Science to practice: translating automated brain MRI volumetry in Alzheimer's disease from research to routine diagnostic use in the work-up of dementia.

The medial temporal lobe (MTL) has longbeen identiﬁed as a key region affectedby neurodegenerative diseases, a commonsource of cognitive decline in the elderly.The importance of the MTL with respectto cognitive decline is furthered by the hip-pocampus’s role in memory formation (1).Impairment of declarative memory is oneof the earliest symptoms of Alzheimer’sdisease (AD), the most common form ofdementia. Early involvement of the MTLin AD is characterized by the presenceof neuroﬁbrillary tangles in the entorhi-nal cortex. As the disease progresses, neu-roﬁbrillary tangles continue to accumu-late and involve the hippocampus, amyg-dala,and ultimately the neocortex (2). Thisgradual progression mirrors the worsen-ing symptoms patients with AD experi-ence. While initial concerns include mem-ory deterioration, patients in later stagesof AD can present with progressive apha-sia (3),visuospatial impairments includingagnosia (4), and apraxia (5).Neuroimaging ﬁndings fromAlzheimer’s patients are consistent withthe pathologic and clinical pattern, sug-gesting potential clinical diagnostic use.Structuralmagneticresonance(MR)imag-ing analysis of patients with mild cognitiveimpairment (MCI) andAD is most notablefor MTL atrophy, including signiﬁcantvolume reduction in the hippocampus,amygdala, parahippocampal gyrus, andentorhinal cortex (6). Structural MRI hasidentiﬁed the entorhinal cortex as the ﬁrstregion to display atrophy in AD. Atrophyin this region is followed by atrophy inthe hippocampus, amygdala, and parahip-pocampal gyrus (7). The next region todisplay atrophy includes the posterior cin-gulate cortex; the atrophy then becomesgeneralized to the temporal neocortex andneocortical association areas (8). Thus,the evolution of neuroimaging ﬁndingson MRI closely mirrors the progression ofneurodegenerative pathology, suggestingthat volume assessment by MRI may be auseful clinical tool for early diagnosis anddisease monitoring.Qualitative visual assessment of tem-poral lobe atrophy on MRI has demon-strated a sensitivity of approximately 80%in distinguishing AD from normal aging,depression, and vascular dementia (9). Arecent study revealed that qualitative visualassessment of MTL atrophy differentiatedpathologically conﬁrmed AD from vas-cular cognitive impairment and demen-tia with Lewy bodies with a sensitivity of91% and speciﬁcity of 94% (10). Atro-phy of the MTL is particularly importantbecause it can be detected earlier thangeneralized whole brain atrophy in AD.Unfortunately, there is signiﬁcant varia-tion in qualitative assessment of MTL atro-phy among radiologists. One investiga-tion of cognitively normal elderly individ-uals revealed a 70% interobserver agree-ment (kappa values of 0.59 and 0.62) inidentifying the presence of MTL atrophyon coronal T1-weighted MRI scans (11).Another study included elderly patientswith dementia and the interobserver agree-ment dropped to 49.7%, with kappa valuesof 0.34 and 0.24 (12). Such poor inter-raterreliability is a major limitation for imple-menting qualitative MTL atrophy assess-ments in a clinical setting on individualpatients.This limitation has been addressed byquantitative volumetric analysis of MTLstructures, which offers improved reliabil-ity and predictive accuracy. A comparisonof qualitative ratings of MTL atrophy andhippocampal volumetry revealed that vol-umetry was more accurate in predictingcognitive decline to AD in MCI patients(100 vs. 78% positive predictive value, 100vs. 87% negative predictive value) (13).A challenge of using any MTL atrophyassessment is that these structures oftendisplay volume loss in cognitively normalpatients, much of which is attributed tothe normal aging process. However, theeffect of AD on MTL atrophy is muchgreater. Even patients with mild AD dis-play signiﬁcantly greater volume loss inMTL structures when compared to cog-nitively normal controls (14). The speciﬁcstructure within the MTL that has demon-strated the most accuracy in predictingthe presence of AD is the hippocampus.A semi-automated tracing-threshold tech-nique for segmenting the hippocampusyielded a sensitivity of 82% and speci-ﬁcity of 80% in identifying patients withAD as compared to controls (14). Serialvolumemeasurementstrackinghippocam-pal change over time show even greatereffects compared to baseline values alone.Rates of hippocampal atrophy were foundto be considerably greater in Alzheimer’spatients (3.98%, 150mm