effects, telcagepant seems to be a new promise in the treatment of migraine, given its good efficacy and the lack of side effects. We are waiting for its marketing.

When Can We Suspect a Back Encephalopathy?

The syndrome of reversible back encephalopathy is now more often recognized than in the past because of a wide spreading of brain imaging techniques, above all MNR. Some researchers at Mayo Clinic have presented a series of 113 patients affected by this syndrome, hospitalized between 1999 and 2009. Inclusion criteria were: 1) acute neurological manifestations, such as convulsions, headache, encephalopathy, vision disorders, focal deficiencies; 2) focal edema shown through imaging; 3) clinical or radiological reversibility. The most frequent primary causes were hypertension, intake of cytotoxic drugs, sepsis, thrombocytopenic purpura, eclampsia and preeclampsia. Renal failure was present in 57% of subjects, while an autoimmune disease was present in 45% of them. Most patients have presented an acute increase in blood pressure (with an average peak of 191/104 mmHg) and, in most cases, convulsive episodes (74%). At MNR, almost everyone had a parieto-occipital involvement, while in 77% of cases, there has been an involvement of the frontal lobe, of the temporal lobe in 64% of cases, of the cerebellum in 53% of cases, of the basic ganglia in 34% of cases and of the brainstem in 27% of cases. During follow-up, there has been an improvement or a recovery in 88% of cases.

When there are patients with acute neurological symptoms, one must always think to a syndrome of back encephalopathy, especially in subjects at risk. We should keep in mind also localization, which is not necessarily always in the back side, and the fact that some neurological deficiencies can also be irreversible.