Alzheimer's Disease
I am developing a mathematical model that, by considering key pathophysiological processes involved in Alzheimer’s such as prion-like propagation of oligomers, axonal dystrophy, excitotoxicity, etc., attempts to predict the temporal course of the disease in terms of:
1) loss of neurons and synapses across the cortex,
2) anomalies in the interareal function connectivity,
3) emergence of early, middle, and late cognitive symptoms (such as language impairment, see below).
Amyloid-beta vs Tau
Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by the progressive decline of memory, cognitive functions, and changes in personality. AD has been estimated to be the cause of 60–70% of cases of dementia. AD’s progression is largely associated with the formation of Aβ oligomers and fibrillary plaques (amyloidosis), the emergence of neurofibrillary tangles (tau hyperphosphorylation), and the gradual loss of neuron-to-neuron connections in the brain.
The amyloid-beta peptide accumulates to amyloid fibrils that build up dense amyloid plaques.
Pathological tau protein phosphorylation leads to disintegration of microtubuli and aggregation to neurofibrillary tangles in neuron axons.
The amyloid-beta peptide accumulates to amyloid fibrils that build up dense amyloid plaques. Pathological tau protein phosphorylation leads to disintegration of microtubuli and aggregation to neurofibrillary tangles in neuron axons.
Research on preclinical AD patients suggests that the earliest accumulation of β-amyloid occurs within the Default-Mode Network (DMN), while the first cortical area to be affected by neurofibrillary tau pathology is the Medial Temporal Lobe (MTL).
I am developing a mathematical model that, by taking into account key pathophysiological processes involved in Alzheimer’s, attempts to explain why MTL and DMN are typically the most vulnerable cortical areas to the disease.
Cortico-cortical axonal connectivity of the human brain (P. Hagmann et al, PLoS Biology 2008),
and cortical regions showing the earliest accumulation of β-amyloid and of neurofibrillary tangles.
Cortico-cortical axonal connectivity of the human brain (P. Hagmann et al, PLoS Biology 2008), and cortical regions showing the earliest accumulation of β-amyloid and of neurofibrillary tangles.
Language Impairment
AD is characterized by progressively worsening deficits in several cognitive domains, including language. The most frequent linguistic communication symptoms include word-finding problems, difficulties in naming objects and in writing a letter, impaired comprehension of instructions, etc.
LANGUAGE NETWORK
The mathematical model I am working on attempts to explain the emergence of language deficits by evaluating functional connectivity anomalies between core regions of the language network, see the picture below.
Core regions of the language network
This network is located in the dominant hemisphere (usually the left), and it is responsible for language comprehension and production. It includes Broca’s area in the inferior frontal gyrus and Wernicke’s area in the posterior superior temporal gyrus (see the picture above).
EPISODIC AND SEMANTIC MEMORY
Episodic and semantic memory are intertwined cognitive functions which play a crucial role in shaping linguistic intelligence. Episodic memory is the ability to recall and mentally reexperience specific episodes from one’s personal past, while semantic memory represents the knowledge about concepts, facts, and the meanings of words and other symbolic units that constitute formal communication systems, such as language or math. Since these memory systems are affected by AD in its early stages, the mathematical model also attempts to predict how their degree of impairment evolves over time in the patients. It is known that areas in the MTL, including the hippocampus proper and the adjacent entorhinal, perirhinal, and parahippocampal cortices (see the pictures below), critically contribute to episodic and semantic memory.
Neural bases of episodic and semantic memory
For this reason, the model evaluates the structural damage to the memory systems by calculating the expected loss of neurons and synapses in those specific cortical regions during the disease course.
VERBAL WORKING MEMORY
The splenium is the thickest and most posterior portion of the corpus callosum, see the picture below.
Lesions to the splenium may affect verbal working memory
It connects superior parietal, posterior temporal, and occipital cortical areas, including key nodes of working memory activation. Specifically, lesions to those nerve tracts are expected to affect the normal functioning of verbal working memory areas in the superior parietal cortex, which are responsible for temporarily storing verbalizable information (such as letters, words, numbers, etc.). For this reason, structural damage to the splenium, which is typically observed since the early stages of the disease, may be used to predict more accurately the deficits in linguistic communication of AD patients.
These are just some of the biomarkers that the mathematical model employs to quantify systematically the cognitive decline of a subject, and to suggest treatments for slowing down the progression of AD.
CREDITS: the 3D meshes of the brain shown in this page are from the BodyParts3D/Anatomography, website maintained by Life Science Databases (LSDB). BodyParts3D © Integrated Database Center for Life Science licensed under CC Attribution 2.1 Japan.