Neurology International 2012; volume 4:e7

Advances in functional are barely amenable to significant interven- tion, the earlier detection is key. Correspondence: Michael Hoffmann, Stroke neuroimaging in Currently PET brain imaging offers the Center, James A. Haley VA Hospital, 13000 Bruce and potential pitfalls most accurate diagnostic method for the 5 B Downs Blvd, Tampa, Florida, 33612, USA. main categories as well as a number Tel. +1.81.9722000.7633 - Fax: +1.813.9785995. Katherine Standley,1 Charles Brock,1 of the subcategories2 (Table 2). A number of E-mail: [email protected] Michael Hoffmann2 patterns have emerged that reliably differenti- Key words: neuroimaging, dementia. 1Neurology Department,University ate the major dementia subtypes. This is important for treatment and prognostic deci- of South Florida; 2Cognitive Neurology Acknowledgments: presented in part at the 2011 sion making. For example the posterior corti- Division, Neurology Service, James A. Annual Meeting of the Florida Society of cal atrophy syndrome (Benson syndrome), an Haley VA Hospital, Tampa, Florida, USA Neurology Lake Buena Vista, Florida September AD variant progresses very slowly with largely 16-18, 2011 retained cognitive function, at the same time dominated by complex visual impairments Contribution: KS, intellectual input and data including visual agnosias and Balint’s syn- gathering; CB, intellectual input; MH, intellectual Abstract drome (Figure 1).3 With FTD (frontotemporal input and manuscript writing. hypoemtabolism) (Figure 2) and AD (tempo- ral, parietal, posterior cingulate) the footprint Received for publication: 16 November 2011. Neuroimaging is continuously advancing at Accepted for publication: 23 February 2012. a rapid rate and has progressed from excluding of hypotemetabolism is relatively easily identi- relatively uncommon secondary causes fied (Figure 3). However with Parkinson’s dis- This work is licensed under a Creative Commons (stroke, tumor) to assisting with early diagno- ease with dementia (PDD) and Diffuse Lewy Attribution NonCommercial 3.0 License (CC BY- sis and subtype of dementia. Structural imag- Body Disease (DLBD), the differentiating fea- NC 3.0). ing has given way to functional, metabolic and tures even on PET scanning are less distinct and considerable overlap in the patterns are ©Copyright K. Standley et al., 2012 receptor imaging. Licensee PAGEPress, Italy seen and consequently confusion may arise. Neurologyonly International 2012; 4:e7 This is particularly the case with PDD, DLDB doi:10.4081/ni.2012.e7 and cortical basal ganglionic (CBG) disease. Introduction PDD and DLBD are particularly challenging as there is no clear PET pattern as for example continues to be elucidated. In relation to Neuroimaging is continuously advancing at with AD and FTD. This is perhaps not surpris-use dementias, memory and pain processing share a rapid rate and has progressed from excluding ing as DLDB and AD share features at a clini- close anatomic relationships. Numerous func- relatively uncommon secondary causes cal, neuroimaging, pathological and pharma- tional neuroimaging studies using positron (stroke, tumor) to assisting with early diagno- cotherapeutic level.4 Futhermore, Parkinson’s emission tomography (PET)11-13 and function- sis and subtype of dementia. Structural imag- disease (PD), PDD, DLBD and AD represent a al magnetic resonance imaging (fMRI)14,15 ing has given way to functional, metabolic and pathological spectrum with loss of both cholin- have demonstrated that the anterior cingulate receptor imaging. An emerging focus is the ergic neurons and dopaminergic neurons as cortex (ACC) and posterior cingulate cortex appreciation of human connectomics, net- the most prominent neurotransmitter pertur- 5 (PCC) have key roles in processing of pain per- work-opathies and their imaging counterparts. bation initially. Adding to the complexity, ception.16 Lesional studies have corroborated 18Fluorodeoxyglucoe positron emission tomog- there is overlap with AD and cognitive vascular 17,18 raphy (18FDG-PET) brain, single photon emis- disorders (CVD), the frontal variant of these findings. The ACC has not been sion computed tomography (SPECT) brain, Alzheimer’s and the frontal variant of FTD that demonstrated to be involved in coding stimu- PET Pittsburgh Compound B (PIB) and PET present added diagnostic challenges in indi- lus intensity or location but participates in receptor (Dopa) imaging are becoming more vidual cases. Even more importantly, diagnosis both the affective and attentional components widespread and gaining acceptance as part of and differentiation may not be possible by clin- of pain sensation and response. Increased the routine work up (Table 1). 18FDG- PET ical means alone especially in the pre-sympto- blood flow is also found in the posterior pari- brain in particular has been an importantNon-commercial tool matic phase when no cognitive impairment etal and prefrontal cortices and is thought to in assisting in the early diagnosis of mild cog- exists particularly in the context of presumed reflect networks for attention and memory nitive impairment (MCI) type of case as well high cognitive reserve. However intervention activated by painful stimulation. Memory and as in differentiating different types of demen- and treatment may yield the most significant pain processing networks are physically close tia, with frontotemporal disorders (FTD) and results at this stage.6 in the cingulate cortex. Episodic memory Alzheimer’s disease (AD) already being an In addition to the 4 most common dementia retrieval is predominately in the caudal portion Food and Drug Administration asserted indica- syndromes discussed, newer dementia etiolo- of the PCC while pain processing occurs in the tion for example.1 Furthermore, basic neuro- gies continuously added and expand the diag- rostral portion of the PCC.19 Given that science is increasingly delineating newer nostic work up. Autoimmune dementias and patients with Alzheimer’s disease and other molecular phenotypes (beta amyloid, alpha the prefrontal atrophy secondary to chronic neurodegenerative dementias are noted to synuclein and TDP-43) and subcategories stimulation of the pain matrix (chronic pain report less pain and may receive less anal- which are particularly complex with FTD (TDP syndrome) is also regarded as a neurodegener- gesics that comparable normal peers, consid- 43, tau, FUS, C90RF2). The pathologies take ative condition today. Brain atrophy and as eration has been provoked that the dementia effect at the synaptic and neuronal level and such neurodegeneration has been associated related neurodegeneration process may be are the earliest events in these disease states. with various chronic pain conditions including affecting pain processing pathways. However, Neuroimaging is increasingly able to decipher fibromyalgia, posttraumatic headache, com- studies have demonstrated heightened magni- these earlier changes long before the clinical plex regional pain syndrome (CRPS), and tude and duration of activity in the ACC and state even emerges or the extensive atrophy chronic back pain.7-10 The potential cause and other pain processing areas during pain stim- seen on structural scans. As late or end stages effect relationship of the atrophy with pain uli in Alzheimer’s disease patients.20 As such

[page 26] [Neurology International 2012; 4:e7] Review

Table 1. Spectrum of current functional imaging modalities. the perception of pain is not diminished in Magnetic resonance imaging multimodaiity Alzheimer’s, and should raise awareness of clinical care providers to insure adequate anal- Magnetic resonance imaging (routine series) gesia for dementia patients with painful condi- T1/T2 fluid attenuated inversion recovery, gradient echo sequence, magnetic resonance angiogram largely to detect degree of concomitant vascular disease, atrophy pattern and other secondary tions. pathologies PET brain scan imaging and cerebrospinal Magnetic resonance imaging - diffusion tensor imaging fluid (CSF) biomarkers are becoming increas- Fiber tract pathology especially in traumatic brain injury, multiple sclerosis ingly important to diagnose dementia syn- Magnetic resonance imaging - quantitative atrophy estimation dromes especially in the setting of overlap syn- At least 5 different patterns of the major dementia syndromes (Seeley WW et al.)22 dromes.21,22 Learning to identify metabolic Magnetic resonance imaging - perfusion uptake patterns by cartographic analysis as Perfusion as a reflection of hypometabolism, similar to single photon emission computed well as semi-quantitative methods may be cru- tomography (perfusion) and positron emission tomography (metabolism) patterns of abnormality cial for correct diagnosis in the face of conflict- Magnetic resonance spectroscopy ing clinical as well as neuro-radiological find- Biochemical analysis, choline, lactate particularly useful in brain tumor diagnosis ings. The four major neurodegenerative dis- Single photon emission computed tomography eases include AD, DLBD, FTD and CVD in approximate order of frequency. AD and FTD Hypoperfusion (in vascular or hypometabolism) Hyperperfusion for example with ictal foci Position emission tomography brain Frontotemporal disorders Alzheimer’s disease Diffuse lewy body disease Parkinson’s Progressive supranuclear palsy only Huntington’s Cortical basal ganglionic cognitive vascular disorders Intrinsic state connectivity maps Default mode use Salience network Parkinson’s (increased connectivity of the basal ganglionic and thalamocortical loops) Cortical basal ganglionic Cognitive vascular disorders ? Quantitative electroencephalographic and magnetoencephalographic Alzheimer’s disease - reduced connectivity of alpha and beta in frontotemporal and frontoparietal regions Frontotemporal disorders - uncertain Parkinson’s - increased connectivity of alpha and beta locally and globally Diffuse lewy body disease - reduced connectivity alpha range locally and globally

Non-commercial

Figure 2. FTD end stage with extensive bifrontal cortical atrophy (top) and 18FDGPET brain of early non fluent apha- sia subtype (down), demonstrating left Figure 1. 18FDGPET brain: posterior cortical atrophy syndrome with marked posterior inferior frontal hypometabolism (arrow) cortical hypometabolism. in context of normal structural MRI scan.

[Neurology International 2012; 4:e7] [page 27] Review

(Figure 2) have distinct and easily identifiable cinations with DLDB is further reason for pre- MCI and AD.28 With the advent of MR perfusion patterns and CVD is guided primarily by stroke cise diagnostic accuracy translating into ther- scanning giving similar information to PET related imaging. The situation with DLBD can apeutic effectiveness.23 There are already sev- brain scanning, this modality may become be difficult due to the overlap of neuropatholo- eral recognized metabolic features of PET more desirable in view of its availability and gies. A correct diagnosis is nevertheless vital scanning that have been identified with DLDB, lack of radiation.29 A continuously expanding to guide care for the patient. Refining the diag- namely i) diffuse glucose hypometabolism in therapeutic armamentarium for DLDB both in nosis may assist with appropriate treatment entire cortex including the occipital region typ- terms of receptors23 for symptom alleviation as and in avoiding serious side effects not the ical feature of DLBD and distinctive from AD, well as disease modifying therapies30 all bode least of which include neuroleptic sensitivity ii) lateral occipital hypometabolism (Figure 3) for precise diagnostic accuracy. such as neuroleptic malignant syndrome or which may have the highest sensitivity and iii) catatonia. People with DLDB generally respond posterior cingulate preserved metabolism or Emerging imaging modalities: better to acetylcholinergic (Ach) therapy in posterior cingulate island sign, (PCIS) which default mode network or intrinsic terms of improved alertness, less fluctuation in may have the highest specificity24-26 (Figure cognition and memory than do people with 4). However, the so called PCIS appears to connectivity networks imaging and AD.4 The complex clinical and neuroradiologi- reflect the much more pronounced occipital other (molecular) networks cal patterns of the dementia syndromes no hypometabolism relative to the also reduced The Default Mode Network (DMN) can be doubt foster misdiagnosis. The neuroradiolog- (but to a lesser extent) or sometimes normal imaged by functional MRI (resting state with- ical findings of DLDB may be initially confused metabolism of the posterior cingulate cortex.22 out activation procedures) and reflects the the diagnosis of AD diagnosis. Hallucinations, With AD on the other hand, hypometabolism basal or default mode activity of the brain. It a hallmark of DLDB can occur with AD as well is seen very early in the medial portions of the links particular brain regions that includes the as other dementias. A recent report of a specif- parietal lobes as well as the posterior cingulate posterior cingulate, the precuneus, lateral ic 5HT - 2A antagonist specific for visual hallu- region. The difficulty posed by the fluctuating parietal, lateral temporal, medial frontal areas. symptomatology adds to the diagnostic dilem- DMN impaired connectivity has already been ma. In addition, the uncertainty of hallucina- shown in AD, FTD, schizophrenia, epilepsy, tion origin, whether drug induced, due to autism later life depression.31 The DMN is DLBD or AD is a frequent frustration shared by activeonly during rest and becomes less active dur- both patients and physicians treating these ing cerebral task engagement. It is implicated conditions. The advent of biomarker assisted in the pathophysiology of AD as the distribu- diagnosis has already initiated new diagnostic tion of the DMN is similar to the fibrillar amy- criteria for AD that enable a pre-mortemusediag- loid deposition in patients with AD (amyloid nosis that is heavily reliant on positive CSF PET scanning).32 The A-beta deposition over- and PET findings.27 The trend of clinical, PET laps considerably with the DMN and the tau and CSF diagnostic features rendering deposition overlaps with the DMN component increased diagnostic accuracy will likely trans- that is concerned with episodic memory.33 It late similarly in the DLDB-Parkinsonism com- has been surmised that over-activity of DMN plex as it has already done for example with (posterior cingulate, later parietal, medial

Table 2. Positron emission tomography brain patterns in dementias. Figure 3. Transaxial 18FDGPET brain Dementia subtype 18Fluorodeoxyglucoe positron emission revealing bilateral predominantly occipital tomography hypometabolism pattern hypometabolism (arrows) in a patient with Alzheimer Relatively symmetric parietotemporal, medial DLBD. temporal, posterior cingulate, frontal association cortex Non-commercial to lesser degree Alzheimer’s disease variant Occipital hypometabolism predominates (Posterior cortical atrophy syndrome) Frontotemporal disorders Frontal and anterior temporal hypometabolism behavioral variant Parkinson’s disease with dementia Temporo-parietal, may be similar to AD Diffuse lewy body disease Occipital and temporal hypometabolism Cognitive vascular disorders Cortical and subcortical, singular or multifocal, correlating with structural imaging abnormality Corticobasal degeneration Global reduction in metabolism as well as asymmetric prefrontal, premotor, pensorimotor superior temporal, parietal hypometabolism with thalamic hypometabolism contralateral to limb apraxia Huntington’s Caudate nucleus hypometabolism, frontal Figure 4. Sagittal 18FDGPET brain reveal- association cortex to a lesser degree ing preserved mid to posterior cingulate Progressive supranuclear palsy Caudate nucleus, putamen, thalamus, pons, superior and metabolism (arrows) with temporoparietal anterior frontal cortex hypometabolism. Note that FDG PET increases diagnostic accuracy beyond that derived from clinical evaluation.1

[page 28] [Neurology International 2012; 4:e7] Review frontal) in younger life may lead to a metabol- Table 3. Intrinsic connectivity network patterns in dementias. ic impairment predisposing people to amyloid Dementia subtype Intrinsic connectivity pattern deposition in later life.34 The DMN is known to subserve several key Alzheimer Default mode network shows reduced connectivity memory processes including episodic encod- Frontotemporal lobe disorder behavioral variant Salience network shows reduced connectivity ing, retrieval, autobiographical, metamemory Parkinson’s Basal Nuclei-thalamocortical loops show increased processes, moral decision making and theory connectivity of mind. Petrella et al. reported lower connec- Diffuse lewy body disease Uncertain at present but may show ascending tivity in DMN in patients with MCI who subse- brainstem projection system quently were diagnosed with AD over a 2-3 Cortical basal ganglionic Uncertain years period.32 This type of functional connec- tivity MRI (fc-MRI), is an attractive tool Table 4. Atrophy patterns in dementia subtypes. because MRI scanners with blood oxygen level Dementia subtype Atrophy pattern dependent (BOLD) capability are widely avail- able and fc-MRI is non invasive, radiation free, Alzheimer Temporoparietal, medial hippocampus, precuneus can be repeated multiple times and have short Frontotemporal disorders behavioral variant Frontotemporal acquisition time of 5-8 min.35 Parkinson’s with dementia Temporoparietal The quest for neuroimaging biomarkers for Diffuse lewy body disease Parietal atrophy but no hippocampal atrophy. diagnosing pre-clinical disease may soon be Caudate atrophy currently debatable realized albeit with perhaps a complementary Vascular cognitive disorder (vascular cognitive Nil specific, subcortical leukoaraiosis as role played by FDG-PET, Pittsburgh compound impairment, vascular dementia) opposed to periventricular rimming B PET (PiB PET), PET neurotransmitter imag- leukoaraiosis is frequent ing and fc-MRI of the DMN and perhaps other Progressive supranuclear palsy Midbrain atrophy (Hummingbird, Penguin signs) networks such as the salience (for FTD) and Cortical basal ganglionic Pronounced fronto-parietal atrophy, often attentional networks.36-39 With intrinsic con- asymmetric, corpus callosum atrophy nectivity networks the pattern for AD and FTD only is fairly clear. However for the PDD and DLDB ferent intrinsic functional connectivity net- Functional imaging studies support the neu- 39 the pattern is less obvious and there may also works. In particular the salience network has ral reserve and neural compensation reflecting be hyperactivity in the BG as opposed to the been shown to correlate with frontotemporal individual compensatory differences to pathol- 40 usual underactivity seen in the other neurode- lobe dementia. This relatively novel useapproach ogy. For example, two people with the same generative conditions (Table 3). of brain analysis, called connectomics by some cognitive impairment may have markedly dif- is showing promising results. Assessment of ferent degrees of underlying AD pathology. Neurotransmitter and neuro- brain connectonomics is regarded as an area This is clearly important for the diagnosis of of priority in future cognitive research (The preclinical Alzheimer’s disease, as mild cogni- transmtter receptor position emis- Human Connectome Project).41 tive impairment (MCI) patients may have both sion tomography (and sometimes minimal pathology or more extensive patholo- single photon emission computed The importance of considering cog- gy. The cognitive reserve (CR) hypothesis, is tomography) imaging nitive reserve status by functional used to describe this variability and is consid- ered an important part of the assessment In the hopes of guiding therapy more accu- imaging in conjunction with cogni- therefore. Clinical evaluation alone cannot be rately, the cholinergic (nicotinic receptors) tive or neuropsychological testing relied on and biomarkers (whether CSF analy- and dopaminergic systems have been investi- No direct relationship exists between the sis of tau and 1-42 or metabolic gated in this regard. An increase in 11C nico- extent of pathology and clinical manifestation imaging) will be part of the work up.44 tinic binding sites as well as associated cogni- of the underlying disease or damage for that Since the proposal of the CR hypothesis, tive improvement were reported after 3 matter. this has been recently supported using the PIB months of rivastigmine for AD patients.36 At Katzman et al., reported on 10 elderly nor- and 18FDG PET in relation to education in mild times neurodegenerative conditions coexist mal women with advanced AD pathology sup- AD. In this study, 12 high educated (15 or more and unraveling the most pertinentNon-commercial neurotrans- ported this premise, speculating that their years) and 13 low educated patient with the mitter systems at fault is useful. This has been 42 brains had more cognitive reserve. Cognitive same degree of cognitive deterioration were shown for acetylcholine involvement in reserve is considered to include: i) brain evaluated with PET brain scanning using both Parkinsons with and without dementia by 11C reserve capacity (correlate - hardware, brain [11C] PIB and 18F- as lig- methyl - 4- piperidyl acetate (MP4A). In this size, neural count or synapse count; ii) cogni- ands. The high-educated people showed study, the dopaminergic system was also meas- tive reserve (correlate - software). Attempting increased PIB uptake in the lateral frontal cor- ured using 18F (FDOPA) which to cope with brain damage using cognitive tex as well as lower glucose metabolic rate in revealed decreased uptake in the striatum and compensatory approaches. Higher education, the temporoparietal cortical regions compared MP4A was decreased in the Parkinson’s group bilingualism, literacy and participation in hob- to low educated people. with dementia.37 bies for example, allow people to withstand brain damage better. How may we utilize the various Cortical atrophy patterns Cognitive reserve in turn has been divided imaging modalities today and in the Cortical atrophy patterns are generally dis- into: i) Neural reserve: cerebral networks less cernible at a later stage of the process and per- susceptible to disruption due to greater inher- near future? haps the least sensitive (Table 4). ent efficiency; ii) neural compensation: post A likely hierarchical approach to using sur- Nevertheless, a recent pivotal study showed 5 brain damage, additional or nonconventional rogate neuroimaging in cognitive patients may different neurodegenerative syndromes and networks are deployed to compensate for brain be as follows may take the following format: i) their atrophy patterns corresponding to 5 dif- damage.43 Resting State Network Imaging (DMN,

[Neurology International 2012; 4:e7] [page 29] Review

Salience and others) by f-MRI; ii) beta amyloid brain in chronic CRPS pain: abnormal al. Serotonin 2 A Receptors and Visual hal- accumulation assessed by PET brain PIB (also gray-white matter interactions in emo- lucinations in Parkinsons Disease. Arch CSF assays); iii) the subsequent synaptic dys- tional and autonomic regions. Neuron Neurol 2010;67:416-21. function assessed by FDG-PET brain; iv) final- 2008;60:570-81. 24. Lim SM, Katsifis A, Villemagne V, et al. The ly, neuronal loss follows, as assessed by volu- 10. Apkarian AV, Sosa Y, Sonty S, et al. Chronic 18 F FDG PET cingulate island sign and metric MRI. back pain is associated with decreased comparison to 123I beta CIT SPECT for prefrontal and thalamic gray matter densi- diagnosis of dementia with Lewy bodies. J ty. J Neurosci 2004;24:10410-5. Nucl Med 2009;50:1638-45. 11. Rainville P, Duncan GH, Price DD, et al. 25. Ishii K, Soma T, Kono AK, et al. Conclusion Pain affect encoded in human anterior Comparison of regional brain volume and cingulate but not somatosensory cortex. glucose metabolism between patients with Since the revised AD criteria now include Science 1997;277:968-71. mild dementia with Lewy bodies and those biomarker testing, neuroimaging (particularly 12. Coghill RC, Sang CN, Maisog JM, Iadarola with mild Alzheimer’s disease. J Nucl Med PET) has gained acceptance. However, the MJ. Pain intensity processing within the 2007;48:704-11. conditions with most ambiguous results on human brain: a bilateral, distributed 26. Fujishiro H, Iseki E, Murayama N, et al. PET scanning (PDD and DLDB), certain neu- mechanism. J Neurophysiol 1999; 82:1934- Diffuse occipital hypometabolism on roradiological identification such as the PCIS 43. [18F]-FDG PET scans in patients with may be an important feature in improving con- 13. Casey KL. Concepts of pain mechanisms: idiopathic REM sleep behavior disorder: fidence in the discrimination between AD and the contribution of functional imaging of prodromal dementia with Lewy bodies? DLBD in clinical overlap syndromes and sup- the human brain. Prog Brain Res Pyschogeriatrics 2010;10:144-52. port differing therapeutics. For all the other 2000;129:277-87. 27. Dubois B, Feldman HH, Jocava C, et al. conditions, PET reliably discerns the differing 14. Kwan CL, Crawley AP, Mikulis DJ, Davis Revising the definition of Alzheimer’s dis- syndromes. The advent of ICN imaging looks KD. An fMRI study of the anterior cingu- ease: a new lexicon. Lancet Neurology promising to enable an even earlier and more late cortex and surrounding medial wall 2010;9:1118-27. precise diagnosis of the ever expanding array activations evoked by noxious cutaneous 28. Landua SM, Havey D, Madson CM, et al. of dementia syndromes. heat and cold stimuli. Pain 2000;85:359-74. Comparingonly predictors of conversion and 15. Sawamoto N, Honda M, Okada T, et al. decline in mild cognitive impairment. Expectation of pain enhances responses to Neurology 2010;75:230-8. nonpainful somatosensory stimulation in 29. Hu WT, Wang Z, Lee VM, et al. Distinct References the anterior cingulate cortex and parietaluse cerebral perfusion patterns in FTLD and operculum/posterior insula: an event- AD. Neurology 2010;75:881-8. related functional magnetic resonance 30. Emre M, Tsolaki M, Bonuccelli U, et al. 1. Foster NL, Heidebrink JL, Clark CM, et al. imaging study. J Neurosc 2000;20:7438-45. Memantine for patients with Parkinson’s FDG PET improves accuracy in distin- 16. Nielsen FA, Balslev D, Hansen LK. Mining disease dementia or dementia with Lewy guishing frontotemporal dementia and the posterior cingulate: segregation bodies: a randomized, double blind, place- Alzheimer’s disease. Brain 2007;130:2616- between memory and pain components. bo controlled trial. Lancet Neurol 35. Neuroimage 2005;27:520-32. 2010;9:969-77. 2. Berti V, Pupi A, Mosconi L. PET/CT in diag- 17. Foltz EL, White LE. The role of rostral cin- 31. Small SA, Schobel SA, Buxton RB, et al. A nosis of dementia. Ann NY Acad Sci gulotomy in pain relief. Int J Neurol pathophysiological framework of hip- 2011;1288:81-92. 1968;6:353-73. pocampal dysfunction in ageing and dis- 3. Migliaccio R, Agosta F, Rascovsky K, et al. 18. Talbot JD, Villemure JG, Bushnell MC, ease. Nat Rev Neurosci 2011;12:585-601. Clinical syndromes associated with poste- Duncan GH. Evaluation of pain perception 32. Petrella JR, Sheldon FC, Prince SE, et al. rior atrophy: early age at onset AD spec- after anterior capsulotomy: a case report. Default mode network connectivity in sta- trum. Neurology 2009:73:1571-8. Somatosens Mot Res 1995;12:115-26. ble vs progressive mild cognitive impair- 4. McKeith I. Lew body diseases. Clinical 19. Vogt BA, Derbyshire S, Jones AK. Pain pro- ment. Neurology 2011;76:511-7. aspects of dementia with Lewy bodies. In: cessing in four regions of human cingu- 33. Pievani M, de Haan W,Wu T, et al. Handbook of Clinical Neurology,Non-commercial 3rd edi- late cortex localized with co-registered Functional network disruption in the tion. London: Elsevier; 2008. pp 307-319. PET and MR imaging. Eur J Neurosci degenerative dementias. Lancet Neurol 5. Klein JC, Eggers C, Kalbe E, et al. 1996;8:1461-73. 2011;10:829-43. Neurotransmitter changes in dementia 20. Cole LJ, Farrell MJ, Duff EP, et al. Pain sen- 34. Andres-Hanna JR, Reidler JS, Sepulcre J, with Lewy bodies and Parkinson disease sitivity and fMRI pain-related brain activi- et al. Functional - anatomic fractionation dementia in vivo. Neurology 2010;74:885- ty in Alzheimer's disease. Brain of the brain’s default mode network. 92. 2006;129:2957-65. Neuron 2010;65:550-62. 6. Stern Y. Cognitive reserve. Alzheimer Dis 21. Mirzaei S, Knoll P, Koehn H, Bruecke T. 35. Galvin JE, Price JL, Yan Z, et al. Resting Assoc Disorders 2006;20:112-7. Assessment of diffuse Lewy body disease bold fMRI differentiates dementia with 7. Robinson ME, Craggs JG, Price DD, et al. by 2-[18F] fluoro-2-deoxy-D-glucose Lewy bodies vs Alzheimer disease. Gray matter volumes of pain-related brain positron emission tomography (FDG PET). Neurology 2011;76:1797-803. areas are decreased in fibromyalgia syn- BMC Nucl Med 2003;3:1. 36. Kadir A, Darreh-Shori T, Almkvist O, et al. drome. J Pain 2011;12:436-43. 22. De Meyer G, Shapiro F, Vanderstichele H, Changes in brain 11C nicotine binding 8. Obermann M, Nebel K, Schumann C, et al. et al. Diagnosis independent Alzheimer sites in patients with mild Alzheimer’s dis- Gray matter changes related to chronic disease biomarker signature in cognitive- ease following rivastigmine treatment as posttraumatic headache. Neurology 2009; ly normal elderly people. Arch Neurol assessed by PET. Psychopharmacol 73:978-83. 2010;67:949-56. 2007;191:1005-14. 9. Geha PY, Baliki MN, Harden RN, et al. The 23. Ballanger B, Strafella AP, van Eimeren T, et 37. Hilker R, Thomas AV, Klein JC, et al.

[page 30] [Neurology International 2012; 4:e7] Review

Dementia in Parkinsons disease: func- 40. Sprons O, Tononi G, Koetter R. The human reserve. J Clin Exp Neuropsychology tional imaging of cholinergic and connectome: a structural description of 2003;5:691-701. dopaminergic pathways. Neurology the human brain. PLoS Comput Biol 2005;65:1716-22. 2005;1:e42. 44. Kemppainen NM, Aalto S, Karrasch M, et 38. Seeley WW, Crawford RK, Zhou J, et al. 41. Katzman R, Aronson M, Fuld P, et al. al. Cognitive reserve hypothesis: Neurodegenerative disease target large Development of dementing illnesses in an Pittsburgh compound B and fluo- scale human brain networks. Neuron 80 year old volunteer cohort. Ann Neurol 2009;62:42-52. 1989;25:307-24. rodeoxyglucose position emission tomog- 39. Seeley WW, Menon V, Schatzberg AF, et al. 42. Stern Y. Cognitive reserve. Neuropsy - raphy in relation to education in mild Dissociable intrinsic connectivity net- chologia 2009;47):2015-28. works for salience processing and execu- 43. Stern Y, Zarahn E, Hilton HJ, et al. Alzheimer’s disease. Ann Neurol 2008; tive control. J Neurosci 2007;27:2349-56. Exploring the neural basis of cognitive 63:112-8.

only use

Non-commercial

[Neurology International 2012; 4:e7] [page 31]