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Trans Am Neurol Assoc 1967; 92 : 23 \200\2236 . This page intentionally left blank CHAPTER 15 Primary Dementia Syndromes and Parkinsonism A.W. Lemstra , H. Seelaar , and J.C. van Swieten Summary Th is chapter addresses neurodegenerative diseases that are pri- marily dementia sy ndromes but are frequently, or by defi nition, accompanied by parkinsonism. In many neurode generative dis- eases cognitive dysfunction and extrapyramidal signs occur during the cours e of the disease. Th is chapter is limited to those diseases in which dementia is a core fe ature and parkinsonism is mostly present early in the disease. We will discuss dementia wit h Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD), syndromes which present w ith parkinsonism. DLB is part of the spectrum of Parkinson \200\231s disease and is clinica lly challenging from the diagnostic and management perspective. Recent advances in genetic and molecular research have greatly improved insight into disease mechanisms in FTLD, with mutations in two MAPT and GRN genes on chromosome 17. We will discuss the clinical and path ological overlap between FTDP-17 and other parkinsonian syndromes. Th e combination of cogn itive dysfunction and extra- pyramidal symptoms in corticobasal degeneration and progressiv e supranuclear palsy may overlap with FTLD, but these diseases are not considered primary d ementia syndromes and are addressed in Chapter 14. described in more detail elsewhere in this book. Familial aggrega- tion in DLB supports the idea of genetic risk factors, and a novel locus on chromosome 2 was found in a Belgian fam ily, although a pathogenic mutation has not been found (2). Th ere is evidence for overlap in genetic determinants for PD based on mutations found in some patients with DLB (3). Pathophysiology Deposits of the synaptic protein -synuclein are the pathological substra te of the diseases known as synucleinopathies which include DLB, Parkinson \200\231s diseas e, multiple system atrophy, and some other rarer clinical conditions. Alpha-synuclein is an abundant brain protein whose precise function remains to be elucidated, but it is probably involved in vesicular processes. Conformational changes convert -synuclein from an - helical structure into a -sheet-rich insoluble state which oligomerizes and aggregates i nto fi brillary structures (4). Th ese aggregates are found in intracytoplasmic inclu- sion bodies, termed Lewy bodies, which are the hallmark patho- logical lesion of DLB. Th ese ag gregates are found more abundantly in dystrophic neurites, termed Lewy neurites (LNs). Th e exact mechanism of the pathogenic pathway remains to be elucidated. It is not clear which species of -synuclein are toxic, but there is grow- ing evidence in favor of the soluble -synuclein oligomers (4, 5). Th e presence of LNs and the successive extensive loss of dendritic spines in postsynaptic areas are probably closely related to the clini- cal sympt omatology (6, 7). Dementia with Lewy bodies Th e term dementia with Lewy bodies (DLB) was coined in 1996; bef ore this the disease was known by various names such as dif- fuse Lewy body disease, Lewy b ody dementia, the Lewy body vari- ant of Alzheimer \200\231s disease, senile dementia of Le wy body type, and dementia associated with Lewy bodies. All autopsy studies show a considerable variability in the bur- den and distribution of Lew y-related pathology in diff erent regions of the nervous system. Th is probably accounts fo r the heterogen- eity of the clinical phenotype. Braak and colleagues described the patholo gical progression of Lewy-related pathology in both DLB and PD as occurring via caudorostra l propagation (8). Although this has been confi rmed in several studies, a substantial port ion of subjects do not match this paradigm, and more research is needed to fully validate t he pathological progression of the disease (9). Th e consensus pathological guidelines, whi ch also take AD pathology DLB has been reported as the second most common form of dementia aft er Alzheimer \200\231s disease (AD), but epidemiological stud- ies of this disorder are lacking. Its estimated pr evalence ranges from zero to 5% in the general population and from zero to 30.5% in dementi a cases. Th e mean age of onset in DLB is 75 years, with a range from 50 to 80 years, and t here is a slight male predominance (1). Th e current knowledge of genetics in Lewy body dis orders is Oxford Textbook of Movement Disorders 152 into account, distinguish three phenotypes: brainstem, transitory/ limbic, and diff use cor tical (9, 10). Th e diagnosis of DLB is based on the severity of the LB/LN pathology presen t in the brainstem, basal forebrain/limbic system, and cortical areas as detected by immuno histochemical staining for -synuclein. DLB is frequently associated to a variable extent with AD pathology, specifi cally amy- loid plaques and neurofi brillary tangles, especiall y in older patients. Guidelines for the pathological assessment of DLB recommend taking int o account both the extent of Lewy-related pathology and the concomitant AD pathology (11). In patients with severe AD pathology (Braak stage V \200\223VI) in combination with Lewy-re lated pathology, the probability that neuropathological fi ndings are asso- ciated with the DLB clinical syndrome is considered to be low. DLB cannot be clearly diff erentiated patho logically from Parkinson \200\231s dis- ease dementia (PDD), as they both result in endstag e diff use brain pathology and similar clinical phenotypes. Some subtle pathologi- cal diff erences have been described. In DLB, Lewy-related pathol- ogy is more extensive in the str iatum than it is in PDD. Neuronal loss in the substantia nigra is greater in PDD, while -amyloid plaques are more frequent in DLB (7). Visual hallucinations are a prominent psychiatric feature of DLB. Th ese hallucinations can be very vivid images of people or ani- mals, which cause great distress to patients and ca regivers. Other frequently occurring neuropsychiatric symptoms are delusions, depression, a nd hallucinations in other modalities. Compared with classic Parkinson \200\231s disease, motor dysfunc- tion may be less prominen t at onset. Based on information from autopsy-confi rmed DLB cases, in some cases parkinson ism may not develop at all during the disease course. Th e most common parkinsonian phenoty pe is that of symmetric hypokinetic rigidity. Postural instability and gait abnormalities a re frequently present. Tremor is less common in DLB, but both action and resting tremor hav e been described (1). REM sleep behavior disorder (RBD) is a supportive feature for the diagnosis of DLB. RBD is common in synucleinopathies and can precede other symptoms by several years. Th e muscle at onia that usually occurs during REM sleep \200\224the dream phase of sleep \200\224is absen t. Patients start acting out their dreams with abnormal behav- iours that can range from si mple twitches to complex integrated movements like kicking and punching, but also screaming and leaving the bed. Th ese behaviors can cause injury and may some- times be dangerous to the patient and their bed partner (14). Cortical LB density does not always correlate well with cognitive dysfunction. Lewy neurite s and neurotransmitter defi ciencies may be more closely related to clinical symptoms (1). Autonomic failure is regularly encountered in DLB patients. Th e most common features are o rthostatic hypotension, leading to diz- ziness and syncope, and micturition problems. A profound loss of cholinergic neurons in the basal forebrain, the basal ganglia, and the p edunculopontine pathway is found in DLB. The cholinergic system is a major modulating syste m of the neocortex and is involved in attentional processes. Cholinergic deficiency is prob ably related to clinical symptoms in DLB, such as attentional deficits, cognitive fluctuati ons, and hallucinations. The cholinergic deficiency in DLB is more extensive than in AD, bu t postsynaptic muscarinic receptors are relatively preserved. This could partly explain why DLB patients can benefit more from cholinesterase inhibitor drugs (12). Other neurotransmi t- ter systems are also affected in DLB. The dopaminergic deficits, although less prominent than in classic PD, are related to par- kinsonian signs. Marked reduction of serotonin lev els has been reported, but the association with clinical symptoms is not yet fully elucidat ed (12). Diagnosis Th e fi rst diagnostic criteria for DLB were published in 1996. Th ese criteria w ere subsequently revised at the third international workshop of the DLB consortium in 2005 (see Table 15.1) (10, 11). Th e central feature is progressive dementia, defi ned as in the previous section. Core features are hallucinations, fl uctuation in cognition, and parkin- sonism. Probable DLB can be diagnosed if two of these three core fea- tures are present wi th the dementia. If only one core feature is present, possible DLB is suggested. Additional symptoms suggestive of DLB are RBD, neuroleptic sensitivity, and low dopamine transporter uptake on SPECT/PET imaging. Possible DLB becomes probable DLB when a suggestive symptom is present. Clinical presentation Th e central feature of DLB is dementia, which is defi ned as a progr essive cognitive decline leading to functional impairment. Patients with DLB show a wide sp ectrum of cognitive symptoms, with an emphasis on attentional defi cits, frontal executive disor- der, and decline of visuospatial and constructional abilities (Fig. 15.1). Memory fu nctions are usually relatively preserved early in the disease course, which can help to dif f erentiate DLB from AD. Patients with AD perform worse in naming and memory tests than pat ients with DLB, but the latter have more visuospatial diffi cul- ties. Th e cognitive profi les of AD and DLB show greater overlap in more advanced stages of the diseases. Fluctuatio ns in cognitive functioning occur in more than 50% of DLB patients; they can occur over min utes, hours, or days, and are associated with epi- sodes of disturbed consciousness and red uced attention and alert- ness (1). Identifi cation and assessment of cognitive fl uctuatio ns is challen ging as the operationalization of the term remains elusive. A few validated s cales for assessing fl uctuations are available, but inter-rater reliability is poor and th e literature on the diagnostic utility of these scales is scarce (13). Fig. 15.1 Example of visuoconstructional dysfunction in a DLB patient. Th e patient was ask ed to copy pentagons from the MMSE and draw a clock in which the hands indicated ten past e leven. CHAPTER 15 Primary Dementia Syndromes and Parkinsonism 153 A range of supportive phenomena , including autonomic dysfunc- tion and EEG characteristics , are listed in the diagnostic criteria (see Table 15.1). Th e presence of these phenomena is not essential to make the diagnosis of DLB. cortical and subcortical atrophy with no specifi c distribution. Substantial medial tempora l lobe atrophy has been described in DLB, but is more indicative of AD (15). Nuclear imagin g has been shown to be helpful in diff erentiating DLB from healthy controls and AD. Reduce d occipital lobe blood fl ow or metabolism on SPECT or PET has been reported in DLB but not in AD patients. Dopamine transporter (DAT) imaging with 123 I-FP-CIT SPECT assesses the pr esynaptic dopaminergic system. A large multicentre study showed that abnormal DAT scans hav e a high overall diag- nostic accuracy of 85.7%, with a sensitivity of 77.7% and a specifi - city of 90.4%, in diff erentiating probable DLB from AD (Fig. 15.2). A DAT scan result is now included in the diagnostic criteria (16, 17). DLB and PDD share many features and are considered by many investigators as opposite ends o f a spectrum due to the same under- lying neuropathology. Th ese two entities are separated by consen- sus using a so-called \200\230one-year rule \200\231: if dementia and parkinso nism appear within less than a year of each other, the clinical diagnosis should be DLB. Ho wever, it has been widely acknowledged that the one-year cut-off is a rather arbitrary time frame and should be used for research settings only. In clinical practice, PDD is diagnose d in cases of dementia that occur in the context of well-established Parkinson \200\231s di sease, while DLB should be diagnosed when demen- tia occurs before or concurrently with par kinsonism (10). A small Australian study found relative preservation of the mid or posterior cingulate gyru s with 18 F-fl uorodeoxyglucose (FDG) PET scanning in DLB patients. Th is \200\230cingulat e island sign \200\231 had a 73% sensitivity and 100% specifi city for DLB when compared wi th AD patients (18) (Fig. 15.3). Th ese fi ndings need replication in a larger cohort. Th e diagnosis of DLB is predominantly based on clinical fea- tures, and some expertise in cognitive neurology is needed to understand this complex disease. Th e most important diff erential diagnosis is probably AD. Th e use of additional investigations to support the dia gnosis of DLB is limited. Structural imaging stud- ies have shown varying results. MRI scan s usually show diff use Amyloid PET imaging with Pittsburgh Compound B (PiB) does not diff erentiate AD from DLB si nce amyloid deposition is found Table 15.1 Diagnostic criteria for DLB \227\206 Central feature (essential for possible or probable DLB): \227\206 dementia \200\224commonly de \201 cits in attention, executive functions, and visuospatial abilities \227\206 Core features (at least two for probable DLB; at least one for possible DLB)*: \227\206 visual hallucinations \227\206 \202 uctuations in cognition \227\206 parkinso nism \227\206 Suggestive features*: \227\206 REM sleep behavior disorder \227\206 Neuroleptic sensitivity \227\206 Low dopam ine transporter uptake (SPECT/PET) \227\206 Supportive features (not proven diagnostic speci \201 city): \227\206 repeated falls and syncope \227\206 transient unexplained loss of consciousness \227\206 severe autonomic dysfunction \227\206 hallucinations in other modalities \227 \206 systematized delusions \227\206 depression \227\206 relative preservation of tempora l lobe structures on CT/MRI \227\206 generalized low uptake on SPECT/PET perfusion scans w ith reduced occipital activity \227\206 abnormal MIBG myocardial scintigraphy \227\206 prominent slow wave activity on E EG with temporal lobe transient sharp waves \227\206 A diagnosis of DLB is less likely: \227\206 in the presence of cerebrovascular disease \227\206 in the presence of another i llness su \203 cient to account for the clinical picture \227\206 if parkinsonism appears for the \201 rst time only in the stage of severe dementia \227\206 Temporal sequence of symptoms: DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism (if present) Probable DLB: dementia plus two core features or dementia plus one core feature and one sug gestive feature. Possible DLB: dementia plus one core feature or dementia plus one or more suggestive featur es. Adapted from McKeith et al. (10). Fig. 15.2 123 I-FP-CIT SPECT scan in AD and DLB patients. Normal DAT scan in the AD patient (upper panel) and abnormal DAT scan showing reduced dopamine transporter uptake in the str iatum in the DLB patient (lower panel). Oxford Textbook of Movement Disorders 154 patient and carer. Diff erent problems can be targeted, and one has to bear in mind that tr eating one feature can be at the expense of worsening others. Treatment goals are reduced c ognitive dysfunc- tion, extrapyramidal motor symptoms, neuropsychiatric features, sleep dis turbances, and autonomic dysfunction. Pharmacological symptomatic treatment is limited (10) . Cholinesterase inhibitors can be prescribed to treat cognitive decline and neuropsychiat- ric symptoms, based on three randomized controlled trials and a few open-label studies whi ch support this strategy (23 \200\22325). Hallucinations and attentional defi cits, in part icular, can show a favorable response to cholinergic treatment. Cholinesterase inhibitors c an be administered orally or via transdermal patches. Doses should be increased gradually t o decrease the occurrence of side eff ects, which commonly include gastrointestinal prob- l ems. Worsening of motor symptoms (tremor, postural instabil- ity) and hypersalivation have been reported in some DLB patients. Treatment with the NMDA receptor antagonist memantine h as been studied in mild to moderate DLB and PDD patients (26). Th ere was a mild benefi cia l eff ect on clinical global impression and improvement of neuropsychiatric features. Howev er, the evidence is limited and the exact role of memantine in the symptomatic treatment of DLB has still to be established. AD DLB Fig. 15.3 Cingulate island sign [ 18 F]-FDG PET. In AD there is biparietal hypometabolism o n FDG PET with involvement of the posterior cingulate. In DLB there is hypometabolism in th e occipital lobe with relative sparing of the posterior cingulate. in both diseases, compatible with the pathological fi ndings men- tioned above (19, 20). Cerebrospinal fl uid (CSF) markers are less useful in the diag- nostic work-up of DLB. For AD, the combination of low CSF amyloid-beta 42 and elevated concentration of tau and phosph or- ylated tau have been shown to increase diagnostic certainty. Because of the concomitant Alzheimer pathology in DLB, these CSF mark- ers can also be abnormal in DLB patients and d o not necessarily diff erentiate AD and DLB. Specifi c CSF markers for DLB have not been fo und to date. Several investigators have studied the value of CSF -synuclein in diff eren tiating dementia disorders. Although some of these studies showed a remarkable positive pre dictive value for lower CSF -synuclein concentration, others could not repro- duce these fi ndings. Th ese diff erences could have been caused by methodological and technical vari ations. Other biological features of CSF -synuclein, such as low concentrations in CSF a nd great inter-individual variability, could hamper the use of this protein as a viable bio marker. More studies of the optimal operational pro- cedures and prospective validation of previous fi ndings in large cohorts are needed (21, 22). Since up to 50% of DLB patients have neuroleptic sensitivity, antipsychotic drugs should be administered with a great deal of caution. Classic neuroleptic drugs with strong D2-recept or antago- nistic activity should be avoided completely. Neuroleptic sensitiv- ity greatly increases mortality. Atypical neuroleptic drugs such as clozapine and quetiapine can be eff ective in treating severe psychi- atric disturbances, but should be started at a low dose and closely monitored since sensitivity reactions have also been described with these agent s (10). Although there is limited evidence that dopaminergic agents can improve motor symptoms in D LB, treatment of signifi cant parkin- sonian features with low-dose levodopa is commonly ac cepted. Response to dopaminergic medication is believed to be limited because postsynaptic striatal pathology has been described in DLB. However, lack of response could be due to fai lure to treat because of fear of side eff ects, and reasonable results have been achieved i n individual patients. Th ere are limited pharmacological options for treating auto- nomic dysfunction such as mic turition disturbances and postural hypotension. Proper education and instructions help pati ents and their carers to deal with these oft en (socially) disabling symptoms. Antispasmodi cs should be avoided in the treatment of urinary incontinence since these agents have an an ticholinergic action and can worsen DLB symptoms via variable penetration of the blood \200 \223 brain barrier. Electroencephalography (EEG) shows slowing of the EEG rhythm in DLB. Th ere is little publi shed evidence of the ability of EEG to discriminate DLB from other dementias. Th ere are se veral reports of frontal intermittent rhythmic delta activity (FIRDA) as a specifi c featur e of DLB compared with AD, but test characteristics are lacking. Although the consensus criteria for the diagnosis of DLB reach a high specifi city of aroun d 90%, sensitivity varies among studies (22 \200\22383%, mean 63%), depending on patient se lection and clinical settings. Th is implies that the criteria are of limited value for scr een- ing DLB cases in a demented population and stresses the need for robust biomarkers. Treatment of RBD should be considered when there is sleep dis- ruption, anxiety, and risk o f injury. Th e treatment of fi rst choice is normally clonazepam, but this is relatively co ntraindicated in demented inattentive patients with postural instability. A few small case series have suggested a benefi cial eff ect for cholinesterase inhibitors. Non-pharmacologi cal interventions have not been sys- tematically studied, but should include providing info rmation to the patient and family on the various aspects of DLB and assess- ment of special needs to provide comfort and safety in the patient \200\231s environment. Physiotherapy ca n be helpful to address fi tness, walk- ing, and balance diffi culties. Management Managing DLB can be a challenge since the disease displays a wide array of sympt oms. As with most neurodegenerative dis- ease, there is no curative treatment for DLB. Aft er establishing the diagnosis, the clinician sets out the symptoms and needs with the CHAPTER 15 Primary Dementia Syndromes and Parkinsonism 155 Key advances Since the fi rst publication of diagnostic criteria for DLB by McKeith and col leagues in 1996 (11), awareness of this disease entity has steadily increased, much to the benefi t of patients and their relatives. DLB is now considered the second most common type of degen- erative dementia in older people. With the advent of cholinesterase inhibitors, symptomatic treatment has become available and the cognitive and neuropsychiatric features of DLB can be improved, at least temporarily, in many of these patients. Accurate diagnosis and heightened awareness of specifi c features of DLB, such as RBD and neuroleptic sensiti vity, have improved management. Th e discovery of -synuclein as the pathological substra te in disorders with Lewy body pathology has further increased knowledge of disease proc- e sses and aetiological factors. It is now commonly believed that PD, PDD, and DLB are part o f a spectrum with diff erent phenotypes, although there is still controversy on the progres sion of -synuclein pathology. Th e mechanisms that underlie the conformational changes o f -synuclein and how this leads to neurodegeneration remain to be clarifi ed, but potent ial links to genetic and metabolic defects are suggested by recent research. Do not administer classic neuroleptics to treat neuropsychiat- ric features in DLB; about 5 0% of patients with DLB experience severe neuroleptic sensitivity reaction. \227\206 Address the clinical phenotype for the purposes of patient man- agement instead of trying t o artifi cially distinguish between DLB and PDD. \227\206 Frontotemporal dementia with parkinsonism Frontotemporal dementia (FTD) is the clinical ter m covering a range of clinical syndromes associated with selective atrophy of the frontal a nd temporal lobes with relative preservation of the more posterior cortices. FTD is a predo minantly presenile dementia, characterized by behavioral changes (disinhibition, apathy, lo ss of empathy) and cognitive impairment comprising language and executive dysfunction. Th e disease that used to be known as Pick \200\231s disease was consid- ered very rare. In the last two decades major advances have been made in the fi eld of FTDs. Th e prevalence is now estimated at about 10 \200\22315 per 100 000 habitants in the age group 45 \200\2236 5 years, and FTD is considered the second most common type of presenile dementia. Th e inci dence in the age group 45 \200\22364 years is around four cases per 100 000 person-years. M ost cases of FTD are sporadic, but heredi- tary forms are found in 20 \200\22330% (27). 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).