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  • Print publication year: 2009
  • Online publication date: July 2009

15 - Early clinical features of the parkinsonian-related dementias



Neurologists are confronted with complex patients in whom accurate diagnoses and improvement of symptoms are expected. One useful strategy is to determine if a patient has a constellation of symptoms and findings that fits within a broad category or syndrome, which then narrows the differential diagnosis and allows the clinician to commence a focused work-up. For example, the differential diagnosis and spectrum of available diagnostic studies for a patient with dementia, or a patient with parkinsonism, are rather wide; these are far more restricted in those who have elements of both dementia and parkinsonism. Furthermore, an insidious onset and progressive course suggests a neurodegenerative disease as the likely underlying process. This scenario is relatively common for community neurologists and very common for behavioral neurology and movement disorder specialists at academic centers.

The primary differential diagnosis in a patient with dementia plus parkinsonism who has experienced an insidious onset and progressive course, in probable decreasing prevalence in the population, includes dementia with Lewy bodies (DLB), Parkinson's disease (PD) with dementia (PDD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS)/corticobasal degeneration (CBD), and frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17). One useful exercise in the clinic is to use the interview and examination to explore the following areas of symptomatology: cognitive/neuropsychological, behavioral/neuropsychiatric, motor/ extrapyramidal, sleep, autonomic, sensory and other/miscellaneous features. In typical cases, these clinical features permit relatively easy differentiation (Table 15.1).

Dickson, D. Dementia with Lewy bodies: neuropathology. J Geriatr Psychiatr Neurol. 2002;15:210–216.
Apaydin, H, Ahlskog, J, Parisi, Jet al. Parkinson's disease neuropathology: later-developing dementia and loss of the Levodopa response. Arch Neurol. 2002;59:102–112.
Tsuboi, Y, Dickson, D.Dementia with Lewy bodies and Parkinson's disease with dementia: are they different?Park Relat Disord. 2005;11:S47–S51.
McKeith, I, Dickson, D, Lowe, Jet al. Dementia with Lewy bodies: diagnosis and management: Third report of the DLB Consortium. Neurology. 2005;65:1863–1872.
Knopman, D, Boeve, B, Petersen, R. Essentials of the proper diagnosis of mild cognitive impairment, dementia, and major subtypes of dementia. Mayo Clin Proc. 2003;78:1290–1308.
Boeve, B. Dementia with Lewy Bodies. In Petersen, R (ed.) Continuum, Vol. 10. Minneapolis: American Academy of Neurology, 2004:81–112.
Boeve, B, Silber, M, Saper, Cet al. Pathophysiology of REM sleep behavior disorder and relevance to neurodegenerative disease. Brain. 2007;130:2770–2788.
Ferman, T, Smith, G, Boeve, Bet al. Neuropsychological differentiation of dementia with Lewy bodies from normal aging and Alzheimer's disease. Clin Neuropsychol. 2006;20:623–636.
Simard, M, Reekum, R, Cohen, T. A review of the cognitive and behavioral symptoms in dementia with Lewy bodies. J Neuropsychiatr Clin Neurosci. 2000;12:425–450.
Arnulf, I, Bonnet, AM, Damier, Pet al. Hallucinations, REM sleep, and Parkinson's disease: a medical hypothesis. Neurology. 2000;55:281–288.
Boeve, B, Silber, M, Parisi, Jet al. Neuropathologic findings in patients with REM sleep behavior disorder and a neurodegenerative disorder. Neurology. 2001;56:A299.
Boeve, B, Silber, M, Ferman, Tet al. REM sleep behavior disorder in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In Bedard, M, Agid, Y, Chouinard, Set al. (eds.) Mental and Behavioral Dysfunction in Movement Disorders. Totowa, NJ: Humana Press, 2003:383–397.
Aarsland, D, Ballard, C, Larsen, J, McKeith, I. A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia. Int J Geriatr Psychiatry. 2001;16:528–536.
Marantz, A, Verghese, J. Capgras' syndrome in dementia with Lewy bodies. J Geriatr Psychiatr Neurol. 2002;15:239–241.
Boeve, B, Silber, M, Ferman, Tet al. Association of REM sleep behavior disorder and neurodegenerative disease. Sleep. 1999;22(Suppl 1):S72.
Boeve, B, Silber, M, Ferman, Tet al. Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord. 2001;16:622–630.
Boeve, B, Silber, M, Ferman, T. Current management of sleep disturbances in dementia. Cur Neurol Neurosci Rep. 2001;2:169–177.
Ballard, C, Shaw, F, McKeith, I, Kenny, R. High prevalence of neurovascular instability in neurodegenerative dementias. Neurology. 1998;51:1760–1762.
Hishikawa, N, Hashizume, Y, Yoshida, M, Sobue, G. Clinical and neuropathological correlates of Lewy body disease. Acta Neuropathol (Berl). 2003;105:341–350.
Thaisetthawatkul, P, Boeve, B, Benarroch, Eet al. Autonomic dysfunction in dementia with Lewy bodies. Neurology. 2004;62:1804–1809.
Pakiam, AS, Bergeron, C, Lang, AE. Diffuse Lewy body disease presenting as multiple system atrophy. Can J Neurol Sci. 1999;26:127–131.
Hawkes, C, Del Tredici, K, Braak, H. Parkinson's disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007;33:599–614.
Walker, Z, Stevens, T. Dementia with Lewy bodies: clinical characteristics and diagnostic criteria. J Geriatr Psychiatry Neurol. 2002;15:188–194.
Walker, M, Ayre, G, Cummings, Jet al. The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale. Two methods to assess fluctuating confusion in dementia. Br J Psychiatry. 2000;177:252–256.
Walker, M, Ayre, G, Cummings, Jet al. Quantifying fluctuation in dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. Neurology. 2000;54:1616–1625.
Walker, M, Ayre, G, Perry, Eet al. Quantification and characterization of fluctuating cognition in dementia with Lewy bodies and Alzheimer's disease. Dem Geriatr Cog Disord. 2000;11:327–335.
Ferman, T, Smith, G, Boeve, Bet al. DLB fluctuations: specific features that reliably differentiate DLB from AD and normal aging. Neurology. 2004;62:181–187.
Emre, M, Aarsland, D, Brown, Ret al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord. 2007;22:1689–1707.
Gjerstad, M, Boeve, B, Wentzel-Larsen, Tet al. Occurrence and clinical correlates of REM sleep behavior disorder in patients with Parkinson's disease over time. J Neurol Neurosurg Psychiatry. 2008; 79(4); 387–391.
Fronczek, R, Overeem, S, Lee, Set al. Hypocretin (orexin) loss in Parkinson's disease. Brain. 2007;130:1577–1585.
Thannickal, T, Lai, Y, Siegel, J. Hypocretin (orexin) cell loss in Parkinson's disease. Brain. 2007;130:1586–1595.
Boeve, B, Silber, M, Ferman, T. REM sleep behavior disorder in Parkinson's disease and dementia with Lewy bodies. J Ger Psychiatr Neurol. 2004;17:146–157.
Boeve, B, Silber, M. Sleep Disturbances in Parkinson's disease. In Martine, R, Duda, J (eds.) Parkinson Disease: Mind, Mood, and Memory. Miami, FL:National Parkinson Foundation, 2005:54–71.
Boeve, B, Ferman, T, Smith, Get al. Mild cognitive impairment preceding dementia with Lewy bodies. Neurology. 2004;62:A86–A87.
Caviness, J, Driver-Dunckley, E, Connor, Det al. Defining mild cognitive impairment in Parkinson's disease. Mov Disord. 2007;22:1272–1277.
Petersen, R. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183–194.
Postuma, R, Lang, A, Massicotte-Marquez, J, Montplaisir, J. Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology. 2006;66:845–851.
Boeve, B, Saper, C. REM sleep behavior disorder: a possible early marker for synucleinopathies. Neurology. 2006;66:796–797.
Boeve, B, Dickson, D, Olson, Eet al. Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease. Sleep Med 2007; 8:60–64.
Fantini, ML, Gagnon, JF, Petit, Det al. Slowing of electroencephalogram in rapid eye movement sleep behavior disorder. Ann Neurol. 2003;53:774–780.
Massicotte-Marquez, J, Carrier, J, Decary, Aet al. Slow-wave sleep and delta power in rapid eye movement sleep behavior disorder. Ann Neurol. 2005;57:277–282.
Eisensehr, I, Linke, R, Noachtar, Set al. Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behavior disorder: comparison with Parkinson's disease and controls. Brain. 2000;123:1155–1160.
Eisensehr, I, Linke, R, Tatsch, Ket al. Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson's disease, and controls. Sleep. 2003;26:507–512.
Mazza, S, Soucy, J, Gravel, Pet al. Assessing whole brain perfusion changes in REM sleep behavior disorder. Neurology. 2006;67:1618–1622.
Caselli, R, Chen, K, Bandy, Det al. A preliminary fluorodeoxyglucose positron emission tomography study in healthy adults reporting dream-enactment behavior. Sleep. 2006;29:927–933.
Ferini-Strambi, L, Di Gioia, M, Castronovo, Vet al. Neuropsychological assessment in idiopathic REM sleep behavior disorder (RBD): does the idiopathic form of RBD really exist?Neurology. 2004;62:41–45.
Stiasny-Kolster, K, Doerr, Y, Möller, Jet al. Combination of “idiopathic” REM sleep behavior disorder and olfactory dysfunction as possible indicator for α-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain. 2005;128:126–137.
Ferini-Strambi, L, Oldani, A, Zucconi, M, Smirne, S. Cardiac autonomic activity during wakefulness and sleep in REM sleep behavior disorder. Sleep. 1996;19:367–369.
Abbott, R, Ross, G, White, Let al. Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology. 2005;65:1442–1446.
Oka, H, Yoshioka, M, Morita, Met al. Reduced cardiac 123I-MIBG uptake reflects cardiac sympathetic dysfunction in Lewy body disease. Neurology. 2007;69:1460–1465.
Miyamoto, T, Miyamoto, M, Inoue, Yet al. Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder. Neurology. 2006;67:2236–2238.
Braak, H, Ghebremedhin, E, Rub, Uet al. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004;318:121–134.
Maurage, C, Ruchoux, M, Vos, Ret al. Retinal involvement in dementia with Lewy bodies: a clue to hallucinations?Ann Neurol. 2003;54:542–547.
Litvan, I, Agid, Y, Calne, Det al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome): report of the NINDS–SPSP International Workshop. Neurology. 1996;47:1–9.
Josephs, K, Duffy, J, Strand, Eet al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain. 2006;129:1385–1398.
Josephs, K, Boeve, B, Duffy, Jet al. Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia. Neurocase. 2005;11:283–296.
Dubois, B, Pillon, B, Legault, Fet al. Slowing of cognitive processing in progressive supranuclear palsy. A comparison with Parkinson's disease. Arch Neurol. 1988;45:1194–1199.
Pillon, B, Deweer, B, Michon, Aet al. Are explicit memory disorders of progressive supranuclear palsy related to damage to striatofrontal circuits? Comparison with Alzheimer's, Parkinson's, and Huntington's diseases. Neurology. 1994;44:1264–1270.
Pillon, B, Blin, J, Vidailhet, Met al. The neuropsychological pattern of corticobasal degeneration: comparison with progressive supranuclear palsy and Alzheimer's disease. Neurology. 1995;45:1477–1483.
Bak, T, Crawford, L, Hearn, Vet al. Subcortical dementia revisited: similarities and differences in cognitive function between progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA). Neurocase. 2005;11:268–273.
Rippon, G, Boeve, B, Parisi, Jet al. Late-onset frontotemporal dementia associated with progressive supranuclear palsy/argyrophilic grain disease/Alzheimer's disease pathology. Neurocase. 2005;11:204–211.
Arnulf, I, Merino-Andreu, M, Bloch, Fet al. REM sleep behavior disorder and REM sleep without atonia in patients with progressive supranuclear palsy. Sleep. 2005;28:349–354.
Karnik, N, D'Apuzzo, M, Greicius, M. Non-fluent progressive aphasia, depression, and OCD in a woman with progressive supranuclear palsy: neuroanatomical and neuropathological correlations. Neurocase. 2006;12:332–338.
Boeve, B. Corticobasal degeneration. In Adler, C, Ahlskog, J (eds.) Parkinson's Disease and Movement Disorders: Diagnosis and Treatment Guidelines for the Practicing Physician. Totawa, NJ: Human Press, 2000:253–261.
Boeve, B, Lang, A, Litvan, I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol. 2003;54:S15–S19.
Boeve, B. Corticobasal degeneration: the syndrome and the disease. In Litvan, I (ed.) Atypical Parkinsonian Disorders. Totawa, NJ: Humana Press, 2005:309–334.
Schneider, J, Watts, R, Gearing, Met al. Corticobasal degeneration: neuropathologic and clinical heterogeneity. Neurology. 1997;48:959–969.
Boeve, BF, Maraganore, DM, Parisi, JEet al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology. 1999;53:795–800.
Massman, P, Kreiter, K, Jankovic, J, Doody, R. Neuropsychological functioning in cortical-basal ganglionic degeneration: differentiation from Alzheimer's disease. Neurology. 1996;46:720–726.
Lehman, M, Duffy, J, Boeve, Bet al. Speech and language disorders associated with corticobasal degeneration. J Med Speech-Lang Pathol. 2003;11:131–146.
Cummings, J, Litvan, I. Neuropsychiatric aspects of corticobasal degeneration. In Litvan, I, Goetz, C, Lang, A (eds.) Corticobasal Degeneration and Related Disorders, Vol. 82. London: Lippincott, Williams & Wilkins, 2000:147–152.
Geda, Y, Boeve, B, Negash, Set al. Neuropsychiatric features in 36 pathologically confirmed cases of corticobasal degeneration. J Neuropsychiatry Clin Neurosci. 2007;19:77–80.
Hutton, M, Lendon, CL, Rizzu, Pet al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702–705.
Baker, M, Mackenzie, I, Pickering-Brown, Set al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442:916–919.
Poorkaj, P, Grossman, M, Steinbart, Eet al. Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol. 2001;58:383–387.
Microtubule-associated protein tau; MAPT
Benussi, L, Binetti, G, Sina, Eet al. A novel deletion in progranulin gene is associated with FTDP-17 and CBS. Neurobiol Aging 2008;29:427–435.
Boeve, B, Baker, M, Dickson, Det al. Frontotemporal dementia and parkinsonism associated with the IVS1+1G→A mutation in progranulin: a clinicopathologic study. Brain. 2006;129:3103–3114.
Cruts, M, Gijselinck, I, Zee, Jet al. Null mutations in progranulin cause ubiquitin positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442:920–924.
Gass, J, Cannon, A, Mackenzie, Iet al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet. 2006;15:2988–3001.
Huey, ED, Grafman, J, Wassermann, EMet al. Characteristics of frontotemporal dementia patients with a progranulin mutation. Ann Neurol. 2006;60:374–380.
Mackenzie, I, Baker, M, Pickering-Brown, Set al. The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain. 2006;129:3081–3090.
Masellis, M, Momeni, P, Meschino, Wet al. Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain. 2006;129:3115–3123.
Mukherjee, O, Pastor, P, Cairns, NJet al. HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol. 2006;60:314–322.
Pickering-Brown, S, Baker, M, Gass, Jet al. Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain. 2006;129:3124–3126.
Snowden, J, Pickering-Brown, S, Mackenzie, Iet al. Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain. 2006;129:3091–3102.
Neumann, M, Sampathu, D, Kwong, Let al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130–133.
Geschwind, DH, Robidoux, J, Alarcon, Met al. Dementia and neurodevelopmental predisposition: cognitive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia. Ann Neurol. 2001;50:741–746.
Ferman, TJ, McRae, CA, Arvanitakis, Zet al. Early and pre-symptomatic neuropsychological dysfunction in the PPND family with the N279K tau mutation. Park Relat Disord. 2003;9:265–270.
Frank, A, Wszolek, Z, Jack CR, J, Boeve, B. Distinctive MRI findings in pallido-ponto-nigral degeneration (PPND). Neurology. 2007;68:620–621.
Miller, BL, Boone, K, Cummings, JLet al. Functional correlates of musical and visual ability in frontotemporal dementia. Br J Psychiatry. 2000;176:458–463.
Miller, BL, Seeley, WW, Mychack, Pet al. Neuroanatomy of the self: evidence from patients with frontotemporal dementia. Neurology. 2001;57:817–821.
Miller, BL, Diehl, J, Freedman, Met al. International approaches to frontotemporal dementia diagnosis: from social cognition to neuropsychology. Ann Neurol. 2003;54:S7–S10.
Rankin, KP, Kramer, JH, Mychack, P, Miller, BL. Double dissociation of social functioning in frontotemporal dementia. Neurology. 2003;60:266–271.
Hodges, JR. Frontotemporal dementia (Pick's disease): clinical features and assessment. Neurology. 2001;56:S6–S10.
Woolley, J, Gorno-Tempini, M, Seeley, Wet al. Binge eating is associated with right orbitofrontal-insular-striatal atrophy in frontotemporal dementia. Neurology. 2007;69:1424–1433.
Arvanitakis, Z, Witte, R, Dickson, Det al. Clinical–pathologic study of biomarkers in FTDP-17 (PPND family with N279K tau mutation). Park Relat Disord. 2007;13:230–239.
Boeve, B, Tremont-Lukats, I, Waclawik, Aet al. Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation. Brain. 2005;128:752–772.
Boeve, B, Lin, S-C, Strongosky, Aet al. Absence of REM sleep behavior disorder in eleven members of the PPND kindred. Arch Neurol. 2006;63:268–272.
Cheshire, WP, Tsuboi, Y, Wszolek, ZK. Physiologic assessment of autonomic dysfunction in pallidopontonigral degeneration with N279K mutation in the tau gene on chromosome 17. Autonom Neurosci Basic Clin. 2002;102:71–77.
Wszolek, ZK, Lagerlund, TD, Steg, RE, McManis, PG. Clinical neurophysiologic findings in patients with rapidly progressive familial parkinsonism and dementia with pallido-ponto-nigral degeneration. Electroenceph Clin Neurophysiol. 1998;107:213–222.