Future directions In the last decade much has been achieved in the recognition of DLB as a disease entity. It is now recognized as a synucleinopathy in a spectrum with PD and PDD. Fu ture clinicopathological studies in well-defi ned prospective autopsy cohorts should furthe r identify mechanisms that are responsible for the variability of Lewy-related pathology an d the subsequent phenotypes in this spectrum. Understanding the pathology of DLB and Lewy b ody disorders in general will probably have implications for the current classifi ca- tion system. Another remaining question is the co-localization of pathologies. Currently, it is not clear what the exact relationship is between these misfolded proteins (i.e. -synucle in, amyloid-beta and tau), how they interact, and if they share common molecular processes. Th e biggest issue is how these pathological processes are related to clinical symptoms. FTD is a clinical syndrome with distinct subtypes. Th e under- lying pathological syndrome of FTD is known as frontotempo- ral lobe degeneration (FTLD), and it can be divided into tw o major neuropathological subtypes depending on the presence or absence of specifi c protei n accumulations in neurons and/or glial cells: FTLD with tau-positive inclusions (FTLD-tau) , and FTLD with ubiquitin-positive and TDP-43-positive inclusions (FTLD-TDP). A third minor neuropathological subtype of FTLD has ubiquitin-positive, TDP-43 negative pathology, but h as shown immunoreactivity with a fused in sarcoma (FUS) antibody. Additionally, several genetic defects have been identifi ed in some forms of hereditary FTD , which have led to growing insight into disease mechanisms. Diff erent clinical variants ( behavioral, aphasic, and motor neuron disease variants) are now recognized as being part of the clinical spectrum of FTD (28). Th e most common form of FTD is the behavioral variant in which changes in behav- iour and executive dysfunction defi ne the clinical picture. In this chapter we will focus on the variants of FTD that are accompanied by parkinsonism. Mos t of these syndromes are linked to genetic mutations, especially on chromosome 17 (FTDP-17) . At present only symptomatic treatment can be off ered to patients suff ering from DLB. Nove l treatment strategies should be directed at the -synuclein pathology. In order to fi nd a rational target for future drug development it is necessary to elucidate the toxic speci es of -synuclein that are responsible for disease pathogenesis. More research is needed to fi nd reliable biomarkers to identify patients as early as possible, ideally even in a p rodromal or preclinical phase. Similar extensive research has already taken place in AD, in clud- ing clinical trials with potential disease-modifying drugs. Th ere are many lessons t o be learned, and this could probably speed up progress to fi nd eff ective treatments in t he synucleinopathies. Microtubule associated protein tau (MAPT) Around 30% of cases of familial FTD are caused by mutations in the microtubule associated protein tau (MAPT) gene on chromosome 17. FTD caus ed by MAPT mutation is an autosomal dominantly inherited disease, although recessive forms have been described. Incomplete penetrance is extremely rare in MAPT mutations, which may h elp to discriminate it from progranulin (PGRN) muta- tions in genetic counseling (29). Top clinical tips Diagnosing DLB can be challenging; recognition of the key symptoms in patients with dementi a in combination with SPECT-imaging can increase diagnostic accuracy. \227\206 Patients with DLB benefi t from cholinesterase inhibitors with regard to cognitive decline and neuropsychiatric problems; par- kinsonism can be treated with dopaminergic drugs titrat ed up to levels that are tolerated in the individual patient. \227\206 Hyperphosphorylated tau in neurons and/or glial cells is the pathological hallmark of MAPT mutations. Tau stabilizes microtu- bules (MTs) and promotes tubulin assembly into microtubu les. In Oxford Textbook of Movement Disorders 156 the human brain, alternate mRNA splicing of exons 2, 3, and 10 of the MAPT gene leads to th e production of six tau isoforms. Th ey diff er by the presence of three or four repeats, w hich constitute the MT-binding domains of tau. More than 40 mutations in tau have been iden tifi ed to date (30). 45 40 MAPT 35 GRN 30 e g a t n e c r e P 25 Mutations in MAPT exert their pathogenic eff ects through sev- eral diff erent actions. Mis sense mutations in exons 9 \200\22313 impair the normal function of tau binding and stabili zation of MT and promotion of tau fi lament formation, while intronic mutations and some co ding mutations disturb alternate splicing and isoform expression. Th ese mechanisms promote hyperphosphorylation and tau fi lament formation. MAPT mutations are associated with diff erent types of neuronal tau inclusions; these include diff use or punctate staining, Pick b odies (intraneuronal argyrophilic inclu- sions, consisting of abnormal three repeat tau pro tein), neurofi - brillary tangles, and pre-tangles. Histopathological examination reveals s evere frontotemporal atrophy with neuronal loss, gliosis, and spongiform changes in layer 2 . Involvement of medial tempo- ral lobe structures (e.g. entorhinal cortex, hippocampus, an d amyg- dala) is more variable. Degeneration of substantia nigra and basal ganglia is commo n. Tau-positive inclusions are most oft en found in frontotemporal cortex and subcortical n uclei, but can also occur in midbrain, brainstem, cerebellum, and spinal cord. Tau-positive inclusions usually refl ect the severity of neuronal loss, but can also be prominent in re gions with less severe nerve cell loss. Glial tan- gles and coiled bodies are found in whit e matter, and these consist mainly of four repeat tau isoforms. Glial tau pathology can be more severe than neuronal pathology (30). 20 15 10 5 0 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 Age at onset (years) Fig. 15.4 Variability in age at onset between patients with MAPT and GRN gene mutations. (R eproduced with permission from Seelaar H, Kamphorst W, Rosso SM, et al. Distinct genetic fo rms of frontotemporal dementia. Neurology 2008; 71: 1220 \200\2236). are characteristic. Disinhibition gives way to impulsive reactions, such as hyper-orality, jocularity, and emotional insensitivity. Poor social conduct leads to embarrassment and ups et for those close to these patients. Apathy and loss of initiative are prominent when the disease manifests. Some patients present with distinct psychiatric features such as obsessi ve \200\223compulsive behaviors or paranoid delu- sions and hallucinations, initially sugge sting a psychiatric disorder. Patients may develop language diffi culties, consisting of in effi - cient word retrieval, anomia, and stereotypical language use. Mildly impaired compre hension can be present. Reduced spontaneous speech results in mutism within 5 years in all patients, although relative preservation of language abilities has been described in some m utations. Th e pattern of cognitive dysfunction is similar for all individuals with MAPT ge ne mutations. Cognitive function may be impaired decades before the presentation of dementi a, and asymptomatic mutation carriers have reduced verbal fl uency, atten- tion, and motor speed, and set-shift ing in their twenties and early thirties. Filamentous tau inclusions are the pathological hallmark of a number of neurodegenerative d isorders, of which AD is the most common, as well as progressive supranuclear palsy (PSP), cortico- basal degeneration (CBD), Pick \200\231s disease, and argyrophilic grain disease ( AGD). Clinical presentation Th e age at onset is usually between 45 and 65 years, although there may be some variation according to type or location of mutation within tau. Th e disease ca n present aft er 65 years of age, but is unusual aft er the age of 70. In some mutations cl inical symptoms can develop before 40 years of age, and even in the mid-twenties (Fig. 15.4 ). Th e mean disease duration is on average 9 years aft er presentation of the fi rst sympt oms. An exception is mutation R406W, which is characterized by a slow rate of disease progr es- sion lasting up to 25 years. An early age at onset is oft en associated with a more rap id disease progression, leading to death within 5 years. Epilepsy, both partial and generalized epileptic seizures, has been reported in some mutations. In the parkinsonism-predominant type characteristic features include resting tremor, rigidi ty, bradykinesia, postural instability, and gait impairment. Th ere is usually no or only a transient benefi t from levodopa treatment. Vertical gaze palsy, saccadic pursuit eye move ments, and axial rigidity can develop even at onset in some mutations. Corticospinal tract signs have been reported in some cases. In some families, patients presented with a cortico basal syn- drome with unilateral rigidity, dystonia, and contractures, in com- bination wit h impaired eye movement. Th ese observations indicate that there is a clinical overlap betw een FTDP-17, PSP, and CBD (27, 29, 31). Two major clinical subtypes can be distinguished in patients with MAPT mutations: dementia- predominant and parkinsonism- predominant (Table 15.2). Both subtypes can occur in patients with the same mutation and even within the same family. Th e dementia phenotype is usually associated with mutations G272V and P301L. Cognitive dysfunction diff ers from that seen i n patients with AD. Episodic memory, orientation, and visuoconstructive func- tions are rel atively intact. Th ere is prominent frontal dysfunction, expressed as impairment in verbal fl uency, abstract thinking, and executive functions, causing diffi culties with planning a nd mental set-shift ing. Impaired judgment and loss of insight aff ect social and professio nal lives. Attention and concentration are decreased and oft en infl uence neuropsychologic al testing. Personality changes Progranulin A substantial proportion (20 \200\22340%) of hereditary FTD cases do not have M APT mutations. Some of these families are histopathologi- cally characterized by ubiquitin- positive but tau-negative inclu- sions and show linkage to chromosome 17q21 \200\22322. It is now known that they have mutations in the progranulin (PGRN) gene (32, 33). More than 60 mutations in the PGRN gene on chromosome 17 have been identifi ed. Th e frequency of PGRN mutations is similar to CHAPTER 15 Primary Dementia Syndromes and Parkinsonism 157 Table 15.2 Clinical and pathological features of FTDP Mean age at onset (years) 55 (40 \200\22365) Mean duration (years) 9 (5 \200\22320) Clinical presentation BvFTD PSP-like CBS Behavioral presentation Disinhibition Obsessive \200\223compulsive Language features Impaired comprehension Pathology MAPT Neuronal and glial tau-positive inclusions PGRN 60 (35 \200\22389) 8 (3 \200\22322) BvFTD PNFA aMCI CBS Apathy Social withdrawal Non- \202 uent speech Ubiquitin- and TDP-43-positive NCI, NII, DN C9orf72 55 (34 \200\22376) 8 (1 \200\22322)* BvFTD MND PPA aMCI Apathy Social withdrawal Non- \202 uent speech Ubiquitin- and TDP-43-positive NCI, NII, DN P62-positive TDP-43-negative inclusions cerebel lar aMCI, amnestic MCI; NCI, neuronal cytoplasmic inclusions; NII, neuronal intranuclear inclus ions; DN, dystrophic neurites; CBS, corticobasal syndrome; MND, motor neuron disease; BvFTD , behavioral variant of FTD. *FTD patients with MND have a signi \201 cant shorter surviva l than FTD patients without MND. that of MAPT gene mutations in hereditary FTD. PGRN mutations have been reported in a few s poradic cases of FTD. Th is apparently non-Mendelian form of the disease might be due to in complete penetrance, de novo mutations, or non-paternity (34). (35, 36) (Fig. 15.5). It is not yet known how PGRN mutations are involved in the accumulati on of TDP-43 protein. PGRN mutations invariably lead to severe frontal cortical atro- phy, and to a lesser extent temporal, perisylvian, and parietal atrophy, oft en with an asymmetric pattern (Fig. 15.6) . Th is can distinguish PGRN mutations from MAPT mutations, where a more symmetrical atroph y is seen without parietal involvement. Subcortical structures are frequently aff ected, wi th marked atrophy of the caudate nucleus and depigmentation of the substantia nigra. Occasi onally, atrophy of cortex and subcortical nuclei may be very mild. Hippocampal atrophy has been reported in some cases (34). Histopathological examination exhibits very similar fi nd ings in diff erent PGRN mutations. Th ere is moderate to severe neuronal Little is known about the function of the progranulin protein that is expressed in specifi c neuronal subsets. PGRN mutations result in a loss of protein, whereas the tau mutations r esult in a toxic gain of function. Th e characteristic feature in FTLD with PGRN muta- tion s is the presence of abundant ubiquitin-positive neuronal cyto- plasmic inclusions (NCI), n euronal intranuclear inclusions (NII), and irregular dystrophic neurites in the neocortex a nd subcorti- cal nuclei. Th e major protein in the ubiquitin-positive inclusions is the hyp erphosphorylated TAR DNA-binding protein (TDP-43) (a) (b) (c) (d) Fig. 15.5 Pathology of an FTD patient with PGRN gene mutation: (a) TDP-43-positive dystroph ic neurites in the frontal cortex; (b) a TDP-43-positive neuronal intranuclear inclusion in the parietal cortex; TDP-43-positive neuronal cytoplasmic inclusions in (c) the hippocampu s and (d) the caudate nucleus and putamen. Scale bar, 20 m. (Reproduced with permissio n from Dopper EG, Seelaar H, Chiu WZ, et al. Symmetrical corticobasal syndrome caused by a novel C.314dup progranulin mutation. J Mol Neurosci 2011; 45: 354 \200\2238. Authors, 201 1) Oxford Textbook of Movement Disorders 158 of the involvement of the parietal cortex amplifi es the confusion with AD. Visuospatial de fi cits are uncommon, although they are reported in a few cases. Hallucinations and delusio ns are reported in up to 25%. Extrapyramidal signs occur throughout the course of the disea se in many patients with FTD as a result of PGRN. Bradykinesia and asymmetric rigidity may occur early in the dis- ease, sometimes with resting tremor and dystonia resembling Parkins on \200\231s disease. Treatment with levodopa usually has no or only a modest benefi t on t he parkinsonian features. A corticobasal syndrome with limb apraxia, asymmetric parkinsonis m, and dys- tonia of the upper extremity can occur, but usually in combination with conside rable cognitive defi cits compared witth non-carriers. Pyramidal signs and primitive refl e xes may be seen in advanced endstage cases (34, 38, 39). (a) (b) Fig. 15.6 Structural MRI and SPECT in FTD with PGRN gene mutation: (a) mild symmetric front oparietal atrophy on MRI scan; (b) symmetric parietal hypoperfusion on SPECT scan. (Reprodu ced with permission from Dopper EG, Seelaar H, Chiu WZ, et al. Symmetrical corticobasal syn drome caused by a novel C.314dup progranulin mutation. J Mol Neurosci 2011; 45: 354 \200 \2238. Authors, 2011) C9orf72 Aft er the identifi cation of PGRN, there remained a number of families, in particu lar familial FTD-MND, that were linked to chromosome 9p. Very recently, hexanucleotide repe at expansions in the chromosome 9 open-reading frame 72 (C9orf72) have been described in fa milies with FTD with or without amyotrophic lateral sclerosis (ALS) (40, 41). Th e expansio n is located in a non-coding region. Th e exact cut-off indicating a pathological repeat ex pansion is still unknown. Quantitative messenger RNA analysis has shown that the presence o f the expanded repeats leads to reduced expres- sion of one of the transcripts of C9orf72 e ncoding a protein with an unknown function, suggesting a (partial) loss-of-function disease mechanism (40). However, a toxic gain-of-function of abnormal messenger RNA has also been hypothesized based on the discovery, using fl uorescence in situ hybridization experiments with a probe targeting the GGGGCC repeat, of multiple nuclear RNA foci in brain tissue from patients carrying the expanded repeats (40). loss in combination with spongiosis in the frontal and temporal cortex (orbital and insular ). White matter is frequently aff ected in PGRN mutations, showing extensive astrocytic gli osis and myelin, and hippocampal sclerosis with severe neuronal loss and gliosis in CA1 and subiculum. Clinical presentation Th e mean age of onset of FTD with PGRN mutations is 60 years, rangin g from 35 to 89 years. Even within families there is consider- able variation in age of ons et with a tendency to present at an earlier age (up to 10 \200\22320 years) in consecutive generations. Th e mean dura- tion of disease from presentation is about 8 years, but again this can vary substantially from 3 to 22 years where a higher age of onset is associated wi th a shorter disease duration. Th e penetrance is 90% by the age of 70 years (see Fig. 15.4 ). Sex or type of mutation do not aff ect age of onset. Th e variation in age at onset can cause failure to recognize an autosomal dominant inheritance pattern in small families with only a few relatives (34). Histopathological examination shows that ubiquitin- and TDP-43 positive neuronal cytoplasmi c inclusions and dystrophic neurites are present in all cases, with neuronal intranuclear i nclu- sions present in several cases. Some inclusions stained positive for p62, but were ne gative for TDP-43, in particular in cerebellar granular cells. Together with the extensive ubiquitin pathology in the hippocampal molecular layer and CA regions found in C9orf72 case s, this may neuropathologically diff erentiate, although not completely, FTD and ALS cases with and without repeat expan- sions (42 \200\22344). How the repeat expansions lead to acc umulation of TDP-43 in the brain, and why some inclusions are TDP-43 negative has yet to be elucidated. PGRN mutations are characterized by heterogeneous symptoma- tology with cognitive decline, behavioral disturbances, neuropsy- chiatric features, and movement disorders (see Table 15. 2). Clinical presentation can vary within families, with a parkinsonian pheno- type in one aff ected relative and dementia phenotype in another. Patients with PGRN mutations have a p ositive family history for dementia or parkinsonism in 70 \200\22390% of cases. Behavioral changes are the most common clinical presentation, with apathy and social withdrawal as pro minent features. Language abilities are frequently aff ected, comprising reduced spontaneou s speech, word-fi nding diffi culties, and phonemic paraphasias evolving into mutism over t he course of the disease. In 20 \200\22325% of patients with PGRN muta- tions language dysf unction presents early and in relative isolation over a considerable period of time, consis tent with the diagnosis of progressive non-fl uent aphasia (37). Clinical presentation Th e discovery of the C9orf72 repeat expansion has extraordinary impo rtance for clinical practice in neurodegenerative diseases. Th is is due in part to its ver y high frequency, varying between 10 and 30% of familial FTD, and between 20 and 50% of fam ilial ALS, and its broad range of clinical manifestations, including an anterograde amnesti c dementia, easily misdiagnosed as AD, and its apparent occurrence in sporadic cases. Th es e and other aspects of C9orf72 expansion repeats are emphasized in two studies (45, 46). Impaired comprehension and semantic paraphasias have occa- sionally been described. Cogniti ve decline is usually revealed by frontal lobe defi cits such as executive dysfunction and reduced ver- bal fl uency. Patients can erroneously be diagnosed with the amnes- tic type o f mild cognitive impairment (aMCI) or AD as episodic memory defi cits occur in the initial stage in 10 \200\22330%. Th e fact that apraxia and dyscalculia are frequently encountered as a refl ection Th ere is considerable variation in age at onset and clinical pres- entation among and with in families with C9orf72 repeat expan- sions (45 \200\22347) with a mean age of 55 years, r anging from 34 to 76 years. For cohorts of pure ALS patients, a younger onset age, co-morbi d FTD, and apathy or dysexecutive behavior are more CHAPTER 15 Primary Dementia Syndromes and Parkinsonism 159 common in carriers with expanded repeats (48). Motor neuron dis- ease occurs in approximate ly 20 \200\22340% of FTD cases with expanded repeats. Th e behavioral variant, predominantl y with apathy and loss of initiative, is the most common clinical manifestation of FTD (45, 46). Th e occurrence of psychotic symptoms has been reported. Delusions are more common th an hallucinations, and sometimes lead to an initial psychiatric diagnosis (44). Primary pro gressive aphasia (PPA) may occur as the presenting clinical manifestation of C9orf72 repeat expansion (44, 49, 50). Parkinsonism and akinetic \200\223 rigid syndromes without resting tremor frequently occur, but are rarely the dominant presentation in patients with C9orf72 repeat expansions (49, 51). with PGRN mutations refl ects the involvement of these regions in the pathogenesis (37). In patients with parkinsonism, SPECT with the radioligand 123 I-FP-CIT shows a severe symme trical decrease of presynaptic dopamine transporter binding in the striatum in individuals with some mutations. Th is technique has probably no added value in the diagnostic work-up of FTD. EEG tends to be normal in FTD, as opposed to AD and DLB. Interictal epileptic disch arges have been described in some MAPT mutations. CSF levels of total and hyper- phosphoryl ated tau are usually normal in FTD with tau pathology, in contrast with elevated levels of CSF-tau in AD and PSP (53). Management No clear risk factors are known in FTD. Supportive care is essential to manage t he behavioral symptoms for the patients, and also for the family and caregivers. Important non-pharmacological options are off ering regularity and structure, oft en in a formal sett ing such as day-care centers or nursing homes. Curative pharmacological options are not ava ilable. Th ere have been no large double-blind placebo-controlled trials performed in FTD. A small double-blind controlled trial with trazodone in 26 FTD patients showed that 150 mg twice daily had a favorable eff ect on the behavioral problems in FTD, especially irritabil ity, agitation, depression, and eating dis- orders (54). Another possible distinctive feature may be the pattern of cer- ebral atrophy on MRI in pat ients with C9orf72 repeat expansions. FTD patients with expansions showed more parietal and bilateral thalamic atrophy than those without expansions. Apart from fron- tal, anterior t emporal, and parietal atrophy, cerebellar atrophy and changes in diff usivity and fractiona l anisotropy in thalamic radia- tions have been reported (49, 51). However, the value of th ese dis- tinct anatomic profi les must be interpreted cautiously in what have been only sma ll studies to date. Diagnosis Th e clinical diagnosis of FTD is based on criteria proposed by the Work Group on Frontotemporal Dementia and Pick \200\231s Disease in 2000 (52). Recently revised diagnost ic criteria for the behavioral variant of FTD have been published in which patients are cla ssi- fi ed as possible, probable, or defi nite bvFTD. Th e most important revisions are the incorporation of neuropsychological, neuroimag- ing, genetic, and pathological fi ndings w ithin the criteria and the expansion of the role of supportive behavioral features for the diagnosis of bvFTD (28). FTD can be diagnosed when there are clear behavioral or cognitive defi cits which interfere with social and occupational functioning. Th ese defi cits are ma nifested by either early and progressive change in personality, characterized by diffi cult y in modulating behavior, oft en resulting in inappro- priate responses or activities, or b y early and progressive change in language. Other features are prominent in FTDP-17, but th ere are no standardized clinical criteria in which these FTD variants are included. Th e only double-blind randomized trial with an SSRI (parox- etine) showed no positive beha vioral changes in FTD (55). Acetyl- cholinesterase inhibitors and glutamate blockers (meman tine) are not currently indicated for FTD. Patients with FTD \200\223MND with dif- fi culty in swallowing are oft en started on riluzole or amitriptyline (personal experience), with generally good response (56). Genetic counseling can be advised in patients with a heredi- tary form of FTD. Th e benefi t of genetic screening depends on the strength of the family history and the clinical subty pe. Both MAPT and PGRN gene defects are most oft en found in patients with an autosomal dom inant form of bvFTD. Screening in sporadic patients will be of little value, as a very few mutations have been found in sporadic cases except for those with a concealed or incomplete fam- ily history. Presymptomatic screening for MAPT or PGRN gene mutations is possible. Th e motivation to pe rform presymptomatic screening is oft en based on life decisions, for example the children \200\231s wishes. Th erefore support by a clinical geneticist and psychologist is indi- cat ed in presymptomatic screening. It must be realized that the age of onset varies widely wit hin families, especially in PGRN families with a range from 35 to 89 years. A clinical diagnosis of FTDP-17 can be supported by neuroimag- ing. Frontotemporal lobar at rophy is the most common neuroradio- logical feature. Atrophy patterns can vary among MAPT mutations. Predominant, oft en asymmetric, temporal atrophy, sometimes with additional hipp ocampal atrophy, has been described. Other patients have a more diff use cerebral atrophy, especially those with intronic mutations (29). Key advances Over the past years three major breakthroughs have been achieved. One of them is the discovery of mutations in the PGRN gene in hereditary FTD. Th e second major breakth rough was the identifi - cation of TDP-43 as major constituent of ubiquitin-positive inclu- sions. Th ese inclusions were found in patients with ALS, indicating that these two distin ct clinical disorders belong to the same clin- icopathological spectrum. All patients with PGRN gene mutations have TDP-43 pathology. It remains unclear how mutations in the PGRN gen e lead to accumulation of TDP-43 in the brain. Th e third important fi nding has been the r ecent identifi cation of repeats in C9orf72 in a number of FTD and ALS patients. In PGRN mutations MRI may occasionally be normal, even a few years aft er onset. Th e cereb ral atrophy of the anterior regions fre- quently extends more posteriorly into the parietal lobe. Th e cerebral atrophy oft en has an asymmetric pattern. Th e ventricles are usually enlarged. Sometimes the cortical atrophy has a more diff use pat- tern, or it may be accomp anied by cerebellar atrophy. Subcortical hyperintensities on T 2 -weighted MR images may be seen in areas of severe cortical involvement (34). Early in the disease, even before morphological changes occur, hypoperfusion and reduced gl ucose metabolism can be observed in the frontal and temporal lobe on SPECT and PET, respect ively. Hypoperfusion of the hippocampus and cingulate gyrus in patients Oxford Textbook of Movement Disorders 160 Future developments Important advances over the last decade have led to an impressive chang e in the clinical recognition of this disease. 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Conclusions Th is chapter has highlighted DLB and FTDP as important pri- mary dementia synd romes that are accompanied by parkinsonism. Parkinsonism is not uncommon in other types of dementia, such as AD and vascular dementia, but parkinsonism usually occurs rela- tively la te in the course of these diseases. DLB and FTD are both challenging neurodegenerative dise ase entities in terms of diagno- sis and management. Th ere is no cure, but symptomatic tre atment is available, especially for DLB, albeit with limited eff ectiveness, and long-term effi cacy needs to be established. DLB shares many features with PD/PDD and future clinical research will probably be directed towards the whole spectrum of disorders with Lewy-relat ed pathology. 11. McKeith IG, Galasko D, Kosaka K, et al . Consensus guidelines for the clinical and path ologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB intern ational workshop. Neurology 1996; 47 : 1113 \200\22324 . 12. 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