Fornix integrity and hippocampal volume predict memory decline and progression to Alzheimer's disease

Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Alzheimer's & dementia: the journal of the Alzheimer's Association (Impact Factor: 12.41). 03/2012; 8(2):105-13. DOI: 10.1016/j.jalz.2011.05.2416
Source: PubMed

ABSTRACT The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer's disease (AD). The aims of the present study were to: (1) examine the cross-sectional relationship between fornix diffusion tensor imaging (DTI) measurements (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity, and radial diffusivity), hippocampal volume, and memory performance, and (2) compare fornix DTI measures with hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment to AD dementia.
Twenty-three mild cognitive impairment participants for whom hippocampal volumetry and DTI were conducted at baseline received detailed evaluations at baseline; 3, 6, and 12 months; and 2.5 years. Six participants converted to AD over the follow-up period. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the Mini-Mental State Examination, Clinical Dementia Rating-sum of boxes, and memory z scores; receiver operating characteristic analyses examined the predictive value for conversion to AD.
There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, radial diffusivity, and axial diffusivity) were cross-sectionally correlated with memory z scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression, with likelihood ratios >83, and better than 90% accuracy.
Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually drawn region of interest within the fornix shows promise comparable with hippocampal volume as a predictive biomarker of progression, and this finding warrants replication in a larger study.

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    • "No correlation between FA and episodic memory; ↓FA with age Mielke et al., 2012 23 aMCI [75. "
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    ABSTRACT: The fornix is a part of the limbic system and constitutes the major efferent and afferent white matter tracts from the hippocampi. The underdevelopment of or injuries to the fornix are strongly associated with memory deficits. Its role in memory impairments was suggested long ago with cases of surgical forniceal transections. However, recent advances in brain imaging techniques, such as diffusion tensor imaging have revealed that macrostructural and microstructural abnormalities of the fornix correlated highly with declarative and episodic memory performance. This structure appears to provide a robust and early imaging predictor for memory deficits not only in neurodegenerative and neuroinflammatory diseases, such as Alzheimer’s disease and multiple sclerosis, but also in schizophrenia and psychiatric disorders, and during neurodevelopment and “typical” aging. The objective of the manuscript is to present a systematic review regarding published brain imaging research on the fornix, including the development of its tracts, its role in various neurological diseases, and its relationship to neurocognitive performance in human studies.
    Frontiers in Aging Neuroscience 01/2015; DOI:10.3389/fnagi.2014.00343 · 4.00 Impact Factor
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    • "Longitudinal observation of cognitively normal elderly or individuals with amnestic MCI indicated that reduced fornix FA predicts conversion from normal cognition to amnestic MCI and from amnestic MCI to AD (Oishi et al., 2012). Moreover, lower fornix FA predicted later cognitive decline and hippocampal atrophy (Mielke et al., 2012). These studies suggest that volume loss and FA reduction of the fornix is one of the earliest anatomical changes in AD that happens before clinical manifestations. "
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    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.
    Frontiers in Aging Neuroscience 09/2014; 6:241. DOI:10.3389/fnagi.2014.00241 · 4.00 Impact Factor
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    • "Patients with MCI are also likely to have different underlying pathology, as for example some subjects have AD pathology in the form of neurofibrillary tangles of hyperphosphorylated tau (p-tau) and beta amyloid (Ab) neuritic plaques [6], which may be responsible for the MCI, whereas others may not have AD pathology, and their MCI is due to other pathologies [5]. Therefore, patients with MCI do not comprise one clinical entity, which limits the predictive validity of MCI imaging abnormalities as a predementia syndrome and/or as biomarkers of AD pathology [7] [8] [9] [10]. Another limiting factor in the study of patients with MCI and AD is the influence of brain atrophy on the sensitivity of dMRI to microstructural changes. "
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    ABSTRACT: Background Brain atrophy in subjects with mild cognitive impairment (MCI) introduces partial volume effects, limiting the sensitivity of diffusion tensor imaging to white matter microstructural degeneration. Appropriate correction isolates microstructural effects in MCI that might be precursors of Alzheimer's disease (AD). Methods Forty-eight participants (18 MCI, 15 AD, and 15 healthy controls) had magnetic resonance imaging scans and clinical evaluations at baseline and follow-up after 36 months. Ten MCI subjects were diagnosed with AD at follow-up and eight remained MCI. Free-water (FW) corrected measures on the white matter skeleton were compared between groups. Results FW corrected radial diffusivity, but not uncorrected radial diffusivity, was increased across the brain of the converted group compared with the nonconverted group (P < .05). The extent of increases was similar to that found comparing AD with controls. Conclusion Partial volume elimination reveals microstructural alterations preceding dementia. These alterations may prove to be an effective and feasible early biomarker of AD.
    Alzheimer's and Dementia 07/2014; 11(5). DOI:10.1016/j.jalz.2014.04.518 · 12.41 Impact Factor
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