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Disease-specific profiles of apathy in Alzheimer’s disease and behavioural-variant frontotemporal dementia differ across the disease course

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Abstract

Apathy is one of the most prevalent and disabling non-cognitive symptoms of dementia. This loss of motivation and pervasive decline in goal-directed behaviour represents a core diagnostic feature of behavioural-variant frontotemporal dementia (bvFTD) and is also common in Alzheimer’s disease (AD). However, despite growing recognition of a multidimensional model, apathy has typically been examined as a unitary symptom. Here, we employed a cross-sectional design to characterise the multidimensional nature of apathy across syndromes and disease course. 92 participants (44 bvFTD, 20 AD, 28 controls) completed the Dimensional Apathy Scale (DAS) to quantify emotional, executive, and initiation apathy. Patients were divided into early and late stages based on time since symptom onset. All participants underwent structural MRI and voxel-based morphometry was used to identify neural correlates of apathy dimensions. In the early stage of the disease (< 5 years since onset), emotional apathy was greater in bvFTD than AD. In contrast, in the late stage (> 5 years since onset), executive apathy was greater in AD than bvFTD, although apathy was elevated across all dimensions compared to controls. Notably, apathy was observed in the absence of self-reported depression in 46.2% of patients, with no patients classified as depressed only. Neuroimaging analyses revealed both common and divergent prefrontal and subcortical neural correlates associated with apathy dimensions. Our results reveal differing profiles of apathy across the disease course, in AD and bvFTD, with distinct brain regions mediating these dimensions. These findings will inform the development of appropriate treatment targets to ameliorate the impact of apathy in dementia.

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References

  1. van Reekum R, Stuss DT, Ostrander L (2005) Apathy: why care? J Neuropsych Clin N 17(1):7–19. https://doi.org/10.1176/appi.neuropsych.17.1.7

    Article  Google Scholar 

  2. Massimo L, Evans LK, Grossman M (2014) Differentiating subtypes of apathy to improve person-centered care in frontotemporal degeneration. J Gerontol Nurs 40(10):58–65. https://doi.org/10.3928/00989134-20140827-01

    Article  PubMed  PubMed Central  Google Scholar 

  3. Vilalta-Franch J, Calvo-Perxas L, Garre-Olmo J, Turro-Garriga O, Lopez-Pousa S (2013) Apathy syndrome in Alzheimer's disease epidemiology: prevalence, incidence, persistence, and risk and mortality factors. J Alzheimers Dis 33(2):535–543. https://doi.org/10.3233/JAD-2012-120913

    Article  PubMed  Google Scholar 

  4. Levy R, Dubois B (2006) Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex 16(7):916–928. https://doi.org/10.1093/cercor/bhj043

    Article  PubMed  Google Scholar 

  5. Marin RS (1991) Apathy—a neuropsychiatric syndrome. J Neuropsych Clin N 3(3):243–254

    Article  CAS  Google Scholar 

  6. Kumfor F, Zhen A, Hodges JR, Piguet O, Irish M (2018) Apathy in Alzheimer's disease and frontotemporal dementia: distinct clinical profiles and neural correlates. Cortex 103:350–359. https://doi.org/10.1016/j.cortex.2018.03.019

    Article  PubMed  Google Scholar 

  7. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, van Swieten JC, Seelaar H, Dopper EG, Onyike CU, Hillis AE, Josephs KA, Boeve BF, Kertesz A, Seeley WW, Rankin KP, Johnson JK, Gorno-Tempini ML, Rosen H, Prioleau-Latham CE, Lee A, Kipps CM, Lillo P, Piguet O, Rohrer JD, Rossor MN, Warren JD, Fox NC, Galasko D, Salmon DP, Black SE, Mesulam M, Weintraub S, Dickerson BC, Diehl-Schmid J, Pasquier F, Deramecourt V, Lebert F, Pijnenburg Y, Chow TW, Manes F, Grafman J, Cappa SF, Freedman M, Grossman M, Miller BL (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134(Pt 9):2456–2477. https://doi.org/10.1093/brain/awr179

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wong S, Balleine BW, Kumfor F (2018) A new framework for conceptualizing symptoms in frontotemporal dementia: from animal models to the clinic. Brain 141(8):2245–2254. https://doi.org/10.1093/brain/awy123

    Article  PubMed  Google Scholar 

  9. Quaranta D, Gainotti G, Rossi C, Masullo C (2012) Different apathy profile in behavioral variant of frontotemporal dementia and alzheimer's disease. Dement Geriatr Cogn 33:252–253

    Google Scholar 

  10. Reus LM, Vijverberg EG, Tijms BM, Kate MT, Gossink F, Krudop WA, Campo MD, Teunissen CE, Barkhof F, van der Flier WM, Visser PJ, Dols A, Pijnenburg YA (2018) Disease trajectories in behavioural variant frontotemporal dementia, primary psychiatric and other neurodegenerative disorders presenting with behavioural change. J Psychiatr Res 104:183–191. https://doi.org/10.1016/j.jpsychires.2018.07.014

    Article  PubMed  Google Scholar 

  11. Brodaty H, Connors MH, Xu J, Woodward M, Ames D, Group Ps (2015) The course of neuropsychiatric symptoms in dementia: a 3-year longitudinal study. J Am Med Dir Assoc 16(5):380–387. https://doi.org/10.1016/j.jamda.2014.12.018

    Article  PubMed  Google Scholar 

  12. Starkstein SE, Ingram L, Garau ML, Mizrahi R (2005) On the overlap between apathy and depression in dementia. J Neurol Neurosurg Psychiatry 76(8):1070–1074. https://doi.org/10.1136/jnnp.2004.052795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Radakovic R, Abrahams S (2014) Developing a new apathy measurement scale: dimensional apathy scale. Psychiatry Res 219(3):658–663. https://doi.org/10.1016/j.psychres.2014.06.010

    Article  PubMed  Google Scholar 

  14. Radakovic R, Starr JM, Abrahams S (2017) A Novel assessment and profiling of multidimensional apathy in alzheimer's disease. J Alzheimers Dis 60(1):57–67. https://doi.org/10.3233/JAD-170292

    Article  PubMed  Google Scholar 

  15. Radakovic R, Stephenson L, Newton J, Crockford C, Swingler R, Chandran S, Abrahams S (2017) Multidimensional apathy and executive dysfunction in amyotrophic lateral sclerosis. Cortex 94:142–151. https://doi.org/10.1016/j.cortex.2017.06.023

    Article  PubMed  Google Scholar 

  16. Radakovic R, Davenport R, Starr JM, Abrahams S (2018) Apathy dimensions in Parkinson's disease. Int J Geriatr Psychiatry 33(1):151–158. https://doi.org/10.1002/gps.4697

    Article  PubMed  Google Scholar 

  17. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7(3):263–269. https://doi.org/10.1016/j.jalz.2011.03.005

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR (2006) The Addenbrooke's cognitive examination revised (ACE-R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry 21(11):1078–1085. https://doi.org/10.1002/gps.1610

    Article  PubMed  Google Scholar 

  19. So M, Foxe D, Kumfor F, Murray C, Hsieh S, Savage G, Ahmed RM, Burrell JR, Hodges JR, Irish M, Piguet O (2018) Addenbrooke's Cognitive Examination III: psychometric characteristics and relations to functional ability in dementia. J Int Neuropsychol Soc 2018:1–10. https://doi.org/10.1017/S1355617718000541

    Article  Google Scholar 

  20. Radakovic R, Stephenson L, Colville S, Swingler R, Chandran S, Abrahams S (2016) Multidimensional apathy in ALS: validation of the dimensional apathy scale. J Neurol Neurosurg Psychiatry 87(6):663–669. https://doi.org/10.1136/jnnp-2015-310772

    Article  PubMed  Google Scholar 

  21. Pasquier F, Richard F, Lebert F (2004) Natural history of frontotemporal dementia: comparison with Alzheimer's disease. Dement Geriatr Cogn Disord 17(4):253–257. https://doi.org/10.1159/000077148

    Article  PubMed  Google Scholar 

  22. Lovibond PF, Lovibond SH (1995) The structure of negative emotional states: comparison of the depression anxiety stress scales (DASS) with the beck depression and anxiety inventories. Behav Res Ther 33(3):335–343

    Article  CAS  PubMed  Google Scholar 

  23. Salmon E, Perani D, Collette F, Feyers D, Kalbe E, Holthoff V, Sorbi S, Herholz K (2008) A comparison of unawareness in frontotemporal dementia and Alzheimer's disease. J Neurol Neurosurg Psychiatry 79(2):176–179. https://doi.org/10.1136/jnnp.2007.122853

    Article  CAS  PubMed  Google Scholar 

  24. Butterfield LC, Cimino CR, Oelke LE, Hauser RA, Sanchez-Ramos J (2010) The independent influence of apathy and depression on cognitive functioning in Parkinson’s disease. Neuropsychology 24(6):721–730. https://doi.org/10.1037/a0019650

    Article  PubMed  Google Scholar 

  25. Ashburner J, Friston KJ (2000) Voxel-based morphometry—the methods. Neuroimage 11(6):805–821. https://doi.org/10.1006/nimg.2000.0582

    Article  CAS  PubMed  Google Scholar 

  26. Mechelli A, Price CJ, Friston KJ, Ashburner J (2005) Voxel-based morphometry of the human brain: methods and applications. Curr Med Imaging Rev 1(2):105–113. https://doi.org/10.2174/1573405054038726

    Article  Google Scholar 

  27. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang YY, De Stefano N, Brady JM, Matthews PM (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23:S208–S219. https://doi.org/10.1016/j.neuroimage.2004.07.051

    Article  PubMed  Google Scholar 

  28. Woolrich MW, Jbabdi S, Patenaude B, Chappell M, Makni S, Behrens T, Beckmann C, Jenkinson M, Smith SM (2009) Bayesian analysis of neuroimaging data in FSL. Neuroimage 45(1):S173–S186. https://doi.org/10.1016/j.neuroimage.2008.10.055

    Article  PubMed  Google Scholar 

  29. Zhang YY, Brady M, Smith S (2001) Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE T Med Imaging 20(1):45–57. https://doi.org/10.1109/42.906424

    Article  CAS  Google Scholar 

  30. Rueckert D, Sonoda LI, Hayes C, Hill DLG, Leach MO, Hawkes DJ (1999) Nonrigid registration using free-form deformations: application to breast MR images. Ieee T Med Imaging 18(8):712–721. https://doi.org/10.1109/42.796284

    Article  CAS  Google Scholar 

  31. Andersson JLJ, Smith MS (2007) Non-linear optimisation. In: FMRIB Technical Report TR07JA1. University of Oxford, Oxford

  32. Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15(1):1–25. https://doi.org/10.1002/hbm.1058

    Article  PubMed  Google Scholar 

  33. Lieberman MD, Cunningham WA (2009) Type I and Type II error concerns in fMRI research: re-balancing the scale. Soc Cogn Affect Neurosci 4(4):423–428. https://doi.org/10.1093/scan/nsp052

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hornberger M, Geng J, Hodges JR (2011) Convergent grey and white matter evidence of orbitofrontal cortex changes related to disinhibition in behavioural variant frontotemporal dementia. Brain 134:2502–2512. https://doi.org/10.1093/brain/awr173

    Article  PubMed  Google Scholar 

  35. Landin-Romero R, Kumfor F, Leyton CE, Irish M, Hodges JR, Piguet O (2017) Disease-specific patterns of cortical and subcortical degeneration in a longitudinal study of Alzheimer's disease and behavioural-variant frontotemporal dementia. Neuroimage 151:72–80. https://doi.org/10.1016/j.neuroimage.2016.03.032

    Article  PubMed  Google Scholar 

  36. Schmahmann JD (2004) Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci 16(3):367–378. https://doi.org/10.1176/jnp.16.3.367

    Article  PubMed  Google Scholar 

  37. Leroi I, O'Hearn E, Marsh L, Lyketsos CG, Rosenblatt A, Ross CA, Brandt J, Margolis RL (2002) Psychopathology in patients with degenerative cerebellar diseases: a comparison to Huntington's disease. Am J Psychiatry 159(8):1306–1314. https://doi.org/10.1176/appi.ajp.159.8.1306

    Article  PubMed  Google Scholar 

  38. Morris JS, Friston KJ, Buchel C, Frith CD, Young AW, Calder AJ, Dolan RJ (1998) A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain 121(Pt 1):47–57

    Article  PubMed  Google Scholar 

  39. Miller EK, Cohen JD (2001) An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24:167–202. https://doi.org/10.1146/annurev.neuro.24.1.167

    Article  CAS  PubMed  Google Scholar 

  40. Massimo L, Powers C, Moore P, Vesely L, Avants B, Gee J, Libon DJ, Grossman M (2009) Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration. Dement Geriatr Cogn 27(1):96–104. https://doi.org/10.1159/000194658

    Article  Google Scholar 

  41. Kumfor F, Irish M, Hodges JR, Piguet O (2013) The orbitofrontal cortex is involved in emotional enhancement of memory: evidence from the dementias. Brain 136:2992–3003. https://doi.org/10.1093/brain/awt185

    Article  PubMed  Google Scholar 

  42. Ursu S, Carter CS (2005) Outcome representations, counterfactual comparisons and the human orbitofrontal cortex: implications for neuroimaging studies of decision-making. Brain Res Cogn Brain Res 23(1):51–60. https://doi.org/10.1016/j.cogbrainres.2005.01.004

    Article  PubMed  Google Scholar 

  43. Devinsky O, Morrell MJ, Vogt BA (1995) Contributions of anterior cingulate cortex to behaviour. Brain 118(Pt 1):279–306

    Article  PubMed  Google Scholar 

  44. Berman K, Brodaty H, Withall A, Seeher K (2012) Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry 20(2):104–122. https://doi.org/10.1097/JGP.0b013e31822001a6

    Article  PubMed  Google Scholar 

  45. Devos D, Moreau C, Maltete D, Lefaucheur R, Kreisler A, Eusebio A, Defer G, Ouk T, Azulay JP, Krystkowiak P, Witjas T, Delliaux M, Destee A, Duhamel A, Bordet R, Defebvre L, Dujardin K (2014) Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial. J Neurol Neurosurg Psychiatry 85(6):668–674. https://doi.org/10.1136/jnnp-2013-306439

    Article  PubMed  Google Scholar 

  46. Levy ML, Cummings JL, Fairbanks LA, Masterman D, Miller BL, Craig AH, Paulsen JS, Litvan I (1998) Apathy is not depression. J Neuropsychiatry Clin Neurosci 10(3):314–319. https://doi.org/10.1176/jnp.10.3.314

    Article  CAS  PubMed  Google Scholar 

  47. Hutchings R, Hodges JR, Piguet O, Kumfor F, Boutoleau-Bretonniere C (2015) Why should i care? Dimensions of socio-emotional cognition in younger-onset dementia. J Alzheimers Dis 48(1):135–147. https://doi.org/10.3233/JAD-150245

    Article  PubMed  Google Scholar 

  48. Marin RS, Biedrzycki RC, Firinciogullari S (1991) Reliability and validity of the apathy evaluation scale. Psychiatry Res 38(2):143–162

    Article  CAS  PubMed  Google Scholar 

  49. Chow TW, Fridhandler JD, Binns MA, Lee A, Merrilees J, Rosen HJ, Ketelle R, Miller BL (2012) Trajectories of behavioral disturbance in dementia. J Alzheimers Dis 31(1):143–149. https://doi.org/10.3233/JAD-2012-111916

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to all the patients and their families for supporting our research. This work was supported in part by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council (NHMRC) (GNT1037746). In addition, this study was supported by NHMRC Project Grant (GNT1121791). FK is supported by an NHMRC Career Development Fellowship (GNT1106031). OP is supported by an NHMRC Senior Research Fellowship (GNT1103258). MI is supported by an ARC Future Fellowship (FT160100096) and an Alzheimer's Australia Dementia Research Foundation Victoria Project Grant.

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Authors and Affiliations

  1. Brain and Mind Centre, The University of Sydney, Sydney, Australia

    Grace Wei, Muireann Irish, John R. Hodges, Olivier Piguet & Fiona Kumfor

  2. School of Psychology, The University of Sydney, Sydney, Australia

    Grace Wei, Muireann Irish, Olivier Piguet & Fiona Kumfor

  3. Sydney Medical School, The University of Sydney, Sydney, Australia

    John R. Hodges

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  1. Grace Wei
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Correspondence to Fiona Kumfor.

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All participants or their Person Responsible provided written informed consent in accordance with the Declaration of Helsinki and its later amendments. The South Eastern Sydney Local Health District ethics committee approved the study (HREC 10/126).

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Wei, G., Irish, M., Hodges, J.R. et al. Disease-specific profiles of apathy in Alzheimer’s disease and behavioural-variant frontotemporal dementia differ across the disease course. J Neurol 267, 1086–1096 (2020). https://doi.org/10.1007/s00415-019-09679-1

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