AGING NEUROSCIENCE MINI REVIEW ARTICLE published: 21 January 2015 doi: 10.3389/fnagi.2015.00001 The fornix in mild cognitive impairment and Alzheimer’s disease Milap A. Nowrangi* and Paul B. Rosenberg Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA Edited by: Fernanda Laezza, University ofTexas Medical Branch, USA Reviewed by: Bogdan O. Popescu, Colentina Clinical Hospital, Romania Shin Murakami,Touro University California, USA *Correspondence: Milap A. Nowrangi , Department of Psychiatry, Johns Hopkins Bayview Medical Center, 5300 Alpha Commons Drive, 4th Floor, Baltimore, MD 21224, USA e-mail: mnowran1@jhmi.edu The fornix is an integral white matter bundle located in the medial diencephalon and is part of the limbic structures. It serves a vital role in memory functions and as such has become the subject of recent research emphasis in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). As the characteristic pathological processes of AD progress, structural and functional changes to the medial temporal lobes and other regions become evident years before clinical symptoms are present.Though gray matter atrophy has been the most studied, degradation of white matter structures especially the fornix may precede these and has become detectable with use of diffusion tensor imaging (DTI) and other compli- mentary imaging techniques. Recent research utilizing DTI measurement of the fornix has shown good discriminability of diagnostic groups, particularly early and preclinical, as well as predictive power for incident MCI and AD. Stimulating and modulating fornix function by the way of DBS has been an exciting new area as pharmacological therapeutics has been slow to develop. Keywords:Alzheimer’s, MCI, fornix, DTI, DBS INTRODUCTION Alzheimer’s disease (AD) is the most common neurodegenerative condition in aging. AD is a growing public health problem that is projected to reach epidemic proportions if disease-modifying therapies are not found. The latest figures from the Alzheimer’s Association indicate that there are an estimated 5.3 million Amer- icans living with AD. By 2050, an estimated 11–16 million people are expected to be diagnosed in the United States alone (Thies et al., 2013). Establishing the diagnosis of Mild Cognitive Impairment (MCI) and AD has evolved over the last 25 years with the most recent iteration of the National Institute on Aging and Alzheimer’s Association criteria (Mckhann et al., 1984, 2011). These criteria place a new emphasis on the use of biomarkers of AD pathophysi- ology whereas the original criteria were based solely on the clinical evaluation. Although the use of biomarkers to establish diagno- sis or track progression is considered a step forward in the field, there is a need for continued development of complementary tech- nologies utilizing biological, physical, cognitive, and behavioral substrates. Broadly, the initial pathologic changes in AD have been shown to involve the medial temporal lobes with the accumulation of neurofibrillary tangles and senile beta amyloid plaques (Bancher et al., 1993; Braak and Braak, 1995; Xu et al., 2000; Braak et al., 2006). This region is thought to mediate the retrieval and learning of semantic and episodic memory – the most common early cog- nitive deficits in AD (Aggleton and Brown, 1999; Behl et al., 2005; Levy and Chelune, 2007; Baldwin and Farias, 2009). The accumu- lation of tangles and plaques is associated with progressive atrophy of the cortical gray matter as loss of large pyramidal neurons (layers III and IV) advances, particularly in cortical association regions (Braak and Braak, 1995). In addition to this, several white matter (WM) abnormalities have been described and are thought to reflect axonal disintegration, rarefaction, oligodendrocytosis, and astrocytosis (Xu et al., 2001; Roher et al., 2002; Shahani et al., 2002). Neuroimaging techniques, particularly magnetic resonance imaging (MRI), is a robust method used to visualize and detect subtle changes in structure and function of the substructures within the medial temporal lobe and related regions as important and perhaps early markers of disease and progression. Though most volumetric imaging studies focused on atrophy of the entorhinal cortex and hippocampus, close inspection of the limbic structures has revealed significant volume reductions in patients with sporadic and familial AD (Decarli, 2001; Cash et al., 2013). The fornix is one structure within the limbic system that is receiving increasing attention recently in part because of its ease of detectability using MRI scanning as well as robust associations to cognitive changes, diagnostic group discrimination, and suscep- tibility to therapeutic intervention (Aggleton and Brown, 1999; Thomas et al., 2011). Because of the increasing interest in this structure, this brief review will serve as an updated survey of the key research over the last 10 years involving the fornix with hopes for continued and increasing efforts to better understand the use of this structure in the diagnosis, progression, and treatment of AD. FORNIX – STRUCTURE AND FUNCTION The fornix is a WM bundle belonging to the medial diencephalon, which also includes the hippocampus, mammillary bodies, and anterior and medial thalamus. Grossly, the fornix is found on the medial aspects of the cerebral hemispheres connecting the medial temporal lobes to the hypothalamus. It is formed at first from the output fibers of the hippocampus in the mesial temporal lobe, beneath the floor of the lateral ventricle. It courses along the curve of the corpus callosum forming its body. At the level of the foramen of Monro, the fornix divides and travels inferiorly and posteriorly Frontiers in Aging Neuroscience www.frontiersin.org January 2015 |Volume 7 | Article 1 | 1