Cognitive Impairment and Dementia in Parkinson’s Disease: Clinical Features, Diagnosis, and Management

Parkinson’s disease (PD) is a common, disabling, neurodegenerative disorder. In addition to classical motor symptoms, non-motor features are now widely accepted as part of the clinical picture, and cognitive decline is a very important aspect of the disease, as it brings an additional significant burden for the patient and caregivers. The diagnosis of cognitive decline in PD, namely mild cognitive impairment (MCI) and dementia, can be extremely challenging, remaining largely based on clinical and cognitive assessments. Diagnostic criteria and methods for PD dementia and MCI have been recently issued by expert work groups. This manuscript has synthesized relevant data in order to obtain a pragmatic and updated review regarding cognitive decline in PD, from milder stages to dementia. This text will summarize clinical features, diagnostic methodology, and therapeutic issues of clinical decline in PD. Relevant clinical genetic issues, including recent advances, will also be approached.

[1]  E. Londos,et al.  Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial , 2009, The Lancet Neurology.

[2]  Christian C. Felder,et al.  Muscarinic mechanisms of antipsychotic atypicality , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[3]  K. Dujardin,et al.  Parkinson's disease dementia can be easily detected in routine clinical practice , 2010, Movement disorders : official journal of the Movement Disorder Society.

[4]  M. Pai,et al.  Education and cognitive decline in Parkinson's disease: a study of 102 patients , 2001, Acta neurologica Scandinavica.

[5]  W K Scott,et al.  Naming in dementia secondary to Parkinson's, Huntington's, and Alzheimer's diseases. , 1996, Journal of communication disorders.

[6]  Tore Wentzel-Larsen,et al.  The rate of cognitive decline in Parkinson disease. , 2004, Archives of neurology.

[7]  R. Petersen,et al.  Mild cognitive impairment , 2006, The Lancet.

[8]  A. Dürr,et al.  Juvenile-onset Parkinsonism as a result of the first mutation in the adenosine triphosphate orientation domain of PINK1. , 2006, Archives of neurology.

[9]  G. Broe,et al.  The Sydney Multicentre Study of Parkinson's disease: a randomised, prospective five year study comparing low dose bromocriptine with low dose levodopa-carbidopa. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[10]  N. Quinn,et al.  The role of pathogenic DJ‐1 mutations in Parkinson's disease , 2003, Annals of neurology.

[11]  B. Boeve,et al.  Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. , 2000, Brain : a journal of neurology.

[12]  E. Sidransky,et al.  The Role of Glucocerebrosidase Mutations in Parkinson Disease and Lewy Body Disorders , 2010, Current neurology and neuroscience reports.

[13]  U P Mosimann,et al.  Visual perception in Parkinson disease dementia and dementia with Lewy bodies , 2004, Neurology.

[14]  Murat Emre,et al.  Rivastigmine in dementia associated with Parkinson's disease and Alzheimer's disease: similarities and differences. , 2007, Journal of Alzheimer's disease : JAD.

[15]  Angie A. Kehagia,et al.  Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease , 2010, The Lancet Neurology.

[16]  T Revesz,et al.  A clinico-pathological study of subtypes in Parkinson's disease. , 2009, Brain : a journal of neurology.

[17]  D. Burn,et al.  Parkinson's disease: The quintessential neuropsychiatric disorder , 2011, Movement disorders : official journal of the Movement Disorder Society.

[18]  P. Bugalho,et al.  Alzheimer’s Disease: A Clinical Practice-Oriented Review , 2012, Front. Neur..

[19]  C. Adler,et al.  Both early and late cognitive dysfunction affects the electroencephalogram in Parkinson's disease. , 2007, Parkinsonism & related disorders.

[20]  P. Bech,et al.  Depression in idiopathic Parkinson's disease treated with citalopram: A placebo-controlled trial , 1998 .

[21]  Cummings Jl The dementias of Parkinson's disease: prevalence, characteristics, neurobiology, and comparison with dementia of the Alzheimer type. , 1988 .

[22]  K. Sigvardt,et al.  Recognition Memory in Parkinson’s Disease With and Without Dementia: Evidence Inconsistent with the Retrieval Deficit Hypothesis , 2005, Journal of clinical and experimental neuropsychology.

[23]  R. Walker,et al.  Incidence and prediction of falls in Parkinson's disease: a prospective multidisciplinary study , 2002, Journal of neurology, neurosurgery, and psychiatry.

[24]  R. Barker,et al.  Mild cognitive impairment in Parkinson disease , 2010, Neurology.

[25]  N. Hattori,et al.  Autosomal recessive parkinsonism linked to parkin gene in a Tunisian family. Clinical, genetic and pathological study. , 2003, Parkinsonism & related disorders.

[26]  E. Tolosa,et al.  Quantification of electromyographic activity during REM sleep in multiple muscles in REM sleep behavior disorder. , 2008, Sleep.

[27]  A. David,et al.  A randomized controlled trial of quetiapine for psychosis in Parkinson’s disease , 2009, Neuropsychiatric disease and treatment.

[28]  K. Marder,et al.  Antecedent clinical features associated with dementia in Parkinson's disease , 1993, Neurology.

[29]  A. Rajput,et al.  Course in Parkinson disease subtypes , 2009, Neurology.

[30]  K. Marder,et al.  The effect of age of onset of PD on risk of dementia , 2007, Journal of Neurology.

[31]  W. Poewe The Sydney multicentre study of Parkinson’s disease , 1999, Journal of neurology, neurosurgery, and psychiatry.

[32]  F J Dunne,et al.  Subcortical dementia. , 1993, BMJ.

[33]  J. Stockman Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease , 2011 .

[34]  J. Henry,et al.  Verbal fluency deficits in Parkinson's disease: A meta-analysis , 2004, Journal of the International Neuropsychological Society.

[35]  J. Kulisevsky,et al.  Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes. , 2011, Archives of neurology.

[36]  L. Forsgren,et al.  The relation between cognition and motor dysfunction in drug‐naive newly diagnosed patients with Parkinson's disease , 2011, Movement disorders : official journal of the Movement Disorder Society.

[37]  S. Papapetropoulos,et al.  A registry‐based, case–control investigation of Parkinson's disease with and without cognitive impairment , 2004, European journal of neurology.

[38]  R. Postuma,et al.  Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease , 2009, Annals of neurology.

[39]  A. Leentjens,et al.  SSRIs in the treatment of depression in Parkinson's disease , 2003, International journal of geriatric psychiatry.

[40]  C. Adler,et al.  MDS task force on mild cognitive impairment in Parkinson's disease: Critical review of PD‐MCI , 2011, Movement disorders : official journal of the Movement Disorder Society.

[41]  J. Grace,et al.  Discrimination of Dementia With Lewy Bodies From Alzheimer Disease and Parkinson Disease Using the Clock Drawing Test , 2003, Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology.

[42]  T. Robbins,et al.  The cognitive ability of an incident cohort of Parkinson's patients in the UK. The CamPaIGN study. , 2004, Brain : a journal of neurology.

[43]  C. M. Wiles,et al.  Parkin‐related disease clinically diagnosed as a pallido‐pyramidal syndrome , 2009, Movement disorders : official journal of the Movement Disorder Society.

[44]  D. Aarsland,et al.  Profile of cognitive impairment in dementia associated with Parkinson’s disease compared with Alzheimer’s disease , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[45]  D. Aarsland,et al.  Mental symptoms in Parkinson's disease are important contributors to caregiver distress , 1999, International journal of geriatric psychiatry.

[46]  A. Tröster Neuropsychological Characteristics of Dementia with Lewy Bodies and Parkinson’s Disease with Dementia: Differentiation, Early Detection, and Implications for “Mild Cognitive Impairment” and Biomarkers , 2008, Neuropsychology Review.

[47]  I. McKeith Dementia with Lewy bodies and Parkinson’s disease with dementia: where two worlds collide , 2007, Practical Neurology.

[48]  W. Weiner,et al.  Practice Parameter: Treatment of nonmotor symptoms of Parkinson disease , 2010, Neurology.

[49]  T. Anderson,et al.  The MoCA , 2010, Neurology.

[50]  Anette Schrag,et al.  Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism , 2006, The Lancet Neurology.

[51]  I. Katz,et al.  Escitalopram for major depression in Parkinson's disease: an open-label, flexible-dosage study. , 2006, The Journal of neuropsychiatry and clinical neurosciences.

[52]  S. Cappa,et al.  Neuropsychological assessment in idiopathic REM sleep behavior disorder (RBD) , 2004, Neurology.

[53]  K. Jellinger The association of incident dementia with mortality in PD , 2003, Neurology.

[54]  I. McKeith,et al.  A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia , 2001, International journal of geriatric psychiatry.

[55]  B. Vellas,et al.  One-year longitudinal evaluation of neuropsychiatric symptoms in Alzheimer's disease. The REAL.FR Study. , 2005, The journal of nutrition, health & aging.

[56]  L. Clare,et al.  Executive functions in Parkinson's disease: Systematic review and meta‐analysis , 2011, Movement disorders : official journal of the Movement Disorder Society.

[57]  David R Williams,et al.  Visual hallucinations in the diagnosis of idiopathic Parkinson's disease: a retrospective autopsy study , 2005, The Lancet Neurology.

[58]  E. Tolosa,et al.  Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study , 2008, The Lancet Neurology.

[59]  I. König,et al.  Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[60]  A. Futerman,et al.  Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond , 2011, Movement disorders : official journal of the Movement Disorder Society.

[61]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[62]  G. Broe,et al.  The neuropsychology of de novo patients with idiopathic Parkinson's disease: the effects of age of onset. , 1989, The International journal of neuroscience.

[63]  G. Lopez,et al.  The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism , 2009, Movement disorders : official journal of the Movement Disorder Society.

[64]  Thomas Foltynie,et al.  The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. , 2009, Brain : a journal of neurology.

[65]  S. Papapetropoulos Levodopa-induced dyskinesias in patients with Parkinson's disease: filling the bench-to-bedside gap , 2011 .

[66]  M. Jeannerod,et al.  Visual cognition: a new look at the two-visual systems model , 2005, Neuropsychologia.

[67]  J. Jankovic,et al.  Genetic testing in Parkinson disease: promises and pitfalls. , 2006, Archives of neurology.

[68]  F. Binkofski,et al.  Nonmotor symptoms in genetic Parkinson disease. , 2010, Archives of neurology.

[69]  E. Tolosa,et al.  Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD , 2005, Neurology.

[70]  J. Massano,et al.  Clinical approach to Parkinson's disease: features, diagnosis, and principles of management. , 2012, Cold Spring Harbor perspectives in medicine.

[71]  Handbook of Psychiatric Drug Therapy, 5th ed , 2007 .

[72]  E. Tolosa,et al.  Clinical diagnostic criteria for dementia associated with Parkinson's disease , 2007, Movement disorders : official journal of the Movement Disorder Society.

[73]  J. Cummings,et al.  Neuropsychiatric differences between Parkinson's disease with dementia and Alzheimer's disease , 2001, International journal of geriatric psychiatry.

[74]  C G Ballard,et al.  Fluctuations in attention , 2002, Neurology.

[75]  Günther Deuschl,et al.  Rivastigmine for dementia associated with Parkinson's disease. , 2004, The New England journal of medicine.

[76]  Y. Agid,et al.  Explicit memory in Alzheimer's, Huntington's, and Parkinson's diseases. , 1993, Archives of neurology.

[77]  Glenda M. Halliday,et al.  Clinical and pathological features of a parkinsonian syndrome in a family with an Ala53Thr α‐synuclein mutation , 2001 .

[78]  H. Braak,et al.  A timeline for Parkinson's disease. , 2010, Parkinsonism & related disorders.

[79]  H. Ross,et al.  A 10-year study of the incidence of and factors predicting dementia in Parkinson’s disease , 2000, Neurology.

[80]  X. Breakefield,et al.  Parkin deletions in a family with adult‐onset, tremor‐dominant parkinsonism: Expanding the phenotype , 2000, Annals of neurology.

[81]  D. Salmon,et al.  Cognitive profiles of individual patients with Parkinson's disease and dementia: Comparison with dementia with lewy bodies and Alzheimer's disease , 2006, Movement disorders : official journal of the Movement Disorder Society.

[82]  W. Rocca,et al.  When does Parkinson disease start? , 2010, Archives of neurology.

[83]  Nir Giladi,et al.  Risk factors for dementia, depression and psychosis in long-standing Parkinson's disease , 2000, Journal of Neural Transmission.

[84]  N. Quinn,et al.  Young‐onset Parkinson's disease revisited—clinical features, natural history, and mortality , 1998, Movement disorders : official journal of the Movement Disorder Society.

[85]  K. Chaudhuri,et al.  Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment , 2009, The Lancet Neurology.

[86]  B. Winblad,et al.  A six‐month double‐blind, randomized, placebo‐controlled study of a transdermal patch in Alzheimer's disease–– rivastigmine patch versus capsule , 2007, International journal of geriatric psychiatry.

[87]  I. Guella,et al.  SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population , 2012, Parkinsonism & related disorders.

[88]  Ann Ashburn,et al.  A meta‐analysis of six prospective studies of falling in Parkinson's disease , 2007, Movement disorders : official journal of the Movement Disorder Society.

[89]  A. Kertesz Pick Complex: An Integrative Approach to Frontotemporal Dementia: Primary Progressive Aphasia, Corticobasal Degeneration, and Progressive Supranuclear Palsy , 2003, The neurologist.

[90]  M. Freedman,et al.  Subcortical Dementia: A Neurobehavioral Approach , 1996, Brain and Cognition.

[91]  C. Goetz The history of Parkinson's disease: early clinical descriptions and neurological therapies. , 2011, Cold Spring Harbor perspectives in medicine.

[92]  Roy W Jones,et al.  Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial , 2010, The Lancet Neurology.

[93]  E. Tolosa,et al.  Diagnostic procedures for Parkinson's disease dementia: Recommendations from the movement disorder society task force , 2007, Movement disorders : official journal of the Movement Disorder Society.

[94]  S. Buyske,et al.  A controlled trial of antidepressants in patients with Parkinson disease and depression , 2009, Neurology.

[95]  K. Sethi,et al.  A controlled trial of antidepressants in patients with Parkinson’s disease and depression , 2009, Current neurology and neuroscience reports.

[96]  M. Hutton,et al.  The genetics of frontotemporal lobar degeneration , 2007, Current neurology and neuroscience reports.

[97]  D. Hernandez,et al.  Lewy bodies and parkinsonism in families with parkin mutations , 2001, Annals of neurology.

[98]  M. Nalls,et al.  Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. , 2009, The New England journal of medicine.

[99]  Thomas Foltynie,et al.  The natural history of treated Parkinson's disease in an incident, community based cohort , 2011, Journal of Neurology, Neurosurgery & Psychiatry.

[100]  G. Stebbins,et al.  Hallucinations in Parkinson disease , 2009, Nature Reviews Neurology.

[101]  G. Fénelon,et al.  Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors. , 2000, Brain : a journal of neurology.

[102]  K. Marder,et al.  Comparison of dementia with Lewy bodies to Alzheimer's disease and Parkinson's disease with dementia , 2004, Movement disorders : official journal of the Movement Disorder Society.

[103]  W. Ondo,et al.  Double‐blind, placebo‐controlled, unforced titration parallel trial of quetiapine for dopaminergic‐induced hallucinations in Parkinson's disease , 2005, Movement disorders : official journal of the Movement Disorder Society.

[104]  E. Mori,et al.  Distinctive neurobehavioral features among neurodegenerative dementias. , 1999, The Journal of neuropsychiatry and clinical neurosciences.

[105]  D. Aarsland,et al.  Development of daytime somnolence over time in Parkinson’s disease , 2002, Neurology.

[106]  M. Merello,et al.  Neuropsychological and psychiatric differences between Alzheimer's disease and Parkinson's disease with dementia. , 1996, Journal of neurology, neurosurgery, and psychiatry.

[107]  H. Braak,et al.  Staging of brain pathology related to sporadic Parkinson’s disease , 2003, Neurobiology of Aging.

[108]  Susan E. Hahn,et al.  Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors: Erratum , 2011, Genetics in Medicine.

[109]  Daniel Weintraub,et al.  Mild cognitive impairment is common in Parkinson's disease patients with normal Mini-Mental State Examination (MMSE) scores. , 2009, Parkinsonism & related disorders.

[110]  A. Murray,et al.  Autonomic dysfunction in dementia , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[111]  T. Gasser Update on the genetics of Parkinson's disease , 2007, Movement disorders : official journal of the Movement Disorder Society.

[112]  Albert Hofman,et al.  Prognosis of Parkinson disease: risk of dementia and mortality: the Rotterdam Study. , 2005, Archives of neurology.

[113]  Richard Mayeux,et al.  Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors , 2011, Genetics in Medicine.

[114]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[115]  P. Hobson,et al.  The estimated life expectancy in a community cohort of Parkinson's disease patients with and without dementia, compared with the UK population , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[116]  J. Kramer,et al.  Aphasia, apraxia, and agnosia in the diagnosis of dementia. , 1996, Dementia.

[117]  P. James An Essay on the Shaking Palsy , 1817, The Medico-Chirurgical Journal and Review.

[118]  L. Defebvre,et al.  Comparison of desipramine and citalopram treatments for depression in Parkinson's disease: A double‐blind, randomized, placebo‐controlled study , 2008, Movement disorders : official journal of the Movement Disorder Society.

[119]  I Litvan,et al.  Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson's disease. , 2001, The Journal of neuropsychiatry and clinical neurosciences.

[120]  Dagmar Verbaan,et al.  The MoCA: Well-suited screen for cognitive impairment in Parkinson disease , 2011, Neurology.

[121]  E. Tolosa,et al.  Diagnosis and the premotor phase of Parkinson disease , 2009, Neurology.

[122]  R. Barker,et al.  Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines , 2012, Movement disorders : official journal of the Movement Disorder Society.

[123]  R. Taipa,et al.  Clinico-Pathological Correlations of the Most Common Neurodegenerative Dementias , 2012, Front. Neur..

[124]  Sergey Raskin,et al.  Bupropion as the treatment of choice in depression associated with Parkinson's disease and it's various treatments. , 2010, Medical hypotheses.

[125]  S Minoshima,et al.  Diagnosis and management of dementia with Lewy bodies , 2005, Neurology.

[126]  M. Reiser,et al.  Loss of response to levodopa in Parkinson’s disease and co-occurrence with dementia: role of D3 and not D2 receptors , 2002, Brain Research.

[127]  G. Ransmayr,et al.  l-Dopa responsiveness in dementia with Lewy bodies, Parkinson disease with and without dementia , 2004, Neurology.

[128]  C. Marsden,et al.  Fronto-striatal cognitive deficits at different stages of Parkinson's disease. , 1992, Brain : a journal of neurology.

[129]  J. Friedman,et al.  Long‐term outcome of clozapine use for psychosis in parkinsonian patients , 2004, Movement disorders : official journal of the Movement Disorder Society.

[130]  Nicholas W Wood,et al.  Parkin disease: a phenotypic study of a large case series. , 2003, Brain : a journal of neurology.

[131]  N. Quinn,et al.  Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia , 2010, Movement disorders : official journal of the Movement Disorder Society.

[132]  J. Hardy,et al.  Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course , 2012, Movement disorders : official journal of the Movement Disorder Society.

[133]  Donald T Stuss,et al.  Functions of the Frontal Lobes: Relation to Executive Functions , 2011, Journal of the International Neuropsychological Society.

[134]  B. Dubois,et al.  Clinical validation of movement disorder society–recommended diagnostic criteria for Parkinson's disease with dementia , 2012, Movement disorders : official journal of the Movement Disorder Society.

[135]  D W Dickson,et al.  Autosomal dominant parkinsonism associated with variable synuclein and tau pathology , 2004, Neurology.

[136]  C. Metzler-Baddeley A Review of Cognitive Impairments in Dementia with Lewy Bodies Relative to Alzheimer's Disease and Parkinson's Disease with Dementia , 2007, Cortex.

[137]  E. Melamed,et al.  Psychosis in advanced Parkinson's disease , 1995, Neurology.

[138]  Matthew A. Menza,et al.  Parkinson's disease and anxiety: Comorbidity with depression , 1993, Biological Psychiatry.

[139]  M. Yahr,et al.  Dementia in idiopathic Parkinson's disease , 1986, Journal of Neural Transmission.

[140]  Christine Klein,et al.  Early-onset parkinsonism associated with PINK1 mutations: Frequency, genotypes, and phenotypes , 2005 .

[141]  A. Singleton,et al.  Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. , 2009, Brain : a journal of neurology.

[142]  Á. Iranzo Sleep–wake changes in the premotor stage of Parkinson disease , 2011, Journal of the Neurological Sciences.

[143]  G. Halliday,et al.  The Sydney multicenter study of Parkinson's disease: The inevitability of dementia at 20 years , 2008, Movement disorders : official journal of the Movement Disorder Society.

[144]  E. Tolosa,et al.  Pramipexole for the treatment of depressive symptoms in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled trial , 2010, The Lancet Neurology.

[145]  D. Aarsland,et al.  Neuropsychiatric disturbances in Parkinson's disease clusters in five groups with different prevalence of dementia , 2005, Acta psychiatrica Scandinavica.

[146]  J. Filoteo,et al.  Neuropsychology of Cortical versus Subcortical Dementia Syndromes , 2007, Seminars in neurology.

[147]  C. Fowler,et al.  Bladder dysfunction in Parkinsonism: Mechanisms, prevalence, symptoms, and management , 2006, Movement disorders : official journal of the Movement Disorder Society.

[148]  M. Hely,et al.  Sydney multicenter study of Parkinson's disease: Non‐L‐dopa–responsive problems dominate at 15 years , 2005, Movement disorders : official journal of the Movement Disorder Society.

[149]  D. Aarsland,et al.  A systematic review of prevalence studies of dementia in Parkinson's disease , 2005, Movement disorders : official journal of the Movement Disorder Society.

[150]  K. Marder,et al.  Association of glucocerebrosidase mutations with dementia with lewy bodies. , 2009, Archives of neurology.

[151]  M. Załuska,et al.  Bupropion in the treatment of depression in Parkinson's disease , 2010, International Psychogeriatrics.

[152]  Nicolaas I. Bohnen,et al.  White matter lesions in Parkinson disease , 2011, Nature Reviews Neurology.

[153]  Janet B W Williams,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[154]  M W Mahowald,et al.  Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. , 2007, Brain : a journal of neurology.

[155]  C. Pantelis,et al.  Brief report: bradyphrenia in Parkinson's disease, Huntington's disease, and schizophrenia. , 1996, Cognitive neuropsychiatry.

[156]  E. Benarroch,et al.  Autonomic and Cognitive dysfunction in Parkinson’s disease , 2007, Clinical Autonomic Research.

[157]  B. Schmand,et al.  Cognitive profile of patients with newly diagnosed Parkinson disease , 2005, Neurology.

[158]  I. McKeith,et al.  Motor subtype and cognitive decline in Parkinson’s disease, Parkinson’s disease with dementia, and dementia with Lewy bodies , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[159]  J. Massano,et al.  Deep Brain Stimulation and Cognitive Decline in Parkinson’s Disease: A Clinical Review , 2012, Front. Neur..

[160]  E. Tolosa,et al.  Molecular and clinical prodrome of Parkinson disease: implications for treatment , 2010, Nature Reviews Neurology.

[161]  D. Watt,et al.  Frontal-Subcortical Dementias , 2012 .

[162]  E. Russo,et al.  The safety of clozapine in the elderly. , 2008, Expert opinion on drug safety.

[163]  Bonifati,et al.  Association between early-onset Parkinson's disease and mutations in the parkin gene. , 2000, The New England journal of medicine.

[164]  H. Shill,et al.  Defining mild cognitive impairment in Parkinson's disease , 2007, Movement disorders : official journal of the Movement Disorder Society.

[165]  A. Lang,et al.  Hereditary parkinsonism: Parkinson disease look‐alikes—An algorithm for clinicians to “PARK” genes and beyond , 2009, Movement disorders : official journal of the Movement Disorder Society.

[166]  S. Engelborghs,et al.  Neuropsychiatric symptoms of dementia: cross‐sectional analysis from a prospective, longitudinal Belgian study , 2005, International journal of geriatric psychiatry.

[167]  J. Grace,et al.  Cognitive and behavioral features discriminate between Alzheimer's and Parkinson's disease. , 2002, Neuropsychiatry, neuropsychology, and behavioral neurology.

[168]  H. Petit,et al.  Which factors predict cognitive decline in Parkinson's disease? , 1995, Journal of neurology, neurosurgery, and psychiatry.

[169]  J. Jankovic,et al.  Genetic analysis of LRRK2 mutations in patients with Parkinson disease , 2006, Journal of the Neurological Sciences.

[170]  D. Aarsland,et al.  The epidemiology of dementia associated with Parkinson disease , 2010, Journal of the Neurological Sciences.

[171]  Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. , 1999, The New England journal of medicine.

[172]  D. Aarsland,et al.  Dementia associated with Parkinson's disease: applying the Movement Disorder Society Task Force criteria. , 2011, Parkinsonism & related disorders.

[173]  J. Aharon-Peretz,et al.  Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. , 2004, The New England journal of medicine.

[174]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[175]  D. Aarsland,et al.  Predictors of Nursing Home Placement in Parkinson's Disease: A Population‐Based, Prospective Study , 2000, Journal of the American Geriatrics Society.

[176]  A. Siderowf,et al.  Genetic influences on cognitive decline in Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[177]  M. Farrer,et al.  Glucocerebrosidase mutations in diffuse Lewy body disease. , 2011, Parkinsonism & related disorders.

[178]  M. Rowan,et al.  Parkinson's dementia and Alzheimer's dementia: an evoked potential comparison. , 1993, Gerontology.

[179]  Vincenzo Bonifati,et al.  Clinical features and neuroimaging of PARK7‐linked parkinsonism , 2003, Movement disorders : official journal of the Movement Disorder Society.

[180]  A. Bentivoglio,et al.  Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. , 2001, American journal of human genetics.

[181]  J. Hoenicka,et al.  The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia , 2004, Annals of neurology.

[182]  Y. Agid,et al.  A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease. , 1999, Human molecular genetics.

[183]  A J Lees,et al.  Bradyphrenia in Parkinson's disease and psychomotor retardation in depressive illness. An experimental study. , 1987, Brain : a journal of neurology.

[184]  J. Cummings The dementias of Parkinson's disease: prevalence, characteristics, neurobiology, and comparison with dementia of the Alzheimer type. , 1988, European neurology.

[185]  D. Berg,et al.  GBA-associated PD presents with nonmotor characteristics , 2011, Neurology.

[186]  E. Sinforiani,et al.  Cognitive performance in REM sleep behaviour disorder: a possible early marker of neurodegenerative disease? , 2008, Sleep medicine.

[187]  M. R. Almeida Glucocerebrosidase Involvement in Parkinson Disease and Other Synucleinopathies , 2012, Front. Neur..

[188]  J. Houwing-Duistermaat,et al.  Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. , 2001, American journal of human genetics.

[189]  Mike P Wattjes Structural MRI , 2011, International Psychogeriatrics.

[190]  D. Salmon,et al.  The neuropsychological profile of Alzheimer disease. , 2012, Cold Spring Harbor perspectives in medicine.

[191]  A. Bentivoglio,et al.  Park6‐linked parkinsonism occurs in several european families , 2002, Annals of neurology.

[192]  J. Rabey,et al.  Effect of quetiapine in psychotic Parkinson's disease patients: A double‐blind labeled study of 3 months' duration , 2007, Movement disorders : official journal of the Movement Disorder Society.

[193]  A. Lang,et al.  Overview of the extranigral aspects of Parkinson disease. , 2009, Archives of neurology.

[194]  J. Kulisevsky,et al.  Cognitive impairment in nondemented Parkinson's disease , 2011, Movement disorders : official journal of the Movement Disorder Society.

[195]  Murat Emre,et al.  Parkinson's disease dementia: Definitions, guidelines, and research perspectives in diagnosis , 2008, Annals of neurology.