Hippocampal pH rise towards alkalinity: A perfect storm for Alzheimer’s disease

Research has found the possible cause of Alzheimer’s disease indicating depletion of Glutathione and elevation of pH levels in the hippocampus (as a reflection of oxidative stress) | 2 min 30 sec read

Like Comment

Alzheimer's disease is a devastating brain disorder, affecting millions of people worldwide (generally age range from 55 years or above). The number of people affected by AD is adding up every day. The most noticeable behavioural changes in AD are forgetfulness and degrading confidence in performing daily chores. The principal reason behind these symptoms is death of specialised neuronal circuits in different regions of the brain, such as the hippocampus, frontal cortices and posterior cingulate cortex, which are associated with thinking, learning, memory and executive processes.

Although AD was discovered more than 110 years ago, the cause of this disease is still unknown. Various independent hypotheses explaining the etiology and pathogenesis of AD have prevailed for three decades and have included amyloid beta (Aβ) deposition and neurofibrillary tangles of hyperphosphorylated tau protein. Contrary to these hypotheses, post-mortem studies have found significant Aβ deposition in the brain of elderly individuals without any history of cognitive deficits. Various efforts are in place to unravel the cause of this dreaded disease.

We are members of the Neuroimaging and Neurospectroscopy (NINS) laboratory at National Brain Research Centre, located a few kilometres away from the hustle and bustle of Gurgaon, India. One of our primary research objectives is investigating the causal process of AD using brain imaging technology.

Oxidative stress (OS) has been found to be a critical event that happens early in AD. Our research has indicated that enhancing levels of brain antioxidant, glutathione (GSH), could be an important strategy to minimise reactive oxygen species implicated in prodromal or mild cognitive impairment (MCI), which might benefit cognitive ability.

Our study found that hippocampal GSH levels positively correlated with cognitive scores recorded from MCI subjects. These results are supported by a multinuclear MRS based database, which contains structural, functional and behavioural data collected from AD patients from the Indian subcontinent. The oxidative stress induced GSH depletion is likely to change the brain microenvironment, and these microenvironment changes can be detected in pH level shifts. In fact, it has been found pH levels differ in various brain disorders and specific anatomical regions as shown in Figure 1.

How do you measure the pH of a brain without inserting an electrode?

Brain pH levels can be measured using 31p MRS spectroscopy, where chemical shifts in Phosphocreatine (PCr) and Inorganic Phosphate (Pi), provide an indirect measurement of brain pH with 100% accuracy. This novel, non-invasive analysis can be performed in 15 minutes and applied to any part of the body.

Cause and event

There is significant research underway to identify early occurrences of GSH depletion and pH level rise in the hippocampus, in comparison to studies showing age matched healthy control subjects. A schematic representation (Figure 2) clearly shows the variations of GSH and pH levels represented by three distinct study groups. These results are encouraging because the research has unraveled the molecular mechanism of AD, and highlighted important features for an artificial intelligence based early prediction method “GAURI”.

Development of novel AD database for global science and community.

For flexible data sharing across users, combined with continuous project monitoring, the team has developed a database called ANSH. It presents a single neuroimaging data platform incorporating diverse data types from healthy control and patient groups to improve current insights about the disease. ANSH is a great scientific achievement that has initiated collaborative research and multi-site data sharing across the globe.

 What next?

Our team is close to ground truth for the cause of AD due to OS. In our forthcoming clinical trial, we aim to enhance brain glutathione levels by delivering daily oral GSH supplements to MCI patients and measure changes to hippocampal GSH and pH levels, through brain imaging and behaviour monitoring.

Photo: Pravat Mandal (Centre) with NINS Lab members at National Brain Research Centre, India.

Acknowledgement

The NINS lab members include: Dr. Deepika Shukla (Scientist), Ms Khushboo Punjabi (Ph. D students), Mr. Ritwick Mishra (R &D Engineer) and Divya Dwivedi (Research Coordinator). Their commitment and  high research values are greatly appreciated.

Thank you to Ms Avantika Samkaria (Researcher, NINS lab) for her artistic design skills and for contributing to the blog’s composition.

Credit also to Dr. Shallu Sharma (Research Scientist) and Ms Palak Handa (Researcher, NINS lab) for proof reading.

Pravat Kumar Mandal

Professor and scientist, National Brain Research Center