Apathy in Parkinson's disease: Diagnosis, neuropsychological correlates, pathophysiology and treatment

Behavioural Neurology

Volumn 27, Issue 4, 2013, Pages 501-513

  Santangelo, Gabriella ^a,b   Trojano, Luigi ^a   Barone, Paolo ^b,c   Errico, Domenico ^a   Grossi, Dario ^a   Vitale, Carmine ^b,d  

^a SECOND UNIVERSITY OF NAPLES   (Italy)

^b Istituto di Diagnosi e Cura Hermitage Capodimonte   (Italy)

^c UNIVERSITY OF SALERNO   (Italy)

^d UNIVERSITY OF NAPLES PARTHENOPE   (Italy)

Author keywords

apathy; depression; frontal executive functions; non motor symptoms; Parkinson's disease

Indexed keywords

AMANTADINE; ATOMOXETINE; LEVODOPA; METHYLPHENIDATE; PLACEBO; PRAMIPEXOLE; RASAGILINE; RIVASTIGMINE; ROPINIROLE; TESTOSTERONE; TIANEPTINE;

ANHEDONIA; APATHY; BASAL GANGLION; BECK DEPRESSION INVENTORY; BRAIN DEPTH STIMULATION; CAREGIVER BURDEN; CEREBELLUM; COGNITION; COGNITIVE DEFECT; COMORBIDITY; DAILY LIFE ACTIVITY; DEPRESSION; DRUG EFFICACY; EDUCATIONAL STATUS; EMOTION; EMOTIONALITY; FOLLOW UP; FRONTAL LOBE; FUNCTIONAL MAGNETIC RESONANCE IMAGING; GLUCOSE METABOLISM; GRAY MATTER; HUMAN; INCIDENCE; INFERIOR FRONTAL GYRUS; INSULA; MAJOR DEPRESSION; META ANALYSIS (TOPIC); MIDDLE FRONTAL GYRUS; MINI MENTAL STATE EXAMINATION; MOTIVATION; MOTOR DYSFUNCTION; MULTICENTER STUDY (TOPIC); NEUROIMAGING; NEUROPSYCHOLOGY; ORBITAL CORTEX; PARIETAL GYRUS; PARKINSON DISEASE; PHENOMENOLOGY; POSTCENTRAL GYRUS; POSTERIOR CINGULATE; PRECUNEUS; PREVALENCE; PRIMARY MOTOR CORTEX; PRIORITY JOURNAL; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RURAL AREA; SELF CONCEPT; STATE DEPENDENT LEARNING; SUBTHALAMIC NUCLEUS; SUPPLEMENTARY MOTOR AREA; TEMPORAL LOBE; TESTOSTERONE BLOOD LEVEL; UNIFIED PARKINSON DISEASE RATING SCALE; VENTROMEDIAL PREFRONTAL CORTEX; VOXEL BASED MORPHOMETRY;

APATHY; DEPRESSION; FRONTAL/EXECUTIVE FUNCTIONS; NON-MOTOR SYMPTOMS; PARKINSON'S DISEASE;

AFFECTIVE SYMPTOMS; APATHY; CAREGIVERS; COGNITION DISORDERS; DEPRESSION; DIAGNOSIS, DIFFERENTIAL; HUMANS; PARKINSON DISEASE; PREVALENCE; QUALITY OF LIFE;

EID: 84887041363     PISSN: 09534180     EISSN: 18758584     Source Type: Journal    
DOI: 10.3233/BEN-129025     Document Type: Review

References (81)

1. Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci. 1991; 3(3): 243-254.
2. Marin RS. Apathy: concept, syndrome, neural mechanisms, and treatment. Semin Clin Neuropsychiatry. 1996; 1(4): 304-314.
3. Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex. 2006; 16(7): 916-928. (Pubitemid 43992442)
4. Brown RG, Pluck G. Negative symptoms: the 'pathology' of motivation and goal-directed behaviour. Trends Neurosci. 2000; 23(9): 412-417.
5. Eslinger PJ, Damasio AR. Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR. Neurology. 1985; 35(12): 1731-1741. (Pubitemid 16222756)
6. Levy R, Czernecki V. Apathy and the basal ganglia. J Neurol. 2006; 253(Suppl 7): VII54-61.
7. Jorge RE, Starkstein SE, Robinson RG. Apathy following stroke. Can J Psychiatry. 2010; 55(6): 350-354.
8. Robert PH, Mulin E, Malĺea P, David R. Apathy diagnosis, assessment, and treatment in Alzheimer's disease. CNS Neurosci Ther. 2010; 16(5): 263-271.
9. Craufurd D, Thompson JC, Snowden JS. Behavioral changes in Huntington Disease. Neuropsychiatry Neuropsychol Behav Neurol. 2001; 14(4): 219-226. (Pubitemid 33051498)
10. Hamilton JM, Salmon DP, Corey-Bloom J, Gamst A, Paulsen JS, Jerkins S, JacobsonMW, Peavy G. Behavioural abnormalities contribute to functional decline in Huntington's disease. J Neurol Neurosurg Psychiatry. 2003; 74(1): 120-122. (Pubitemid 36069050)
11. Thompson JC, Snowden JS, Craufurd D, Neary D. Behavior in Huntington's disease: dissociating cognition-based andmoodbased changes. J Neuropsychiatry Clin Neurosci. 2002; 14(1): 37-43. (Pubitemid 34117021)
12. Aarsland D, Litvan I, Larsen JP. Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson's disease. J Neuropsychiatry Clin Neurosci. 2001; 13(1): 42-49. (Pubitemid 32151915)
13. Litvan I, Hauw JJ, Bartko JJ, Lantos PL,Daniel SE, Horoupian DS, McKee A, Dickson D, Bancher C, Tabaton M, Jellinger K, Anderson DW. Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol. 1996; 55(1): 97-105. (Pubitemid 26013790)
14. Litvan I, Paulsen JS, Mega MS, Cummings JL. Neuropsychiatric assessment of patients with hyperkinetic and hypokinetic movement disorders. Arch Neurol. 1998; 55(10): 1313-1319.
15. Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG. Reliability, validity, and clinical correlates of apathy in Parkinson's disease. J Neuropsychiatry Clin Neurosci. 1992; 4(2): 134-139.
16. Aarsland D, Larsen JP, Lim NG, Janvin C, Karlsen K, Tandberg E, Cummings JL.Range of neuropsychiatric disturbances in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 1999; 67(4): 492-496. (Pubitemid 29438205)
17. Isella V, Melzi P, Grimaldi M, Iurlaro S, Piolti R, Ferrarese C, Frattola L, Appollonio I. Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson's disease.Mov Disord. 2002; 17(2): 366-371. (Pubitemid 36041307)
18. Pluck GC, Brown RG. Apathy in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2002; 73(6): 636-642. (Pubitemid 35448846)
19. Kirsch-Darrow L, Fernandez HH, Marsiske M, Okun MS, Bowers D. Dissociating apathy and depression in Parkinson disease. Neurology. 2006; 67(1): 33-38. (Pubitemid 44305458)
20. Aarsland D, Brønnick K, Ehrt U, De Deyn PP, Tekin S, Emre M, Cummings JL. Neuropsychiatric symptoms in patients with Parkinson's disease and dementia: frequency, profile and associated care giver stress. J Neurol Neurosurg Psychiatry. 2007; 78(1): 36-42. (Pubitemid 46048261)
21. Dujardin K, Sockeel P, Devos D, Delliaux M, Krystkowiak P, Dest́ee A, Defebvre L. Characteristics of apathy in Parkinson's disease. Mov Disord. 2007; 22(6): 778-784. (Pubitemid 46800097)
22. Kulisevsky J, Pagonabarraga J, Pascual-Sedano B, Garća- Śanchez C, Gironell A; Trapecio Group Study. Prevalence and correlates of neuropsychiatric symptoms in Parkinson's disease without dementia. Mov Disord. 2008; 23(13): 1889-1896.
23. Pedersen KF, Larsen JP, Aarsland D. Validation of the Unified Parkinson's Disease Rating Scale (UPDRS) section I as a screening and diagnostic instrument for apathy in patients with Parkinson's disease. Parkinsonism Relat Disord. 2008; 14(3): 183-186. (Pubitemid 351458418)
24. Kirsch-Darrow L, Zahodne LB, Hass C, Mikos A, Okun MS, Fernandez HH, Bowers D. How cautious should we be when assessing apathy with the Unified Parkinson's Disease Rating Scale? Mov Disord. 2009; 24(5): 684-688.
25. Pedersen KF, Larsen JP, Alves G, Aarsland D. Prevalence and clinical correlates of apathy in Parkinson's disease: a community-based study. Parkinsonism Relat Disord. 2009; 15(4): 295-299.
26. Pedersen KF, Alves G, Aarsland D, Larsen JP. Occurrence and risk factors for apathy in Parkinson disease: a 4-year prospective longitudinal study. J Neurol Neurosurg Psychiatry. 2009; 80(11): 1279-1282.
27. Starkstein SE, Merello M, Jorge R, Brockman S, Bruce D, Power B. The syndromal validity and nosological position of apathy in Parkinson's disease. Mov Disord. 2009; 24(8): 1211-1216.
28. Aarsland D, Brønnick K, Alves G, Tysnes OB, Pedersen KF, Ehrt U, Larsen JP. The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson's disease. J Neurol Neurosurg Psychiatry. 2009; 80(8): 928-930.
29. Reijnders JS, Scholtissen B, Weber WE, Aalten P, Verhey FR, Leentjens AF. Neuroanatomical correlates of apathy in Parkinson's disease: A magnetic resonance imaging study using voxel-based morphometry. Mov Disord. 2010; 25(14): 2318-2325.
30. Leiknes I, Tysnes OB, Aarsland D, Larsen JP. Caregiver distress associated with neuropsychiatric problems in patients with early Parkinson's disease: the Norwegian ParkWest study. Acta Neurol Scand. 2010; 122(6): 418-424.
31. Drijgers RL, Dujardin K, Reijnders JS, Defebvre L, Leentjens AF. Validation of diagnostic criteria for apathy in Parkinson's disease. Parkinsonism Relat Disord. 2010; 16(10): 656-660.
32. Pedersen KF, Alves G, Brønnick K, Aarsland D, Tysnes OB, Larsen JP. Apathy in drug-nä?ve patients with incident Parkinson's disease: the Norwegian ParkWest study. J Neurol. 2010; 257(2): 217-223.
33. Kirsch-Darrow L, Marsiske M, Okun MS, Bauer R, Bowers D. Apathy and depression: separate factors in Parkinson's disease. J Int Neuropsychol Soc. 2011; 17(6): 1058-1066.
34. Varanese S, Perfetti B, Ghilardi MF, Di Rocco A. Apathy, but not depression, reflects inefficient cognitive strategies in Parkinson's disease. PLoS One. 2011; 6(3): e17846.
35. Leroi I, Harbishettar V, Andrews M, McDonald K, Byrne EJ, Burns A. Carer burden in apathy and impulse control disorders in Parkinson's disease. Int J Geriatr Psychiatry. 2012; 27(2): 160-166.
36. Leroi I, Andrews M, McDonald K, Harbishettar V, Elliott R, Byrne EJ, Burns A. Apathy and impulse control disorders in Parkinson's disease: a direct comparison. Parkinsonism Relat Disord. 2012; 18(2): 198-203.
37. Ziropadja Lj, Stefanova E, PetrovicM, Stojkovic T,Kostic VS. Apathy and depression in Parkinson's disease: the Belgrade PD study report. Parkinsonism Relat Disord. 2012; 18(4): 339-342.
38. Benito-Léon J, Cubo E, Coronell C; ANIMO Study Group. Impact of apathy on health-related quality of life in recently diagnosed Parkinson's disease: the ANIMO study. Mov Disord. 2012; 27(2): 211-218.
39. Cubo E, Benito-Léon J, Coronell C, Armesto D, ANIMO Study Group. Clinical correlates of apathy in patients recently diagnosed with Parkinson's disease: the ANIMO study. Neuroepidemiology. 2012; 38(1): 48-55.
40. Starkstein SE, Petracca G, Chemerinski E, Kremer J. Syndromic validity of apathy in Alzheimer's disease. Am J Psychiatry. 2001; 158(6): 872-877. (Pubitemid 32547615)
41. Starkstein SE, Jorge R, Mizrahi R, Robinson RG. A prospective longitudinal study of apathy in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2006; 77(1): 8-11. (Pubitemid 43022682)
42. Robert P, Onyike CU, Leentjens AF, Dujardin K, Aalten P, Starkstein S, Verhey FR, Yessavage J, Clement JP, Drapier D, Bayle F, Benoit M, Boyer P, Lorca PM, Thibaut F, Gauthier S, Grossberg G, Vellas B, Byrne J. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur Psychiatry. 2009; 24(2): 98-104.
43. Starkstein SE, Leentjens AF. The nosological position of apathy in clinical practice. J Neurol Neurosurg Psychiatry. 2008; 79(10): 1088-1092.
44. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 1991; 38(2): 143-62.
45. Starkstein SE.Apathy and withdrawal. Int Psychogeriatr 2000; 12(Suppl 1): 135-138.
46. Leentjens AF, Dujardin K, Marsh L, Martinez-Martin P, Richard IH, Starkstein SE, Weintraub D, Sampaio C, Poewe W, Rascol O, Stebbins GT, Goetz CG. Apathy and anhedonia rating scales in Parkinson's disease: critique and recommendations. Mov Disord. 2008; 23(14): 2004-2014.
47. Sockeel P, Dujardin K, Devos D, Deǹeve C, Dest́ee A, Defebvre L. The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2006; 77(5): 579-584. (Pubitemid 43844578)
48. Zahodne LB, Young S, Kirsch-Darrow L, Nisenzon A, Fernandez HH, Okun MS, Bowers D. Examination of the Lille Apathy Rating Scale in Parkinson disease. Mov Disord. 2009; 24(5): 677-683.
49. Dujardin K, Sockeel P, Delliaux M, Dest́ee A, Defebvre L. The Lille Apathy Rating Scale: validation of a caregiver-based version. Mov Disord. 2008; 23(6): 845-849.
50. Grossi D, Santangelo G, Barbarulo AM, Vitale C, Castaldo G, Proto MG, Siano P, Barone P, Trojano L. Apathy and related Executive Syndromes in Dementia associated with Parkinson's Disease and in Alzheimer's Disease. Behav Neurol; In press.
51. Schrag A, Barone P, Brown RG, Leentjens AF, McDonald WM, Starkstein S,Weintraub D, PoeweW, Rascol O, Sampaio C, Stebbins GT, Goetz CG. Depression rating scales in Parkinson's disease: critique and recommendations. Mov Disord. 2007; 22(8): 1077-1092. (Pubitemid 47067217)
52. Santangelo G, Vitale C, Trojano L, Longo K, Cozzolino A, Grossi D, Barone P. Relationship between depression and cognitive dysfunctions in Parkinson's disease without dementia. J Neurol. 2009; 256(4): 632-638.
53. Santangelo G, Morgante L, Savica R, Marconi R, Grasso L, Antonini A, De Gaspari D, Ottaviani D, Tiple D, Simoni L, Barone P, PRIAMO Study Group. Anhedonia and cognitive impairment in Parkinson's disease: Italian validation of the Snaith-Hamilton Pleasure Scale and its application in the clinical routine practice during the PRIAMO study. Parkinsonism Relat Disord. 2009; 15(8): 576-581.
54. Zahodne LB,MarsiskeM, Okun MS, Rodriguez RL, Malaty I, Bowers D. Mood andmotor trajectories in Parkinson's disease: multivariate latent growth curve modeling. Neuropsychology. 2012; 26(1): 71-80.
55. Dujardin K, Sockeel P,Delliaux M,Dest́ee A, Defebvre L. Apathymay herald cognitive decline and dementia in Parkinson's disease. Mov Disord. 2009; 24(16): 2391-2397.
56. Ready RE, Friedman J, Grace J, Fernandez H. Testosterone deficiency and apathy in Parkinson's disease: a pilot study. J Neurol Neurosurg Psychiatry. 2004; 75(9): 1323-1326. (Pubitemid 39141342)
57. Kehagia AA, Barker RA, Robbins TW. Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease. Lancet Neurol. 2010; 9(12): 1200-1213.
58. Figiel G, Sadowsky C.Asystematic reviewof the effectiveness of rivastigmine for the treatment of behavioral disturbances in dementia and other neurological disorders. Curr Med Res Opin. 2008 Jan; 24(1): 157-66. (Pubitemid 351160249)
59. Wynn ZJ, Cummings JL. Cholinesterase inhibitor therapies and neuropsychiatric manifestations of Alzheimer's disease. Dement Geriatr Cogn Disord. 2004; 17(1-2): 100-8. (Pubitemid 37499973)
60. Zgaljardic DJ, Borod JC, Foldi NS, Rocco M, Mattis PJ, Gordon MF, Feigin AS, Eidelberg D. Relationship between selfreported apathy and executive dysfunction in nondemented patients with Parkinson disease. Cogn Behav Neurol. 2007; 20(3): 184-192. (Pubitemid 350195186)
61. Leroi I, Ahearn DJ, Andrews M, McDonald KR, Byrne EJ, Burns A. Behavioural disorders, disability and quality of life in Parkinson's disease. Age Ageing. 2011; 40(5): 614-621.
62. Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, Avarello TP, Bottacchi E, Cannas A, Ceravolo G, Ceravolo R, Cicarelli G, Gaglio RM, Giglia RM, Iemolo F, Manfredi M, Meco G, Nicoletti A, Pederzoli M, Petrone A, Pisani A, Pontieri FE, Quatrale R, Ramat S, Scala R, Volpe G, Zappulla S, Bentivoglio AR, Stocchi F, Trianni G, Dotto PD, PRIAMO study group. The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease. Mov Disord. 2009; 24(11): 1641-1649.
63. McKinlay A, Grace RC, Dalrymple-Alford JC, Anderson T, Fink J, Roger D. A profile of neuropsychiatric problems and their relationship to quality of life for Parkinson's disease patients without dementia. Parkinsonism Relat Disord. 2008; 14(1): 37-42.
64. Zarit SH, ToddPA, ZaritJM. Subjective burden of husbands and wives as caregivers: a longitudinal study. Gerontologist. 1986; 26: 260-266.
65. Skidmore FM,YangM, Baxter L, vonDeneen K, Collingwood J, He G, Tandon R, Korenkevych D, Savenkov A, Heilman KM, Gold M, Liu Y. Apathy, depression, and motor symptoms have distinct and separable resting activity patterns in idiopathic Parkinson disease. Neuroimage. 2011 Jul 14; In press.
66. Remy P, DoderM, Lees A, TurjanskiN,Brooks D. Depressionin Parkinson's disease: loss of dopamine and noradrenaline innervations in the limbic system. Brain 2005; 128(Part 6): 1314-1322. (Pubitemid 40826185)
67. Le Jeune F, Drapier D, Bourguignon A, Peron J, Mesbah H, Drapier S, et al. Subthalamic nucleus stimulation in Parkinson disease induces apathy: a PET study. Neurology 2009; 73(21): 1746-1751.
68. Robert G, Le Jeune F, Lozachmeur C, Drapier S, Dondaine T, Ṕeron J, Travers D, Sauleau P, Millet B, V́erin M, Drapier D. Apathy in patients with Parkinson disease without dementia or depression: A PET study. Neurology. 2012; 79 (11): 1155-1160.
69. Chase TN. Apathy in neuropsychiatric disease: diagnosis, pathophysiology, and treatment. Neurotox Res. 2011; 19(2): 266-278.
70. Borek LL, Chou KL, Friedman JH. Management of the behavioral aspects of Parkinson's disease. Expert Rev Neurother. 2007; 7(6): 711-725. (Pubitemid 46911618)
71. Czernecki V, Schipbach M, Yaici S, Levy R, Bardinet E, Yelnik J, Dubois B, Agid Y. Apathy following subthalamic stimulation in Parkinson disease: a dopamine responsive symptom. Mov Disord. 2008; 23(7): 964-969.
72. Ferreri F, Agbokou C, Gauthier S. Recognition and management of neuropsychiatric complications in Parkinson's disease. CMAJ. 2006; 175(12): 1545-1552. (Pubitemid 44955118)
73. Czernecki V, Pillon B, Houeto JL, Pochon JB, Levy R, Dubois B. Motivation, reward, and Parkinson's disease: influence of dopatherapy. Neuropsychologia 2002; 40(13): 2257-2267. (Pubitemid 35303365)
74. Leentjens AF, Koester J, Fruh B, Shephard DT, Barone P, Houben JJ. The effect of pramipexole on mood and motivational symptoms in Parkinson's disease: a meta-analysis of placebo-controlled studies. Clin Ther 2009; 31(3): 89-98.
75. Lhomḿee E, Klinger H, Thobois S, Schmitt E, Ardouin C, Bichon A, KistnerA, FraixV, Xie J,AyaKomboM, Chabard̀es S, Seigneuret E, Benabid AL, Mertens P, Polo G, Carnicella S, Quesada JL, Bosson JL, Broussolle E, Pollak P, Krack P. Subthalamic stimulation in Parkinson's disease: restoring the balance of motivated behaviours. Brain. 2012 May; 135(Pt 5): 1463-77.
76. Thobois S, Ardouin C, Lhomḿee E, Klinger H, Lagrange C, Xie J, Fraix V, Coelho Braga MC, Hassani R, Kistner A, Juphard A, Seigneuret E, Chabardes S, Mertens P, Polo G, Reilhac A, Costes N, LeBars D, Savasta M, Tremblay L, Quesada JL, Bosson JL, Benabid AL, Broussolle E, Pollak P, Krack P. Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation. Brain. 2010 Apr; 133(Pt 4): 1111-27.
77. Starkstein SE. Apathy in Parkinson's disease: diagnostic and etiological dilemmas. Mov Disord. 2012; 27(2): 174-178.
78. Starkstein SE, Brockman S. Apathy and Parkinson's disease. Curr Treat Options Neurol. 2011; 13(3): 267-273.
79. Weintraub D, Mavandadi S, Mamikonyan E, Siderowf AD, Duda JE, Hurtig HI, Colcher A, Horn SS, Nazem S, Ten Have TR, Stern MB. Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease. Neurology. 2010; 75(5): 448-455.
80. Levin OS. Coaxil (tianeptine) in the treatment of depression in Parkinson's disease. Neurosci Behav Physiol. 2007; 37(4): 419-424. (Pubitemid 46681136)
81. Chatterjee A, Fahn S. Methylphenidate treats apathy in Parkinson's disease. J Neuropsychiatry Clin Neurosci 2002; 14(4): 461-462.