Alzheimer’s disease and the fornix

Abstract

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. Researchers have long been focused on the cortical pathology of AD, since the most important pathologic features are the senile plaques found in the cortex, and the neurofibrillary tangles and neuronal loss that begin in the entorhinal cortex and the hippocampus. In addition to these gray matter (GM) structures, histopathological studies indicate that the white matter (WM) is also a good target for both the early diagnosis of AD and for monitoring disease progression. The fornix is a WM bundle that constitutes a core element of the limbic circuits, and is one of the most important anatomical structures related to memory. Functional and anatomical features of the fornix have naturally captured researchers’ attention as possible diagnostic and prognostic markers of AD. Indeed, neurodegeneration of the fornix has been histologically observed in AD, and growing evidence indicates that the alterations seen in the fornix are potentially a good marker to predict future conversion from mild cognitive impairment (MCI) to AD, and even from cognitively normal individuals to AD. The degree of alteration is correlated with the degree of memory impairment, indicating the potential for the use of the fornix as a functional marker. Moreover, there have been attempts to stimulate the fornix using deep brain stimulation (DBS) to augment cognitive function in AD, and ongoing research has suggested positive effects of DBS on brain glucose metabolism in AD patients. On the other hand, disease specificity for fornix degeneration, methodologies to evaluate fornix degeneration, and the clinical significance of the fornix DBS, especially for the long-term impact on the quality of life, are mostly unknown and need to be elucidated.

Dissociable diffusion MRI patterns of white matter microstructure and connectivity in Alzheimer’s disease spectrum

“…The CDM pattern was also bidirectional showing both increased and decreased connectivity probability in AD. Specifically, we observed reduced connection density in AD in association pathways with known involvement in the disease, including the fornices34 and the uncinate fasciculi35. The same pattern was also seen in the genu of the corpus callosum.…”

“…Although there is much debate on the pathophysiology underlying AD-related WM changes, the retrogenesis hypothesis states that oligodendrocytes and myelin homeostasis are viewed as upstream players in aging and AD-related cognitive decline7. According to the model, later-myelinating neurons such as those of limbic association pathways3435, are more susceptible to environmental and metabolic insults compared with tracts that myelinate early in ontogeny, such as the corticospinal pathways. In line with this model, Stricker et al .…”

Regional susceptibility to dose-dependent white matter damage after brain radiotherapy

“…The fornices originate from the bilateral hippocampi, merge at midline, and again diverge to the septal nuclei, nucleus accumbens, and hypothalamus. An essential element of the limbic circuit, injury or transection of the fornix is associated with memory loss, particularly in episodic memory [37], which is the most common deficit seen after brain radiotherapy [38]. Studies have implicated the fornix as the site of the earliest and most robust changes in Alzheimer’s disease [37].…”

“…An essential element of the limbic circuit, injury or transection of the fornix is associated with memory loss, particularly in episodic memory [37], which is the most common deficit seen after brain radiotherapy [38]. Studies have implicated the fornix as the site of the earliest and most robust changes in Alzheimer’s disease [37]. While there has been intense focus on the effect of radiation on the hippocampus [4] with hippocampal-sparing RT evaluated in nationwide clinical trials [5,39], the associated white matter regions within the hippocampal network have largely been ignored.…”

The fornix provides multiple biomarkers to characterize circuit disruption in a mouse model of Alzheimer's disease

“…We also sought to understand the underlying causes for DTI changes using histological and ultrastructural imaging. The demonstration of white matter abnormalities in the CVN-AD mouse model, in tracts relevant to AD, would support that changes in white matter have an important role in AD, and potential predictive value, suggesting that white matter protection and repair may provide valid therapeutic targets (Oishi and Lyketsos, 2014; Douet and Chang, 2015). …”