title: The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features.
abstract: A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer's disease with a behavioural-predominant presentation (behavioural Alzheimer's disease) and a neuropathological diagnosis of high-likelihood Alzheimer's disease (n = 17) and/or biomarker evidence of Alzheimer's disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer's disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer's disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer's disease: 53%; dysexecutive Alzheimer's disease: 83%) than behavioural (behavioural Alzheimer's disease: 25%; dysexecutive Alzheimer's disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer's disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer's disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer's disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer's disease (typical Alzheimer's disease, n = 58), autopsy-confirmed/Alzheimer's disease biomarker-negative behavioural variant frontotemporal dementia (n = 59), and controls (n = 61). Patients with behavioural Alzheimer's disease showed worse memory scores than behavioural variant frontotemporal dementia and did not differ from typical Alzheimer's disease, while executive function composite scores were lower compared to behavioural variant frontotemporal dementia and typical Alzheimer's disease. Voxel-wise contrasts between behavioural and dysexecutive Alzheimer's disease patients and controls revealed marked atrophy in bilateral temporoparietal regions and only limited atrophy in the frontal cortex. In direct comparison with behavioural and those with dysexecutive Alzheimer's disease, patients with behavioural variant frontotemporal dementia showed more frontal atrophy and less posterior involvement, whereas patients with typical Alzheimer's disease were slightly more affected posteriorly and showed less frontal atrophy (P < 0.001 uncorrected). Among 24 autopsied behavioural Alzheimer's disease/dysexecutive Alzheimer's disease patients, only two had primary co-morbid FTD-spectrum pathology (progressive supranuclear palsy). In conclusion, behavioural Alzheimer's disease presentations are characterized by a milder and more restricted behavioural profile than in behavioural variant frontotemporal dementia, co-occurrence of memory dysfunction and high APOE ε4 prevalence. Dysexecutive Alzheimer's disease presented as a primarily cognitive phenotype with minimal behavioural abnormalities and intermediate APOE ε4 prevalence. Both behavioural Alzheimer's disease and dysexecutive Alzheimer's disease presentations are distinguished by temporoparietal-predominant atrophy. Based on the relative sparing of frontal grey matter, we propose to redefine these clinical syndromes as 'the behavioural/dysexecutive variant of Alzheimer's disease' rather than frontal variant Alzheimer's disease. Further work is needed to determine whether behavioural and dysexecutive-predominant presentations of Alzheimer's disease represent distinct phenotypes or a single continuum.
authors.affiliation: 1 Memory and Aging Center, University of California San Francisco, San Francisco, USA 2 Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, USA 3 Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands 4 Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands r.ossenkoppele@vumc.nl.
authors.forename: Rik
authors.initials: R
authors.lastname: Ossenkoppele
authors.affiliation: 3 Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Yolande A L
authors.initials: YA
authors.lastname: Pijnenburg
authors.affiliation: 1 Memory and Aging Center, University of California San Francisco, San Francisco, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Perry
authors.affiliation: 1 Memory and Aging Center, University of California San Francisco, San Francisco, USA.
authors.forename: Brendan I
authors.initials: BI
authors.lastname: Cohn-Sheehy
authors.affiliation: 3 Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Nienke M E
authors.initials: NM
authors.lastname: Scheltens
authors.affiliation: 2 Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, USA.
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Vogel
authors.affiliation: 1 Memory and Aging Center, University of California San Francisco, San Francisco, USA.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.affiliation: 3 Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Annelies E
authors.initials: AE
authors.lastname: van der Vlies
authors.affiliation: 2 Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, USA.
authors.forename: Renaud
authors.initials: R
authors.lastname: La Joie
authors.affiliation: 1 Memory and Aging Center, University of California San Francisco, San Francisco, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: 3 Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands 5 Department of Epidemiology and Biostatistics VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: 1 Memory and Aging Center, University of California San Francisco, San Francisco, USA 6 Department of Pathology, University of California San Francisco, San Francisco, USA.
authors.forename: Lea T
authors.initials: LT
authors.lastname: Grinberg
authors.affiliation: 3 Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Annemieke J
authors.initials: AJ
authors.lastname: Rozemuller
authors.affiliation: 6 Department of Pathology, University of California San Francisco, San Francisco, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: 4 Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Bart N M
authors.initials: BN
authors.lastname: van Berckel
authors.affiliation: 1 Memory and Aging Center, University of California San Francisco, San Francisco, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: 4 Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: 2 Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
authors.affiliation: 3 Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: 1 Memory and Aging Center, University of California San Francisco, San Francisco, USA 6 Department of Pathology, University of California San Francisco, San Francisco, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: 1 Memory and Aging Center, University of California San Francisco, San Francisco, USA 2 Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, USA.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000473:pathology*; D003072:Cognition Disorders / Q000209:etiology*; D056344:Executive Function / Q000502:physiology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D001523:Mental Disorders / Q000209:etiology*; D008609:Mental Status Schedule; D008875:Middle Aged; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography
chemical_list: D001057:Apolipoproteins E
keywords: Alzheimer’s disease; executive function; frontal, behaviour; frontotemporal dementia