The potential for one drug, administered at the earliest preclinical stage, to prevent the subsequent decline of cognition that eventuates in dementia

Abstract

In the process that eventuates in mild cognitive impairment (MCI) and ultimately in Alzheimer's dementia, the earliest identifiable change is in the function of synapses. If started at that early point in time, when there is subjective but not objective memory loss plus abnormal brain imaging with fluorodeoxyglucose and Pittsburgh compound B, treatment with a single drug directed at synaptic dysfunction might prevent development of cognitive impairment. Each of four drugs, dantrolene, lithium, minocycline, and piracetam, benefits synaptic impairment. This presentation has two sections. In the first, evidence is discussed at length, for abnormality in the axo‐spinous synapse as being the earliest change before objective cognitive decline. The second section explains the benefits to synapses provided by the four mentioned drugs. Dantrolene and lithium perhaps have the strongest supporting data for use as single agents: their efficacy should be subjected to clinical trial.

A vaccine to prevent initial loss of cognition and eventual Alzheimer's disease in elderly persons

“…49 Those high levels of Ca 2+ may be prevented by dantrolene, discussed in detail in Fessel. 3 Finally, and of note, Mattiason et al showed that mitochondria isolated from the hippocampal CA1 region are more susceptible to an excessive Ca 2+ load than are mitochondria isolated from the CA3 region, 50 which is relevant in the present context because CA1 is more important than is CA3 for memory and cognition.…”

“…Further, extrusion of excessive Ca 2+ requires ATP and causes its further depletion 49 . Those high levels of Ca 2+ may be prevented by dantrolene, discussed in detail in Fessel 3 . Finally, and of note, Mattiason et al.…”

“…The most likely reason why, subsequently, so many trials based upon the amyloid hypothesis have failed either to reverse or halt AD, is because once the causal process is in motion it may be unstoppable due to the known multiplicity of abnormalities of the brain in AD, many of which are also present at the earlier stage of mild cognitive impairment (MCI). On the other hand, it may be possible to prevent AD before it has even commenced, which is the time when there is not yet cognitive loss but when amyloid is detectable by Pittsburgh compound B positron emission tomography (PIB‐PET) scan and when synaptic metabolism as shown by fluorodeoxyglucose PET ( 18 F‐FDG‐PET) scan is reduced 3 . That condition has been termed pre‐clinical AD 4 .…”

“…On the other hand, it may be possible to prevent AD before it has even commenced, which is the time when there is not yet cognitive loss but when amyloid is detectable by Pittsburgh compound B positron emission tomography (PIB-PET) scan and when synaptic metabolism as shown by fluorodeoxyglucose PET ( 18 F-FDG-PET) scan is reduced. 3 That condition has been termed pre-clinical AD. 4 Because synapses account for a large portion of the brain's energy use, an immediate question is whether preventing this reduction of neuronal adenosine triphosphate (ATP) might prevent the start of cognitive loss in predisposed persons.…”