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A debilitating disease of the aging mind, Alzheimer’s Disease affects 5 million people over the age of 65 years. Women are affected at a higher rate than men because they tend to live longer. The hallmark lesion of Alzheimer’s is a build up of pertinacious amyloid, resulting in the death of nerve cells and demise of neural pathways. The first cells to die are those associated with memory, specifically cells of the entorhinal cortex and hippocampus. These changes may be seen years before clinical signs of Alzheimer’s are apparent.
Diagnostic criteria for Alzheimer’s were previously based upon the physician’s observations, family history, cognitive tests and neurological assessments. Much has been learned about Alzheimer’s over the past 20 years, most notably, that changes in the brain and markers in the cerebrospinal fluid and blood can be detected years before clinical symptoms are observed.
Research efforts on biomarkers for Alzheimer’s are looking at brain changes in diagnostic imaging, cerebrospinal fluid and blood protein detection and genetic risk profiling as promising candidates for predicting future Alzheimer’s onset. While some of these methods still require validation, the 2011 proposed criteria include biomarkers for beta amyloid in CSF and plasma, and evidence of injured or degenerating neurons. If these markers are identified early in the disease progression, effective interventions to preserve function can be implemented. In addition, treatment effectiveness can be monitored through biomarker vigilance.
Bioimaging technologies allow for three types of Alzheimer’s assessments: 1)structural, in which areas of neuronal degeneration show up as altered shape, position or volume on magnetic resonance imaging (MRI) or computed tomography (CT); 2) functional, in which abnormal cells are identified via metabolic indicators such as glucose or oxygen on positron emission tomography (PET) or functional MRI (fMRI); and 3) molecular, in which radiotracing is used to evaluate cellular change on PET, fMRI, or single photon emission computed tomography (SPECT).
Cortical thinning in the medial temporal regions associated with memory is known to be a structural predictor of Alzheimer’s dementia and can be seen up to 10 years before onset of clinical signs. Hippocampal and entorhinal cortical changes seen with preclinical Alzheimer’s are also associated with episodic memory decline.
In a recently published study, researchers at Rush University Medical Center and Harvard Medical School proposed that parahippocampal white matter (PWM) in the perforant pathway, the fibers tracts between the neocortex and the hippocampus, would also show measureable changes in cognitively healthy individuals. These might also be correlated with decline in episodic memory and serve as a biomarker of Alzheimer’s. They were especially interested in the anterior medial part of the parahippocampal gyrus because this perforant pathway relays sensory information to the hippocampus, critical for episodic memory function, and has been shown to be affected early in the Alzheimer’s process, specifically cell layer II of the ER cortex.
Cognitively healthy seniors at Rush University Medical Center and Massachusetts General Hospital underwent clinical observations, neuropsychological testing and high resolution structural MRI scans. Episodic memory Z-scores were computed for both populations. Yearly follow up visits repeated the clinical exams and patients were assessed as cognitively healthy, mild cognitive impairment, or dementia. Patients included in the study had at least 4 follow up visits and only patients who were cognitively normal or dementia were used. Those with mild cognitive impairment were excluded, because the full extent of their decline could not be known. A clinical diagnosis of probable Alzheimer’s required a history of cognitive decline and evidence of neuropsychological impairment on testing in a least 2 domains, one being memory.
MRI scans were obtained at baseline and at the time of last evaluation to assess PWM. Comparison was made to hippocampal and entorhinal cortical scans acquired previously on the same populations, by the same researchers. The Analyze visualization and analysis software suite was used to compute volume measures for all structures.
Patients with Alzheimer’s had significant PWM volume loss compared to those without and PWM volume was a good predictor of Alzheimer’s onset as many as ten years before clinical signs or decline in episodic memory performance. PWM volume loss was thought to be related to perforant pathway fiber loss in cells from the entorhinal cortex, since these cells have been shown to degenerate early in the Alzheimer’s process. Age and/or disease-related demyelination were also suggested.
Significantly, while both hippocampal volume and PWM volume were shown to predict episodic memory performance at the mild cognitive impairment stage of disease, PWM volume was able to predict episodic memory performance earlier, in clinically normal patients.
These findings further define structures of the medial temporal lobe memory system (PWM) that show structural abnormalities prior to clinical onset of Alzheimer’s, and can be effectively used to detect the disease early in its progression. Further study may look to diffusion tensor imaging (DTI) to evaluate micro-structural changes in white matter fibers of the same region.
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Tags: Alzheimer's Disease, Brain Studies, Brain Volume, Dementia