Heterogeneity in mild cognitive impairment: Differences in neuropsychological profile and associated white matter lesion pathology

“Ward’s minimum variance cluster analysis (Kaufman & Rousseau, 1990 ; Ward, 1963 ) was performed to identify patterns of impairment and assess for the presence of groups based on neuropsychological performance.”

“Finally, we employed the 15-item Geriatric Depression Scale (GDS; Yesavage et al., 1983 ), a brief measure widely used to assess depression in older adult samples.”

“…the concept of Mild Cognitive Impairment (MCI), a clinical construct thought to represent a transitional state between normal aging and dementia (Petersen et al., 1999 ; 2001 ), it became apparent that the original defi nition requiring a strict memory impairment was limiting and restrictive.”

“All neuropsychological scores were standardized with a z-score transformation on the basis of the CERAD or other normative data of the neuropsychological tests (Welsh et al., 1994 ).”

“E-mail: ldelano@ucsd.edu a whole (Davis & Rockwood, 2004 ; De Carli, 2003 ; Kavé & Heinik, 2004 ; Petersen & Morris, 2005 ).”

“…have demonstrated a link between WML pathology and cognitive impairment across the aging spectrum (Delano-Wood et al., 2008 ; Garrett et al., 2004 ; Gunning-Dixon & Raz, 2000 ; Inzitari, 2000 ), and important distinctions have been made between the two WML subtypes [deep white matter lesions…”

“In contrast to PVL, studies have suggested that DWML are related to underlying vascular risk and the presence of vascular disease (Fernando et al., 2006 ; Thomas et al., 2002 ).”

“…to Establish a Registry for Alzheimer’s Disease (CERAD; Welsh, Butters, & Mohs, 1994 ), a reliable, well-standardized neuropsychological battery often used to detect impairment in mildly impaired populations (Chandler et al., 2005 ; Fillenbaum et al., 2008 ; Schmidtke & Hermeneit, 2007 ).”

“…to Establish a Registry for Alzheimer’s Disease (CERAD; Welsh, Butters, & Mohs, 1994 ), a reliable, well-standardized neuropsychological battery often used to detect impairment in mildly impaired populations (Chandler et al., 2005 ; Fillenbaum et al., 2008 ; Schmidtke & Hermeneit, 2007 ).”

“…for their inability to adequately capture the range of variability often observed in patients with milder forms of cognitive impairment, and it was argued that MCI may not represent a separate and homogeneous clinical syndrome in terms of its neuropsychological profi le (Ritchie & Touchon, 2000 ).”

“In contrast to PVL, studies have suggested that DWML are related to underlying vascular risk and the presence of vascular disease (Fernando et al., 2006 ; Thomas et al., 2002 ).”

“…there is a vast literature suggesting that episodic memory impairment is greater than naming defi cits in early AD (Bondi et al., 1994 , 1999 ; Collie & Maruff, 2000 ; Rubin et al., 1998 ; Testa et al., 2004 ), and it is important to note that, given the cross-sectional nature of this study,…”

“…suggesting that episodic memory impairment is greater than naming defi cits in early AD (Bondi et al., 1994 , 1999 ; Collie & Maruff, 2000 ; Rubin et al., 1998 ; Testa et al., 2004 ), and it is important to note that, given the cross-sectional nature of this study, individuals with…”

“…each region in cubic centimeters was calculated by multiplying the summed pixel cross-sectional area in square centimeters by slice thickness in centimeters, and WML volumes were normalized to the intracranial cavity (ICC) volume for each participant (Delano-Wood et al., 2008 ; Raz et al., 2003 ).”

“…MCI (Petersen et al., 1999 ) and is also one of the major MCI subtypes in Petersen’s MCI classifi cation scheme; other researchers have also found this subgroup to represent a sizable portion of their respective MCI samples (Bombois et al., 2007 ; Loewenstein et al., 2006 ; Storandt et al., 2006 ).”

“However, there is a vast literature suggesting that episodic memory impairment is greater than naming defi cits in early AD (Bondi et al., 1994 , 1999 ; Collie & Maruff, 2000 ; Rubin et al., 1998 ; Testa et al., 2004 ), and it is important to note that, given the cross-sectional nature of this…”

“Conversely, the Memory/ Language subgroup appears to be consistent with what might be expected from a cortical, degenerative etiology such as AD, with prominent decline in episodic and semantic memory functions (Mickes et al., 2007 ; Powell et al., 2006 ; Salmon et al., 2002 ).”

“In regard to the latter, much attention has been focused on the contribution of white matter lesion (WML) pathology to cognitive, behavioral, and motor decline seen in dementia and, recently, in more subtle neuropsychological impairment (Garrett et al., 2004 ; Stephens et al., 2004 ).”

“Indeed, PVL are commonly observed in nondemented, healthy older adults (Shinkawa et al., 1995 ; Simpson et al., 2007 ), and some studies have suggested that WML located along the borders of the ventricles refl ect primarily breakdown of the ependymal lining and are therefore more common and less…”

“Given associations reported in the literature between DWML, microangiopathy, and hypoperfusion (Tomimoto et al., 2003 ), it may be that early manifestations of vascular cognitive impairment (VCI) associated with DWML lead to dysexecutive defi cits in cognition, thought to be dependent on the…”

“Using the methodology of Libon et al. ( 2007) , composite scores were computed for memory (CERAD Word List Delayed Free Recall and Recognition; r = .38, p = .01), as well as executive functioning (Trails B and the Stroop ColorWord Test Interference score; r = .69, p < .001) prior to statistical…”

“Although no reliable cut-off for defi ning impairment in MCI has yet been defi ned, Busse et al. ( 2003 , 2006) have shown that a more liberal cut-off (i.e., 1 SD below the mean) is optimal, because it offers higher sensitivity and predictive power than the traditional cut-off of 1.5 SD.”

“Indeed, PVL are commonly observed in nondemented, healthy older adults (Shinkawa et al., 1995 ; Simpson et al., 2007 ), and some studies have suggested that WML located along the borders of the ventricles refl ect primarily breakdown of the ependymal lining and are therefore more common and less…”

“…have investigated differences across MCI subgroups diagnosed clinically using Petersen’s classifi cation criteria (e.g., Busse, Bischkopf, Riedel-Heller, & Angermeyer, 2003 ; Busse, Hensel, Guhne, Angermeyer, & Riedel-Heller, 2006 ; Storandt, Grant, Miller, & Morris, 2006 ; Zanetti et al., 2006 ).”

“In regard to the latter, much attention has been focused on the contribution of white matter lesion (WML) pathology to cognitive, behavioral, and motor decline seen in dementia and, recently, in more subtle neuropsychological impairment (Garrett et al., 2004 ; Stephens et al., 2004 ).”

“…to Establish a Registry for Alzheimer’s Disease (CERAD; Welsh, Butters, & Mohs, 1994 ), a reliable, well-standardized neuropsychological battery often used to detect impairment in mildly impaired populations (Chandler et al., 2005 ; Fillenbaum et al., 2008 ; Schmidtke & Hermeneit, 2007 ).”

“DWML tend to predominate in the dorsolateral prefrontal cortex, and thus, concomitant cognitive defi cits may be the result of small vessel disease disrupting frontal-subcortical pathways (Vataja et al., 2003 ).”

“…each region in cubic centimeters was calculated by multiplying the summed pixel cross-sectional area in square centimeters by slice thickness in centimeters, and WML volumes were normalized to the intracranial cavity (ICC) volume for each participant (Delano-Wood et al., 2008 ; Raz et al., 2003 ).”

“E-mail: ldelano@ucsd.edu a whole (Davis & Rockwood, 2004 ; De Carli, 2003 ; Kavé & Heinik, 2004 ; Petersen & Morris, 2005 ).”

“Thus, because MCI likely represents a heterogeneous group of individuals with different pathologies and neuro- psychological profi les (Bowler, 2002 ; Rockwood et al., 2003 ), the current study was designed to assess: (1) whether distinct groups could be empirically gleaned from a clinical…”

“Conversely, the Memory/ Language subgroup appears to be consistent with what might be expected from a cortical, degenerative etiology such as AD, with prominent decline in episodic and semantic memory functions (Mickes et al., 2007 ; Powell et al., 2006 ; Salmon et al., 2002 ).”

“…MCI (Petersen et al., 1999 ) and is also one of the major MCI subtypes in Petersen’s MCI classifi cation scheme; other researchers have also found this subgroup to represent a sizable portion of their respective MCI samples (Bombois et al., 2007 ; Loewenstein et al., 2006 ; Storandt et al., 2006 ).”

“Our results are consistent with other recent studies that have shown that PVL, but not DWML, may represent an agerelated phenomenon (Lazarus et al., 2005 ; Prins et al., 2004 ).”

“…MCI (Petersen et al., 1999 ) and is also one of the major MCI subtypes in Petersen’s MCI classifi cation scheme; other researchers have also found this subgroup to represent a sizable portion of their respective MCI samples (Bombois et al., 2007 ; Loewenstein et al., 2006 ; Storandt et al., 2006 ).”

“…episodic memory impairment is greater than naming defi cits in early AD (Bondi et al., 1994 , 1999 ; Collie & Maruff, 2000 ; Rubin et al., 1998 ; Testa et al., 2004 ), and it is important to note that, given the cross-sectional nature of this study, individuals with differing etiologies…”

“Conversely, the Memory/ Language subgroup appears to be consistent with what might be expected from a cortical, degenerative etiology such as AD, with prominent decline in episodic and semantic memory functions (Mickes et al., 2007 ; Powell et al., 2006 ; Salmon et al., 2002 ).”

“E-mail: ldelano@ucsd.edu a whole (Davis & Rockwood, 2004 ; De Carli, 2003 ; Kavé & Heinik, 2004 ; Petersen & Morris, 2005 ).”

“…, and mixed MCI subtypes MCI had been determined using the actuarial neuropsychological method, consistent with the of Delano-Wood et al. [27] and Libon et al. [ In contrast, when MCI had been determined the conventional “one test” MCI criteria, Clark sub-types, and a third…”

“A hierarchical cluster analysis was performed on the z scores using Ward’s method, consistent with previous MCI studies [4,5].”

“…demonstrate deficits primarily in one area of cognitive ability (e.g., memory, executive functioning, language), while others demonstrate impairments in multiple cognitive domains (Bondi et al., 2014; Clark et al., 2013; Delano-Wood et al., 2009; Edmonds et al., 2014; Libon et al., 2010).”

“: +1 858 552 8585/Ext. 2809; Fax: +1 858 642 1218; E-mail: mbondi@ucsd.edu.”