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Neuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia

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Neuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia ORIGINAL CONTRIBUTION Neuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia Gregory A. Jicha, MD, PhD; Joseph E. Parisi, MD; Dennis W. Dickson, MD; Kris Johnson, RN; Ruth Cha, MS; Robert J. Ivnik, PhD; Eric G. Tangalos, MD; Bradley F. Boeve, MD; David S. Knopman, MD; Heiko Braak, MD; Ronald C. Petersen, PhD, MD Background: The pathologic outcome of patients di- pathologic abnormalities. All of the cases were found to agnosed with mild cognitive impairment (MCI) follow- have sufficient pathologic abnormalities in mesial tem- ing progression to dementia is poorly understood. poral lobe structures to account for their amnestic symp- toms regardless of the cause. Most subjects were found Objective: To determine the pathologic substrates of to have secondary contributing pathologic abnormali- dementia in cases with prior diagnosis of amnestic MCI. ties in addition to primary pathologic diagnoses. No sig- nificant differences between subjects with and without Design and Setting: Community-based cohort. neuropathologically proven AD were detected in demo- graphic variables, apolipoprotein E genotype, or cogni- Patients: Thirty-four subjects followed up prospec- tive test measures at onset of MCI, onset of dementia, or tively as part of a community-based study who were di- last clinical evaluation. agnosed with amnestic MCI, progressed to clinical de- mentia, and underwent subsequent postmortem brain analysis. Conclusions: The neuropathologic outcome of amnes- tic MCI following progression to dementia is heterog- Main Outcome Measures: Neuropathologic analy- eneous, and it includes AD at a high frequency. Com- ses resulted in assignment of a primary pathologic diag- plex neuropathologic findings including 2 or more distinct nosis and included staging of Alzheimer pathologic ab- pathologic entities contributing to dementia may be com- normalities and identification of contributing vascular mon in community-based cohorts. Neither demo- disease, Lewy bodies, and argyrophilic grains. graphic variables nor cognitive measures had predictive value in determining which patients diagnosed with MCI Results: Although the majority of subjects progressed will develop the neuropathologic features of AD. both clinically and pathologically to Alzheimer disease (AD), 10 (29%) of them developed non-AD primary Arch Neurol. 2006;63:674-681 HE CONCEPT OF MILD COG- changes, including both neurofibrillary nitive impairment (MCI) tangles and neuritic plaques. Not all cases has become a focus for of MCI show these changes, suggesting study of the evolution of that pathologic heterogeneity exists.9-14 Alzheimer disease (AD).1-3 Cases of MCI with neuropathologic find- TEarly identification of patients destined to ings that range from a complete absence of develop AD will allow for earlier inter- significant AD pathologic abnormalities to vention in an attempt to slow or halt the sufficient pathologic abnormalities to war- progression of disease. Clinically, sub- rant a firm neuropathologic diagnosis of AD types of MCI have been recognized, with the amnestic subtype (aMCI) having an el- For editorial comment evated risk of progressing to clinical AD.1-4 see also page 647 It is unclear whether the clinical diagno- sis of aMCI predicts progression to patho- have been reported. Other cases with pre- logic AD. Pathologic confirmation of AD dominant neuropathologic findings con- in these cases is important to validate these sistent with the diagnoses of vascular de- clinical observations and to justify our use mentia, dementia with Lewy bodies, and of treatments for AD in aMCI.5-8 argyrophilic grain disease (AGD) have been Several small studies9-14 focusing on reported.9-14 The presence of neurofibril- postmortem neuropathologic evaluation lary tangles and neuritic plaques in cogni- Author Affiliations are listed at of MCI cases have concluded that many tively normal individuals further compli- the end of this article. of these patients exhibit typical AD cates the neuropathologic analysis, making (REPRINTED) ARCH NEUROL / VOL 63, MAY 2006 WWW.ARCHNEUROL.COM 674 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 the assessment of AD pathologic abnormalities quantita- Rating Scale.30 Apolipoprotein E (APOE) genotyping was per- tive rather than absolute.10,11,14-21 Detailed neuropatho- formed on blood samples according to established protocols.31 logic analyses need to be performed to validate the con- clusion that aMCI represents early AD pathologically. AUTOPSY PROCEDURE Large-scale neuropathologic studies of aMCI are lacking owing to limited brain tissue availability. The brains were processed in accordance with the recommen- An alternative strategy addressing the issue of clinico- dations of the Consortium to Establish a Registry for Alzhei- pathologic correlation in aMCI includes neuropatho- mer Disease (CERAD).32 Brain tissue from the left hemisphere logic analysis of patients with aMCI who are prospec- was fixed in 10% to 15% buffered formalin for 7 to 10 days. tively followed up and have converted to dementia. Brain areas that were sampled included superior and middle These patients would be expected to show full develop- frontal gyri (plane just anterior to temporal tip), superior and middle temporal gyri (plane of mammillary body), inferior pa- ment of the neuropathologic features underlying the rietal lobule (plane 1 cm behind posterior pole of splenium), cognitive impairment. This would facilitate the quantita- calcarine (primary visual) cortex, anterior cingulate (plane of tive assessment of AD pathologic abnormalities as well anterior commissure), hippocampus with adjacent inferior tem- as allow for higher sensitivity in detecting possible con- poral cortex (level of the lateral geniculate body), amygdala and tributing pathologic abnormalities. Currently, such stud- entorhinal cortex (level of the mammillary bodies), nucleus ba- ies are lacking in the literature. Our study was under- salis, basal ganglia, cerebellum, thalamus with subthalamic taken to clarify unanswered questions and concerns nucleus, midbrain (with substantia nigra), pons (with locus co- related to the pathologic outcome of subjects progress- eruleus), and cerebellum as well as representative sections of ing from aMCI to dementia. any lesions noted grossly. Following routine processing in par- affin and cutting, sections were stained with hematoxylin- eosin. Selected sections were stained with modified Biel- METHODS schowsky, Luxol fast blue and periodic acid–Schiff, and thioflavin-S and immunostained for ␤-amyloid (clone 6F/3D; Novocastra, Newcastle upon Tyne, England), phosphorylated CLINICAL EVALUATION tau (clone AT8; Endogen, Woburn, Mass), 4-repeat tau (ET3, recognizing exon 10 of the tau protein specifically33; a gift from We identified all of the subjects enrolled in the Mayo Alzhei- Peter Davies, PhD, Albert Einstein College of Medicine, Bronx, mer Disease Patient Registry community-based cohort who were NY), ␣-synuclein (clone LB509; Zymed Laboratories, San Fran- diagnosed with aMCI from 1993 to 2001, were prospectively cisco, Calif), ubiquitin (polyclonal; Dako, Glostrup, Den- followed up, converted to dementia, and underwent neuro- ␣ ␤ 4,22 mark), neurofilament protein (clone 2F11; Dako), - - pathologic examination. Nonamnestic forms of MCI were crystallin (polyclonal; Chemicon, Temecula, Calif), and glial excluded from the present analysis. Neurologic testing, neu- fibrillary acid protein (polyclonal; Dako). ropsychologic examinations, neuroimaging, and laboratory analyses were performed at entry into the Mayo Alzheimer Dis- ease Patient Registry and then annually or biennially during NEUROPATHOLOGIC ASSESSMENT the follow-up period. Clinical diagnosis was determined by a consensus committee comprising neurologists, neuropsycholo- Neuropathologic evaluation included classification according gists, a neuropsychiatrist, nurse specialists, and a geriatrician to criteria by Khachaturian,34 CERAD,32 National Institute on following review of all of the available data. Inclusion criteria Aging and Reagan Institute Working Group on Diagnostic for the present analysis included a prospectively determined Criteria for the Neuropathological Assessment of Alzheimer’s diagnosis of aMCI on at least 1 consensus evaluation,3 subse- Disease,35 and Braak staging of neurofibrillary degeneration.36 quent progression to clinical dementia, and neuropathologic Clinical information was available to the neuropathologist to evaluation. These studies have been approved by the Mayo In- assist in the final determination of CERAD assignment.32 Size, stitutional Review Board, Rochester, Minn. location, and histologic age of large and small vessel infarcts Clinical criteria for the diagnosis of aMCI included a memory were recorded. Acute or subacute infarcts were not considered problem, intact general cognitive functions and activities of daily clinically significant with respect to chronic antemortem neu- living, evidence of cognitive dysfunction with predominant rologic features. Microvascular disease, microinfarcts, amyloid memory involvement on formal testing, and absence of de- angiopathy, and intracranial atherosclerosis were assessed mentia.3 Specific neuropsychologic cutoff scores were not used; using semiquantitative grading scales according to the rather, the subjects were diagnosed with aMCI if their memory National Alzheimer Coordinating Center protocol.37 The pres- performance was impaired
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