0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Strategic Subcortical Hyperintensities in Cholinergic Pathways and Executive Function Decline in Treated Alzheimer Patients FREE

Pearl Behl, PhD; Christian Bocti, MD; Richard H. Swartz, MD, PhD; FuQiang Gao, MD; Demetrios J. Sahlas, MD; Krista L. Lanctot, PhD; David L. Streiner, PhD; Sandra E. Black, MD
[+] Author Affiliations

Author Affiliations: Division of Neurology, Department of Medicine (Drs Swartz, Gao, Sahlas, and Black) and Department of Psychiatry (Drs Lanctot and Streiner), Sunnybrook Health Sciences Centre, and Institute of Medical Science, University of Toronto (Drs Behl, Swartz, Sahlas, Lanctot, Streiner, and Black), Toronto, Ontario; Division of Neurology, Department of Medicine, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, Quebec (Dr Bocti); and Kunin-Lunenfeld Applied Research Unit, Baycrest, Toronto (Dr Streiner).


Arch Neurol. 2007;64(2):266-272. doi:10.1001/archneur.64.2.266.
Text Size: A A A
Published online

Objective  To investigate changes in cognition, function, and behavior after 1 year in patients with Alzheimer disease being treated with cholinesterase inhibitors, in relation to the presence or absence of subcortical hyperintensities involving the cholinergic pathways.

Design  One-year prospective cohort study.

Setting  Memory Clinic, Sunnybrook Health Sciences Centre, University of Toronto.

Patients  Ninety patients with possible/probable Alzheimer disease who were being treated with cholinesterase inhibitors at baseline.

Interventions  Yearly standardized neuropsychological testing and brain magnetic resonance imaging (MRI). The Cholinergic Pathways Hyperintensities Scale (CHIPS) was applied to baseline MRIs to rate the severity of subcortical hyperintensities in cholinergic pathways. The consensus-derived Age-Related White Matter Changes (ARWMC) Rating Scale was used as a general measure of white matter disease burden.

Main Outcome Measures  Tests of global cognition, function, and behavior and specific cognitive and functional domains.

Results  Patients in the low CHIPS group were equivalent to those in the high CHIPS group with regard to baseline demographic characteristics, cognitive severity, and vascular risk factors. After covarying age and education, no differences were found after 1 year in overall cognition, function, and behavior or on memory, language, and visuospatial tasks. Patients in the high CHIPS group showed improvement on executive function and working memory tasks compared with those in the low CHIPS group. For the ARWMC scale, groups with and without white matter abnormalities were equivalent on baseline demographics and in cognitive, functional, and behavioral outcomes.

Conclusion  Cerebrovascular compromise of the cholinergic pathways may be a factor that contributes more selectively than does total white matter lesion burden to response to cholinergic therapy in Alzheimer disease, particularly on frontal/executive tasks.

Figures in this Article

Cholinesterase inhibitors (CHEIs) provide symptomatic benefits in mild to moderate Alzheimer disease (AD).1 Executive function tests may be most sensitive to cholinergic treatment.2 Cells in the basal forebrain are the source of cholinergic output to the hippocampus and the cerebral cortex. The trajectories of the unmyelinated cholinergic fibers from the nucleus basalis of Meynert to their synaptic endings in the neocortex have been traced immunohistochemically in the human brain. These fibers consist of 2 discrete bundles traveling medially through the cingulum and laterally through the external capsule, then fanning out to all neocortical areas.3 Strategic ischemic lesions in these pathways, in the absence of AD pathology, have been demonstrated in a young patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)4 and vascular dementia of Binswanger type.5

Subcortical hyperintensities (SHs) usually represent small-vessel ischemic disease, including incomplete or complete infarction. Strategically located SHs in cholinergic pathways are associated with greater relative deficits in executive function in patients with AD who also have cerebrovascular disease and vascular cognitive impairment.6,7

Given this potentially more specific cognitive impact and results from large-scale clinical trials in vascular dementia8 and mixed dementia9 suggesting benefits with CHEI treatment, we investigated changes in cognition, function, and behavior after 1 year in treated patients with AD, in relation to the presence or absence of SHs in the cholinergic pathway. We hypothesized that patients with cholinergic pathway injury from vascular disease matched in cognitive status may have less relative AD pathology and that the partial injury caused by vascular disease in the cholinergic pathways might be more amenable to treatment with CHEIs. Thus, we predicted that treated patients with more severe cholinergic pathways involvement (high Cholinergic Pathways Hyperintensities Scale [CHIPS] score) would show less decline compared with patients with no or minimal cholinergic tract involvement (low CHIPS score), especially on frontal/executive tasks.

Participants were recruited from the Sunnybrook Dementia Study, a longitudinal imaging observational study of AD and other dementias, if they had sufficient English fluency, visual and auditory acuity to complete neuropsychological testing, and baseline magnetic resonance imaging (MRI) and neuropsychological testing less than 12 weeks apart. The study sample was derived from 183 patients of the Memory Clinic at the Sunnybrook Health Sciences Centre, University of Toronto, who met criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association for probable (n = 180) or possible (n = 3) AD, if cerebrovascular disease was the only other contributing pathology. Those with lacunar infarcts were excluded (Figure 1).

Place holder to copy figure label and caption
Figure 1.

The process of arriving at the 90 study patients with Alzheimer disease (AD). MMSE indicates Mini-Mental State Examination.

Graphic Jump Location

To be included, patients underwent standardized assessments at baseline and at annual follow-up visits. The baseline assessments occurred within 1 month before or after the start of therapy with donepezil hydrochloride or 2 months after the start of therapy with rivastigmine tartrate or galantamine hydrobromide. All patients were receiving treatment throughout the study, titrated to the maximum tolerated dose. All achieved the therapeutic range. The burden of cerebrovascular risk factors and comorbid disease was documented for each patient.10

Although patients had SHs on their MRIs, none had severe enough white matter disease to meet the imaging criteria established by the National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neuroscience for possible or probable vascular dementia.11

COGNITIVE ASSESSMENT

The cognitive assessment included the Mattis Dementia Rating Scale (DRS)12 as a test of general cognition; California Verbal Learning Test (CVLT)13 to assess learning and memory; Boston Naming Test14 as a language index; backward digit span test15 to measure working memory; Controlled Word Association Test using the letters F, A, and S16 as a test of phonemic fluency; Wisconsin Card Sorting Test (WCST)17; and Trail-Making Test A18 to sample executive functions. The Trail-Making Test B18 could not be used because several patients were unable to complete the test. The Rey-Osterrieth Complex Figure Test19 was used to probe visuospatial attention and visuoconstructive skill. The Disability Assessment for Dementia Scale (DAD) total score and separate scores for instrumental and basic activities of daily living were used to assess functional capacity.20 Behavioral symptoms were assessed on the Behavioral Pathology in Alzheimer Disease Scale (BEHAVE-AD).21

STRUCTURAL MRI

All brain images were acquired using a 1.5-T MRI system (Signa; General Electric Medical Systems, Milwaukee, Wis). A 12-minute, standard interleaved spin-echo acquisition (T2 and proton density [PD]) was performed in the axial plane, covering the whole brain and using 3-mm-thick sections (echo time, 30.80 milliseconds; revolution time, 3000 milliseconds; number of excitations, 0.5; field of view, 20 × 20 cm; and matrix, 256 × 192 pixels), as well as 3-dimensional T1-weighted imaging with 1-mm-thick sections (echo time, 5.35 milliseconds; flip angle, 35°; number of excitations, 1; field of view, 20 × 20 cm; and matrix, 256 × 192 pixels).

Cholinergic Pathways Hyperintensities Scale

Axial sections from T2- and PD-weighted MRIs were used to rate SHs in cholinergic pathways using a recently developed visual rating scale7 (Figure 2 and Figure 3).

Place holder to copy figure label and caption
Figure 2.

Example of mild Cholinergic Pathways Hyperintensities Scale score as illustrated on T2-weighted magnetic resonance images. A, Low external capsule: anterior (right = 0, left = 0) and posterior (right = 0, left = 0). Add scores and multiply by 4 for a subtotal of 0. B, High external capsule: anterior (right = 0, left = 0), posterior (right = 0, left = 0), and cingulate (right = 0, left = 0). Add scores and multiply by 3 for a subtotal of 0. C, Corona radiata: anterior (right = 1, left = 0), posterior (right = 0, left = 1), and cingulate (right = 0, left = 0). Add scores and multiply by 2 for a subtotal of 4. D, Centrum semiovale: anterior (right = 0, left = 0), and posterior (right = 0, left = 0). Add scores and multiply by 1 for a subtotal of 0. The total score for all sections is 4. Arrow shows subcortical hyperintensity in a cholinergic pathway. E, Immunohistochemical tracings of the cholinergic pathways from Selden et al3 (reprinted with permission from Oxford University Press), with levels for the selected sections (A-D).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Example of severe Cholinergic Pathways Hyperintensities Scale score as illustrated on T2-weighted magnetic resonance images. A, Low external capsule: anterior (right = 2, left = 0) and posterior (right = 0, left = 0). Add scores and multiply by 4 for a subtotal of 8. B, High external capsule: anterior (right = 1, left = 0), posterior (right = 2, left = 0), and cingulate (right = 0, left = 0). Add scores and multiply by 3 for a subtotal of 9. C, Corona radiata: anterior (right = 2, left = 2), posterior (right = 2, left = 2), and cingulate (right = 0, left = 0). Add scores and multiply by 2 for a subtotal of 16. D, Centrum semiovale: anterior (right = 1, left = 1) and posterior (right = 2, left = 1). Add scores and multiply by 1 for a subtotal of 5. The total score for all sections is 38. Arrows show subcortical hyperintensities in cholinergic pathways. E, Immunohistochemical tracings of the cholinergic pathways from Selden et al3 (reprinted with permission from Oxford University Press), with levels for the selected sections (A-D).

Graphic Jump Location
Age-Related White Matter Changes Rating Scale

Axial sections from either T2- or PD-weighted MRIs were used to evaluate the degree of white matter changes visible in the baseline images.22 The images were assessed in random order by 2 experienced raters (C.B. and F.G.) blind to clinical and demographic information.

STATISTICAL ANALYSES

Groups were separated into low CHIPS (score, <4) and high CHIPS (score, ≥4) groups by using a median split (median score, 4). The median split supported the clinical impression that a total score of 0, 1, 2, or 3 represented few hyperintensities with minimal pathway involvement. Independent-samples t tests were performed for age, education, duration of illness, and baseline Mini-Mental State Examination (MMSE) score. We performed χ2 analyses, including the Fisher Exact test, for sex, number of vascular risk factors, and cerebrovascular, cardiac, and peripheral vascular disease. The P values were corrected for multiple comparisons by using the Holm correction.23

Groups were separated into patients with and without lesions in the subcortical gray and cerebral white matter on the basis of ratings of the Age-Related White Matter Changes Rating Scale (ARWMC), also using a median split (median rating, 3). We performed independent-samples t tests for the means of continuous variables and χ2 analyses, including the Fisher Exact test, for categorical variables (as described in the preceding paragraph). Again, the P values were corrected for multiple comparisons by using the Holm correction.

Spearman rank correlation coefficients were used to compute associations between the 2 rating scales. Two raters (C.B. and F.G.) independently assessed a validation sample while blinded to clinical information to derive intraclass correlation coefficients as a measure of interrater and intrarater reliability.7 The CHIPS rating scale showed excellent agreement for both interrater (intraclass correlation coefficient, 0.97) and intrarater (intraclass correlation coefficient, 0.94) reliability.7

Separate repeated measures multivariate analyses of covariance (MANCOVAs) were performed for CHIPS and ARWMC scores to compare the groups on cognitive, functional, and behavioral measures, after covarying age and education.

The 90 patients followed up in this study were comparable on baseline demographic characteristics of age, education, and MMSE score (mean score, 23.5) to those lost to follow-up (mean MMSE score, 18.1) and to those unwilling to continue the longitudinal study (mean MMSE score, 23.2). In addition, we found no significant difference between the 3 groups with regard to MMSE score (Figure 1).

Because most of this sample was recruited when donepezil was the only CHEI available, most (approximately 80%) were receiving donepezil and the rest were receiving rivastigmine or galantamine in equal proportions. No patients discontinued the study because of adverse events. When adverse effects did occur, patients were successfully switched to another CHEI right away.

CHIPS MEASUREMENTS

Forty-two patients had no or minimal cholinergic pathway involvement and constituted the low CHIPS group. CHIPS involvement was identified in 48 patients, who constituted the high CHIPS group (range, 0-48 white matter changes). The low CHIPS group was not significantly different from the high CHIPS group on baseline demographic characteristics, cognitive severity, vascular risk factors, or the presence of cerebrovascular, cardiac, and peripheral vascular disease after correcting for multiple comparisons (Table 1). The groups did not differ significantly on baseline neuropsychological performance after correcting for multiple comparisons (Table 2).

Table Graphic Jump LocationTable 1. Demographic Characteristics by CHIPS Score*
Table Graphic Jump LocationTable 2. Baseline Neuropsychological Performance in the CHIPS Groups*

There was a significant group × time interaction on the overall MANCOVA (F1,73 = 4.4; P = .04) after covarying age and education. The repeated measures MANCOVA results indicated no significant differences over time in scores on the MMSE, overall DRS, Boston Naming Test, CVLT (acquisition after 5 trials, long delay free recall), Trail-Making Test A, and Rey-Osterrieth Complex Figure Test. Furthermore, no difference was seen in functional ability or behavior between the 2 groups after 1 year.

Compared with the low CHIPS group, the high CHIPS group showed a significant increase on the number correct on the WCST (F1,73 = 9.5; P = .002) and fewer perseverations to previous response after 1 year (F1,73 = 8.5; P = .005). The high CHIPS group also showed less decline on the backward digit span test (F1,73 = 6.9; P = .01) (Table 3).

Table Graphic Jump LocationTable 3. Average Change in Neuropsychological and Neurobehavioral Test Scores in the CHIPS Groups in 1 Year
ARWMC MEASUREMENTS

Forty-eight patients had no or minimal white matter changes, whereas 42 patients had more severe changes (range, 0-19 white matter changes). The group with no or minimal changes did not differ significantly from the more severe group on baseline demographic characteristics, cognitive severity, and vascular risk factors after correcting for multiple comparisons (Table 4). There were also no differences in the baseline neuropsychological performance.

Table Graphic Jump LocationTable 4. Demographic Characteristics by ARWMC Score*

The MANCOVA results were not significant for changes in cognitive performance on the ARWMC after 1 year, taking into account age and education (F1,73 = 1.02; P = .32). The correlation between the CHIPS and ARWMC scores was high (Spearman ρ = 0.78; P<.001).

Treated AD patients with a high CHIPS score decline less after 1 year on executive and working memory tasks believed to implicate left dorsolateral prefrontal function, whereas no differences emerged in overall white matter disease burden, even though ARWMC scores correlated with CHIPS scores.

Previous studies6,24 demonstrate that estimates of total white matter lesion volume do not correlate with global cognitive impairment or memory impairment; rather, white matter lesion burden is thought to contribute primarily to the dysexecutive syndrome. Some evidence suggests that SHs within the frontal white matter tracts are especially detrimental relative to other locations25 and may relate particularly to dorsolateral prefrontal function.26 Although cholinergic tracts were not specifically examined in those studies, the presence of SHs in cholinergic pathways correlated with poorer scores on executive function tasks in a preliminary study of patients with AD and vascular cognitive impairment.6

In our methodology study7 using CHIPS, strategically located SHs in cholinergic pathways correlated with performance on the DRS, an executively loaded cognitive battery. The general white matter disease burden scale, however, did not correlate with cognitive performance, although it was highly correlated with the CHIPS score. This suggested that strategic compromise of the cholinergic pathways may more specifically relate to executive functions.

Eleven patients overlapped between the current study and our methodology study.7 In the present study, although there was a trend toward a significant correlation, the correlation may not have reached significance because of the smaller range of CHIPS scores (0-48). The CHIPS scores ranged from 0 to 70 in the previous study.7

The risk of clinical expression of dementia increases when the burden of neuropathologic changes exceeds a certain threshold, but this can be modified by various genetic and environmental factors. In particular, the risk can be amplified by the presence of vascular pathology.27 This finding has been corroborated in other studies, which also suggested that white matter lesions can influence the clinical expression of AD pathology in an additive or synergistic manner.2832 In some studies, most of the variance for cognitive loss was explained by vascular lesions and not by neurofibrillary tangles or amyloid plaques,33,34 particularly when the AD changes were mild.35

Given no differences in baseline neuropsychological performance between the low and high CHIPS groups in our sample, it is possible that patients with AD and SHs in cholinergic tracts may be reaching the same level of cognitive impairment as those with little white matter disease but by different mechanisms. Partial injury to cholinergic projections could exacerbate executive impairments, requiring less damage to the cholinergic neurons from AD pathology for the same degree of impairment. The resulting cholinergic synaptic deficiency may be more amenable to rescue by acetylcholinesterase inhibition, expressed as less decline in some executive function tasks. Recent trials of vascular dementia treated with CHEIs report positive, though modest, cognitive benefits.9 A recent study5 suggested that damage and disintegration of the cholinergic pathways in vascular dementia of Binswanger type may be due in part to a preferential susceptibility of these pathways to ischemic lesions.

A few studies using computed tomography36,37 and MRI38,39 to rate white matter changes have examined the influence of SHs on cognitive decline in patients being treated for AD. In general, results suggest that the presence of SHs may be associated with increased response to therapy after 1 year,38,39 no response,36 or worse response after 6 months.37 Those studies have been limited in that they were based on a small sample size, used simple cognitive measures, and studied white matter lesions that were spread throughout the hemispheres and included lacunar infarcts.

Studies are lending credibility to the idea that white matter lesions due in part to vascular risk factors play a role in the evolution of AD dementia.40 Ischemic white matter lesions have consistently been associated with a history of hypertension.41 Such injury increases the likelihood that individuals with AD lesions will express the dementia syndrome, and some suggest that these subjects may be more likely to benefit from cholinergic therapies.42 Unrecognized cerebrovascular disease in AD becomes especially common in older age.6,43 The frequency of silent infarcts increases with age, and silent infarcts increase risk of clinical dementia.44

However, involvement of cholinergic pathways may explain only part of the story; myelinated association fibers in the superior longitudinal fasciculus that join anterior and posterior cortical regions likely intermingle with the unmyelinated cholinergic pathways and are also important for working memory and executive control. Hence, it is possible that some of these differential effects could relate to association tract compromise as well. Application of new techniques such as diffusion tensor imaging may allow better appreciation of injury to the long association tracts such as the superior longitudinal fasciculus.

Further replication in larger community-based samples would be informative, and periods of follow-up longer than 1 year would be needed to determine more definitively whether strategically located SHs in cholinergic pathways affect cognitive decline in patients with AD and influence response to CHEIs.

Our data suggest that white matter changes previously described as “non-specific,” when in strategic locations such as the cholinergic tracts, may correlate with different patterns of cognitive decline and modulate responsivity to cholinergic treatment in AD. Evaluating the degree of compromise of cholinergic pathways would be useful in future studies of cholinergic therapy in AD and vascular dementia because it may shed light on the heterogeneity in individual responses to treatment, especially in frontal/executive tasks.

Correspondence: Pearl Behl, PhD, Faculty of Medicine, University of Toronto, 160 Russell Jarvis Dr, Markham, Ontario, Canada L3S 4E8 (pearl.behl@gmail.com).

Accepted for Publication: July 7, 2006.

Author Contributions:Study concept and design: Bocti, Swartz, and Black. Acquisition of data: Behl, Gao, and Black. Analysis and interpretation of data: Behl, Swartz, Sahlas, Lanctot, Streiner, and Black. Drafting of the manuscript: Behl, Streiner, and Black. Critical revision of the manuscript for important intellectual content: Bocti, Swartz, Gao, Sahlas, Lanctot, Streiner, and Black. Statistical analysis: Behl, Swartz, and Streiner. Obtained funding: Black. Administrative, technical, and material support: Black. Study supervision: Bocti, Swartz, Sahlas, Streiner, and Black.

Financial Disclosure: Dr Bocti has served as a consultant to or on speakers bureaus for Pfizer Inc, Janssen-Ortho, and Lunbeck. Dr Lanctot has received honoraria and contact research funding from or served as a consultant to Pfizer Inc and Janssen-Ortho Inc. Dr Sahlas has received honoraria from Pfizer Inc, Sanofi-Aventis, and Boehringer Ingelheim. Dr Black has received honoraria or operating funds from or served as a consultant to Pfizer Inc, Janssen-Ortho Inc, Novartis Pharmaceuticals, H. Lundbeck, Myriad Pharmaceuticals, Sanofi-Aventis, Astra-Zeneca, Boehringer Ingelheim, and Novo Nordisk.

Funding/Support: This study was supported in part by grant 13129 from the Canadian Institutes of Health Research, the Alzheimer Society of Canada, the Alzheimer's Association (United States), and the L. C. Campbell Foundation.

Role of the Sponsor: This study was conducted independently of any pharmaceutical company sponsorship.

Previous Presentation: This study was a poster presentation at the Second Congress of the International Society for Vascular, Cognitive, and Behavioural Disorders; June 8-12, 2005; Florence, Italy.

Acknowledgment: We thank the following institutions for personal support: Ontario Graduate Scholarship, Scace Graduate Fellowship, Scottish Rite Charitable Foundation (Dr Behl), the Alzheimer Society of Canada (Dr Bocti), and the Heart and Stroke Foundation Centre for Stroke Recovery (Drs Swartz and Streiner). We also thank Mario Masellis, MD, for his valuable feedback.

Lanctot  KLHerrmann  NYau  KK Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 2003;169557- 564
PubMed
Perry  RJHodges  JR Attention and executive deficits in Alzheimer's disease: a critical review. Brain 1999;122383- 404
PubMed Link to Article
Selden  NRGitelman  DRSalamon-Murayama  NParrish  TBMesulam  MM Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 1998;1212249- 2257
PubMed Link to Article
Mesulam  MSiddique  TCohen  B Cholinergic denervation in a pure multi-infarct state: observations on CADASIL. Neurology 2003;601183- 1185
PubMed Link to Article
Tomimoto  HOhtani  RShibata  MNakamura  NIhara  M Loss of cholinergic pathways in vascular dementia of the Binswanger type. Dement Geriatr Cogn Disord 2005;19282- 288
PubMed Link to Article
Swartz  RHSahlas  DJBlack  SE Strategic involvement of cholinergic pathways and executive dysfunction. J Stroke Cerebrovasc Dis 2003;1229- 36
Link to Article
Bocti  CSwartz  RHGao  FQSahlas  DJBehl  PBlack  SE A new visual rating scale to assess strategic white matter hyperintensities within cholinergic pathways in dementia. Stroke 2005;362126- 2131
PubMed Link to Article
Black  SRoman  GCGeldmacher  DSDonepezil 307 Vascular Dementia Study Group, Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke 2003;342323- 2330
PubMed Link to Article
Erkinjuntti  TRoman  GGauthier  S Treatment of vascular dementia—evidence from clinical trials with cholinesterase inhibitors. J Neurol Sci 2004;22663- 66
PubMed Link to Article
Behl  PLanctot  KLStreiner  DLGuimont  IBlack  SE Cholinesterase inhibitors slow decline in executive functions, rather than memory, in Alzheimer's disease: a 1-year observational study in the Sunnybrook dementia cohort. Curr Alzheimer Res 2006;3147- 156
PubMed Link to Article
van Straaten  ECScheltens  PKnol  DL Operational definitions for the NINDS-AIREN criteria for vascular dementia. Stroke 2003;341907- 1912
PubMed Link to Article
Mattis  S Mental status examination for organic mental syndrome in the elderly patient.  In: Bellak  L, Karasu  TB, eds. Geriatric Psychiatry. New York, NY: Grune & Stratton; 1976:77-121
Delis  DCKramer  JHKaplan  EOber  BA California Verbal Learning Test: Adult Version.  San Antonio, Tex: Psychological Corp; 1987
Kaplan  EGoodglass  HWeintraub  S The Boston Naming Test.  Boston, Mass: Lea & Febiger; 1978
 Wechsler Memory Scale: Revised Manual.  San Antonio, Tex: Psychological Corp; 1987
Lezack  MD Neuropsychological Assessment.  New York, NY: Oxford University Press; 1983
Heaton  RK Wisconsin Card Sorting Test Manual.  Odessa, Fla: Psychological Assessment Resources; 1981
Spreen  OStrauss  E A Compendium of Neuropsychological Tests.  New York, NY: Oxford University Press; 1991
Corwin  JBylsma  FW Commentary (on Rey & Osterreith). Clin Neuropsychol 1993;715- 21
Link to Article
Gelinas  IGauthier  LMcIntyre  MGauthier  S Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am J Occup Ther 1999;53471- 481
PubMed Link to Article
Reisberg  BBorenstein  JSalob  SPFerris  SHFranssen  EGeorgotas  A Behavioral symptoms in Alzheimer's disease: phenomenology and treatment. J Clin Psychiatry 1987;48(suppl)9- 15
PubMed
Wahlund  LOBarkhof  FFazekas  FEuropean Task Force on Age-Related White Matter Changes, A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 2001;321318- 1322
PubMed Link to Article
Holland  BSCopenhaver  MD Improved Bonferroni-type multiple testing procedures. Psychol Bull 1988;104145- 149
Link to Article
Hirono  NKitagaki  HKazui  HHashimoto  MMori  E Impact of white matter changes on clinical manifestation of Alzheimer's disease. Stroke 2000;312182- 2188
PubMed Link to Article
Schuff  NCapizzano  AADu  AT Different patterns of N-acetylaspartate loss in subcortical ischemic vascular dementia and AD. Neurology 2003;61358- 364
PubMed Link to Article
Nordahl  CWRanganath  CYonelinas  APDeCarli  CFletcher  EJagust  WJ White matter changes compromise prefrontal cortex function in healthy elderly individuals. J Cogn Neurosci 2006;18418- 429
PubMed Link to Article
Snowdon  DAGreiner  LHMortimer  JARiley  KPGreiner  PAMarkesbery  WR Brain infarction and the clinical expression of Alzheimer disease: the Nun Study. JAMA 1997;277813- 817
PubMed Link to Article
Riekse  RGLeverenz  JBMcCormick  W Effect of vascular lesions on cognition in Alzheimer's disease: a community-based study. J Am Geriatr Soc 2004;521442- 1448
PubMed Link to Article
Schneider  JAWilson  RSBienias  JLEvans  DABennett  DA Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 2004;621148- 1155
PubMed Link to Article
Knopman  DSParisi  JEBoeve  BF Vascular dementia in a population-based autopsy study. Arch Neurol 2003;60569- 575
PubMed Link to Article
Zekry  DDuyckaerts  CMoulias  R Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol (Berl) 2002;103481- 487
PubMed Link to Article
Esiri  MMNagy  ZSmith  MZBarnetson  LSmith  AD Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet 1999;354919- 920
PubMed Link to Article
White  LPetrovitch  HHardman  J Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci 2002;9779- 23
PubMed Link to Article
Kovari  EGold  GHerrmann  FR Cortical microinfarcts and demyelination significantly affect cognition in brain aging. Stroke 2004;35410- 414
PubMed Link to Article
Esiri  MMWilcock  GKMorris  JH Neuropathological assessment of the lesions of significance in vascular dementia. J Neurol Neurosurg Psychiatry 1997;63749- 753
PubMed Link to Article
Amar  KWilcock  GKScot  MLewis  T The presence of leuko-araiosis in patients with Alzheimer's disease predicts poor tolerance to tacrine, but does not discriminate responders from non-responders. Age Ageing 1997;2625- 29
PubMed Link to Article
Connelly  PJPrentice  NPFowler  KG Hypertension, white matter change and response to cholinesterase inhibitors in Alzheimer's disease. Int J Geriatr Psychiatry 2005;20623- 628
PubMed Link to Article
Fukui  TTaguchi  S Do vascular lesions and related risk factors influence responsiveness to donepezil chloride in patients with Alzheimer's disease? Dement Geriatr Cogn Disord 2005;2015- 24
PubMed Link to Article
Blasko  IBodner  TKnaus  G Efficacy of donepezil treatment in Alzheimer patients with and without subcortical vascular lesions. Pharmacology 2004;721- 5
PubMed Link to Article
De Leeuw  FEBarkhof  FScheltens  P Alzheimer's disease—one clinical syndrome, two radiological expressions: a study on blood pressure. J Neurol Neurosurg Psychiatry 2004;751270- 1274
PubMed Link to Article
De Leeuw  FEBarkhof  FScheltens  P Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 2002;125765- 772
PubMed Link to Article
Kumar  VAnand  RMessina  JHartman  RVeach  J An efficacy and safety analysis of Exelon in Alzheimer's disease patients with concurrent vascular risk factors. Eur J Neurol 2000;7159- 169
PubMed Link to Article
van Gool  WAEikelenboom  P The two faces of Alzheimer's disease. J Neurol 2000;247500- 505
PubMed Link to Article
Vermeer  SEDen Heijer  TKoudstaal  PJOudkerk  MHofman  ABreteler  MMRotterdam Scan Study, Incidence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke 2003;34392- 396
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

The process of arriving at the 90 study patients with Alzheimer disease (AD). MMSE indicates Mini-Mental State Examination.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Example of mild Cholinergic Pathways Hyperintensities Scale score as illustrated on T2-weighted magnetic resonance images. A, Low external capsule: anterior (right = 0, left = 0) and posterior (right = 0, left = 0). Add scores and multiply by 4 for a subtotal of 0. B, High external capsule: anterior (right = 0, left = 0), posterior (right = 0, left = 0), and cingulate (right = 0, left = 0). Add scores and multiply by 3 for a subtotal of 0. C, Corona radiata: anterior (right = 1, left = 0), posterior (right = 0, left = 1), and cingulate (right = 0, left = 0). Add scores and multiply by 2 for a subtotal of 4. D, Centrum semiovale: anterior (right = 0, left = 0), and posterior (right = 0, left = 0). Add scores and multiply by 1 for a subtotal of 0. The total score for all sections is 4. Arrow shows subcortical hyperintensity in a cholinergic pathway. E, Immunohistochemical tracings of the cholinergic pathways from Selden et al3 (reprinted with permission from Oxford University Press), with levels for the selected sections (A-D).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Example of severe Cholinergic Pathways Hyperintensities Scale score as illustrated on T2-weighted magnetic resonance images. A, Low external capsule: anterior (right = 2, left = 0) and posterior (right = 0, left = 0). Add scores and multiply by 4 for a subtotal of 8. B, High external capsule: anterior (right = 1, left = 0), posterior (right = 2, left = 0), and cingulate (right = 0, left = 0). Add scores and multiply by 3 for a subtotal of 9. C, Corona radiata: anterior (right = 2, left = 2), posterior (right = 2, left = 2), and cingulate (right = 0, left = 0). Add scores and multiply by 2 for a subtotal of 16. D, Centrum semiovale: anterior (right = 1, left = 1) and posterior (right = 2, left = 1). Add scores and multiply by 1 for a subtotal of 5. The total score for all sections is 38. Arrows show subcortical hyperintensities in cholinergic pathways. E, Immunohistochemical tracings of the cholinergic pathways from Selden et al3 (reprinted with permission from Oxford University Press), with levels for the selected sections (A-D).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic Characteristics by CHIPS Score*
Table Graphic Jump LocationTable 2. Baseline Neuropsychological Performance in the CHIPS Groups*
Table Graphic Jump LocationTable 3. Average Change in Neuropsychological and Neurobehavioral Test Scores in the CHIPS Groups in 1 Year
Table Graphic Jump LocationTable 4. Demographic Characteristics by ARWMC Score*

References

Lanctot  KLHerrmann  NYau  KK Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 2003;169557- 564
PubMed
Perry  RJHodges  JR Attention and executive deficits in Alzheimer's disease: a critical review. Brain 1999;122383- 404
PubMed Link to Article
Selden  NRGitelman  DRSalamon-Murayama  NParrish  TBMesulam  MM Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 1998;1212249- 2257
PubMed Link to Article
Mesulam  MSiddique  TCohen  B Cholinergic denervation in a pure multi-infarct state: observations on CADASIL. Neurology 2003;601183- 1185
PubMed Link to Article
Tomimoto  HOhtani  RShibata  MNakamura  NIhara  M Loss of cholinergic pathways in vascular dementia of the Binswanger type. Dement Geriatr Cogn Disord 2005;19282- 288
PubMed Link to Article
Swartz  RHSahlas  DJBlack  SE Strategic involvement of cholinergic pathways and executive dysfunction. J Stroke Cerebrovasc Dis 2003;1229- 36
Link to Article
Bocti  CSwartz  RHGao  FQSahlas  DJBehl  PBlack  SE A new visual rating scale to assess strategic white matter hyperintensities within cholinergic pathways in dementia. Stroke 2005;362126- 2131
PubMed Link to Article
Black  SRoman  GCGeldmacher  DSDonepezil 307 Vascular Dementia Study Group, Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke 2003;342323- 2330
PubMed Link to Article
Erkinjuntti  TRoman  GGauthier  S Treatment of vascular dementia—evidence from clinical trials with cholinesterase inhibitors. J Neurol Sci 2004;22663- 66
PubMed Link to Article
Behl  PLanctot  KLStreiner  DLGuimont  IBlack  SE Cholinesterase inhibitors slow decline in executive functions, rather than memory, in Alzheimer's disease: a 1-year observational study in the Sunnybrook dementia cohort. Curr Alzheimer Res 2006;3147- 156
PubMed Link to Article
van Straaten  ECScheltens  PKnol  DL Operational definitions for the NINDS-AIREN criteria for vascular dementia. Stroke 2003;341907- 1912
PubMed Link to Article
Mattis  S Mental status examination for organic mental syndrome in the elderly patient.  In: Bellak  L, Karasu  TB, eds. Geriatric Psychiatry. New York, NY: Grune & Stratton; 1976:77-121
Delis  DCKramer  JHKaplan  EOber  BA California Verbal Learning Test: Adult Version.  San Antonio, Tex: Psychological Corp; 1987
Kaplan  EGoodglass  HWeintraub  S The Boston Naming Test.  Boston, Mass: Lea & Febiger; 1978
 Wechsler Memory Scale: Revised Manual.  San Antonio, Tex: Psychological Corp; 1987
Lezack  MD Neuropsychological Assessment.  New York, NY: Oxford University Press; 1983
Heaton  RK Wisconsin Card Sorting Test Manual.  Odessa, Fla: Psychological Assessment Resources; 1981
Spreen  OStrauss  E A Compendium of Neuropsychological Tests.  New York, NY: Oxford University Press; 1991
Corwin  JBylsma  FW Commentary (on Rey & Osterreith). Clin Neuropsychol 1993;715- 21
Link to Article
Gelinas  IGauthier  LMcIntyre  MGauthier  S Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am J Occup Ther 1999;53471- 481
PubMed Link to Article
Reisberg  BBorenstein  JSalob  SPFerris  SHFranssen  EGeorgotas  A Behavioral symptoms in Alzheimer's disease: phenomenology and treatment. J Clin Psychiatry 1987;48(suppl)9- 15
PubMed
Wahlund  LOBarkhof  FFazekas  FEuropean Task Force on Age-Related White Matter Changes, A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 2001;321318- 1322
PubMed Link to Article
Holland  BSCopenhaver  MD Improved Bonferroni-type multiple testing procedures. Psychol Bull 1988;104145- 149
Link to Article
Hirono  NKitagaki  HKazui  HHashimoto  MMori  E Impact of white matter changes on clinical manifestation of Alzheimer's disease. Stroke 2000;312182- 2188
PubMed Link to Article
Schuff  NCapizzano  AADu  AT Different patterns of N-acetylaspartate loss in subcortical ischemic vascular dementia and AD. Neurology 2003;61358- 364
PubMed Link to Article
Nordahl  CWRanganath  CYonelinas  APDeCarli  CFletcher  EJagust  WJ White matter changes compromise prefrontal cortex function in healthy elderly individuals. J Cogn Neurosci 2006;18418- 429
PubMed Link to Article
Snowdon  DAGreiner  LHMortimer  JARiley  KPGreiner  PAMarkesbery  WR Brain infarction and the clinical expression of Alzheimer disease: the Nun Study. JAMA 1997;277813- 817
PubMed Link to Article
Riekse  RGLeverenz  JBMcCormick  W Effect of vascular lesions on cognition in Alzheimer's disease: a community-based study. J Am Geriatr Soc 2004;521442- 1448
PubMed Link to Article
Schneider  JAWilson  RSBienias  JLEvans  DABennett  DA Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 2004;621148- 1155
PubMed Link to Article
Knopman  DSParisi  JEBoeve  BF Vascular dementia in a population-based autopsy study. Arch Neurol 2003;60569- 575
PubMed Link to Article
Zekry  DDuyckaerts  CMoulias  R Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol (Berl) 2002;103481- 487
PubMed Link to Article
Esiri  MMNagy  ZSmith  MZBarnetson  LSmith  AD Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet 1999;354919- 920
PubMed Link to Article
White  LPetrovitch  HHardman  J Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci 2002;9779- 23
PubMed Link to Article
Kovari  EGold  GHerrmann  FR Cortical microinfarcts and demyelination significantly affect cognition in brain aging. Stroke 2004;35410- 414
PubMed Link to Article
Esiri  MMWilcock  GKMorris  JH Neuropathological assessment of the lesions of significance in vascular dementia. J Neurol Neurosurg Psychiatry 1997;63749- 753
PubMed Link to Article
Amar  KWilcock  GKScot  MLewis  T The presence of leuko-araiosis in patients with Alzheimer's disease predicts poor tolerance to tacrine, but does not discriminate responders from non-responders. Age Ageing 1997;2625- 29
PubMed Link to Article
Connelly  PJPrentice  NPFowler  KG Hypertension, white matter change and response to cholinesterase inhibitors in Alzheimer's disease. Int J Geriatr Psychiatry 2005;20623- 628
PubMed Link to Article
Fukui  TTaguchi  S Do vascular lesions and related risk factors influence responsiveness to donepezil chloride in patients with Alzheimer's disease? Dement Geriatr Cogn Disord 2005;2015- 24
PubMed Link to Article
Blasko  IBodner  TKnaus  G Efficacy of donepezil treatment in Alzheimer patients with and without subcortical vascular lesions. Pharmacology 2004;721- 5
PubMed Link to Article
De Leeuw  FEBarkhof  FScheltens  P Alzheimer's disease—one clinical syndrome, two radiological expressions: a study on blood pressure. J Neurol Neurosurg Psychiatry 2004;751270- 1274
PubMed Link to Article
De Leeuw  FEBarkhof  FScheltens  P Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 2002;125765- 772
PubMed Link to Article
Kumar  VAnand  RMessina  JHartman  RVeach  J An efficacy and safety analysis of Exelon in Alzheimer's disease patients with concurrent vascular risk factors. Eur J Neurol 2000;7159- 169
PubMed Link to Article
van Gool  WAEikelenboom  P The two faces of Alzheimer's disease. J Neurol 2000;247500- 505
PubMed Link to Article
Vermeer  SEDen Heijer  TKoudstaal  PJOudkerk  MHofman  ABreteler  MMRotterdam Scan Study, Incidence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke 2003;34392- 396
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 27

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Resolution

Users' Guides to the Medical Literature
Clinical Scenario