An Evolution of the Diagnostic Criteria for Tauopathies

Despite the complexity of dementias, and the overlap of one diagnosis with another, new methods are appearing to help distinguish different conditions. Furthermore, increased knowledge of tauopathies and TDP-43 proteinopathies (now frequently called tardopathies), and of the genetic mutations associated with them, is helping specialists and physicians learn more about dementias, and their root problems in the central nervous system.

By Marie-Pierre Thibodeau, MD; Howard Chertkow, MD, FRCPC; and Gabriel C. Léger, MDCM, FRCPC

linicians have approached demen- many of the neurodegenerative diseases moting vital axonal transport.3,5 Tau Ctias based on crude clinical sub- that cause dementia. These can now be abnormalities, in the form of hyper- groupings (e.g., cortical vs. subcorti- classified not just based on the clinical phosphorylated insoluble inclusions, cal), or based on the clinical syndrome phenotype, but also on the type of pro- have been noted in many different enti- approach and accepted criteria for clin- tein that accumulates in tissue, and ties (Table 1).3 Although a number of ical entities. Progress in immunohis- might ultimately be the target of specif- mutations within the gene coding for tolochemical methods in recent years ic therapies. Dementia can result from tau (MAPT, or microtubule associated has led to a better understanding of the accumulation of amyloid,1 produc- protein tau) have been linked to tau- ing Alzheimer’s disease (AD: an amy- related diseases, the primary cause of loidopathy); synuclein,2 producing the most tauopathies remains unknown.5 Marie-Pierre Thibodeau, MD synucleinopathies Parkinson’s disease A few comments on tau biochem- Resident in Geriatric Medicine, (PD) and dementia with Lewy bodies; istry. A detailed analysis of tau bio- Université de Montréal the microtubule-associated protein chemistry is beyond the scope of this 3 Howard Chertkow, MD, FRCPC tau, producing tauopathies; and the short clinical review, but a few words Professor of Neurology, McGill recently discovered TDP-434 (TAR- are warranted. Tau is coded for by the University; Director, Bloomfield DNA binding protein-43), producing MAPT gene, found on chromosome Centre for Research in Aging, Lady tardopathies. The clinical presentations 17. The protein structure is complex Davis Institute; Dept. of Clinical of tauopathies and tardopathies overlap and varies according to post-transcrip- Neurosciences, Sir Mortimer B. greatly, especially with regard to fron- tional processing. In the human brain, Davis - Jewish General Hospital; totemporal dementias (FTDs). However, differential splicing of its mRNA can Institut Universitaire de Gériatrie the clinical spectrum associated with involve up to three different exons de Montréal; Montreal, Quebec tauopathies is unique and is the subject (exon 2, 3, and 10), potentially pro- of this review. ducing six different tau isoforms. Gabriel C. Léger, MDCM, FRCPC Tauopathies are a group of disor- Exon 10 contains sequences coding Assistant Professor of Medicine, Division of Neurology, Université ders associated with prominent accu- for one of four microtubule binding de Montréal; Associate mulation of intracellular . domains. Referring to the number of Neurologist, McGill Center for the This protein is abundant in the central microtubule binding domains, the Studies in Aging, Douglas nervous system (CNS), where it is absence or presence of exon 10 pro- Hospital; Associate Neurologist, expressed mainly in axons. It promotes duces “three-repeat” (3R) or “four- Memory Clinic of the Sir Mortimer assembly and stabilization of micro- repeat” (4R) tau respectively. The pro- B. Davis - Jewish General Hospital tubules by binding to tubulin, thus pro- portions of 3R and 4R tau appear to

4 • The Canadian Review of Alzheimer’s Disease and Other Dementias Diagnostic Criteria for Tauopathies

determine the clinical phenotype. For There are five new cases of PSP instance, progressive supranuclear diagnosed per 100,000 every year. Table 1 palsy (PSP) and corticobasal degener- The disease affects mainly males at an Diseases Associated with ation (CBD) are 4R tau predominant average age of 63 years. Patients Tau (as the Most Dominant disorders, while Pick’s disease (fron- become dependent on others for care Feature)3 totemporal lobar degeneration with within three to four years of the diag- • Argyrophilic grain dementia argyrophilic Pick bodies) is associated nosis, and have a survival rate of six with 3R tau. Other tau disorders are years.8 The most common causes of • Corticobasal degeneration associated with a mixture of 3R and death are aspiration pneumonia, pri- • Dementia pugilistica 4R tau. MAPT mutations produce dis- mary neurogenic respiratory failure or • eases with either 3R tau, 4R tau, or pulmonary emboli.9 with linked to chromosome 17 both. The presence of tau inclusions is Clinical findings. Postural instabil- usually detected using anti-tau antibod- ity with recurrent falls (especially back- • Pick’s disease ies (immunohistochemistry), while the wards) are the most common present- • Progressive subcortical gliosis characterization of isoforms requires ing complaints, with patients becoming • Progressive supranuclear electrophoresis with immunoblotting. wheelchair bound because of the sever- palsy Tau accumulation occurs mostly in ity of their mobility disorder. Other fea- • Post-encephalitic neuronal cell bodies. The specific brain tures characterizing PSP are oculomo- parkinsonism areas involved, as well as presence of tor and bulbar dysfunction.10,11 • Parkinson’s disease complex accumulation in other structures such as Patients with PSP have a very char- of Guam dendrites (neuropil) and astrocytes, help acteristic surprised facial appearance define the pathological diagnostic crite- with eyelid retraction and staring gaze square wave-jerks (saccadic intrusions) ria for the various entities. Additionally, caused by overactivity of the frontalis occurring while staring at an object.10,11 the morphology of these deposits as muscle. Many patients are seen early Axial rigidity with abnormal extensor seen by electron microscopy can differ. in their disease course when they do positioning of the neck (retrocollis) can In this review, we focus on two not have such striking clinical signs, also be seen. common tauopathies: PSP and CBD. making the diagnosis difficult. Thus, it Symmetric bradykinesia affects FTD, which is the consequence of a is advisable to wait for further visits to nearly half of patients by the time of in about 50% of cases, is commit to a diagnosis. The average diagnosis, and up to 95% during the discussed in other articles within this PSP patient remains undiagnosed for cou rse of the illness. A resting “pill issue. The main clinical characteris- about three years. rolling” tremor, as seen in Parkinson’s tics of these diseases, as well as inves- Obvious supranuclear gaze palsy, di s ease, is rare.12 These sym p toms do tigations used to support each diagno- which is the inability to pursue a moving not respond to levodopa therapy. sis, are discussed. Due to the com- target or perform voluntary saccades Dysarthria and dysphagia due to plexity and overlap of these syn- (but significantly improved with the pseudobulbar palsy are also early dromes, misdiagnosis is common, doll’s eyes maneuver), is considered a symptoms. Speech may become unin- especially during the early stages of hallmark of PSP but is usually a late telligible and choking may ultimately the disease.6 Clinical diagnostic crite- finding. Simple slowing of vertical sac- motivate a gastrostomy. ria are also presented. cadic eye movements often precedes Personality change or cognitive this, and should also be specifically slowing is common within the first Progressive Supranuclear Palsy sought. Downward vertical gaze palsy is two years. Frontal lobe symptoms (Steele-Richardson-Olszewski) considered more specific to PSP because consist mainly of perseveration, diffi- PSP was first described in 1963 by upward gaze restriction can be seen in culty with problem solving, decreased Richardson as a combination of supra - other neurodegenerative diseases and, to verbal fluency, concreteness in think- nuclear gaze palsy, akinetic-rigid fea- a certain degree, in normal aging. ing and lack of insight. Behavioral tures, early postural instability and fron- Horizontal gaze may be affected later in disturbances include apathy (in 90% to-limbic dementia.7 Clinical character- the disease evolution. Other common of patients),12 disinhibition, depres- istics were subsequently refined as features are apraxia of the eye opening, sion and anxiety while short-term described below. impaired spontaneous blink rate and memory is relatively spared.8 Sleep

The Canadian Review of Alzheimer’s Disease and Other Dementias • 5 Tauopathies

Table 2 NINDS-SPSP Clinical Diagnostic Criteria for the Diagnosis of PSP10

Inclusion criteria Exclusion criteria Supportive criteria For possible and probable: For possible and probable: • Symmetric akinesia or rigidity • Gradually progressive disorder • Recent history of encephalitis • Proximal more than distal with age at onset of 40 years or • Alien limb • Abnormal neck posture, especially later • Focal frontal and temporoparietal retrocollis • Cortical sensory deficits atrophy • Poor or absent reponse of Possible: • Hallucinations or delusions parkinsonism to levodopa • Either vertical supranuclear palsy unrelated to dopaminergic therapy • Early dysphagia, dyarthria or slowing of vertical saccades • Cortical dementia of Alzheimer • Early onset of cognitive and postural instability with falls type impairment including > 2 of: < 1 year after disease onset • Prominent early cerebellar apathy, impairment in abstract Probable: symptoms or unexplained thought, decreased verbal fluency, • Vertical supranuclear palsy and utilization or imitiation behavior or frontal release signs prominent postural instability with • Neuroradiological evidence of falls within first year of disease relevant structural anomaly onset • Whipples disease confirmed by Definite: polymerase chain reaction • All criteria for possible or probable • Evidence of other diseases that PSP are met and histopathologic could explain the clinical features confirmation at autopsy disturbances may also follow the system atrophy (MSA).15 Differential lism.12,16,19 An electro-oculographic onset of motor and ocular signs (fol- diagnosis should include PD, MSA, recording can also be useful to help lowing involvement of certain brain- CBD and FTD. differentiate PSP from CBD and PD.20 stem nuclei),9 but this has not been Investigations. PSP is a clinical The CSF ratio of two tau isoforms has well studied and is much less com- diagnosis, but some investigations recently been demonstrated as a spe- mon than in disorders due to synucle- may be helpful in supporting the diag- cific and reliable marker of PSP, but inopathies.13 nosis or excluding other disorders. remains experimental.21 Different clinical phenotypes have Midbrain atrophy on an MRI scan is a Neuropathology. Neuropathology been described, such as PSP-parkin- well-known radiologic feature of the of PSP is characterized by high-densi- sonism, PAGF (PSP-pure akinesia with disease. The so-called Hummingbird ty tau deposition in pallidum, subthal- gait freezing), PSP-CBS (PSP-corti- or Penguin silhouette signs have been amic nucleus, substantia nigra and cobasal syndrome) and PSP-PNFA described to define the thinning of the pons, with lower densities found in (PSP-progressive non-fluent aphasia). quadrigeminal plate and periaqueduc- other subcortical structures. An These clinico-pathological variants can tal region.16-18 Other supporting fea- intriguing fairly specific finding is that be distinguished by the distribution tures include thinning and smudging of tau-positive “tufted” astrocytes. and severity of pathological changes, of the substantia nigra, atrophy of the Another common feature of PSP and and by their clinical characteristics.9,14 putamen, atrophy and signal changes CBD is the presence of tau-positive In the usual clinical setting, these dis- of the globus pallidus and atrophy of “coiled bodies” in oligodendrocytes.22 tinctions are not significant. the red nucleus. Blood-flow studies Diagnostic criteria. More than In one study, 90% of patients with a have demonstrated marked reductions seven sets of diagnostic criteria have clinical diagnosis of PSP also had PSP of frontal and basal ganglia perfusion, been proposed for PSP. Validated diag- on postmortem pathology. Missed but this is also seen in PD, CBD and nostic criteria, which are highly specif- pathologically diagnosed PSP carried MSA. PET-FDG has shown a global ic but lack senstivity, have been pro- clinical diagnoses of PD and multiple reduction of cortical glucose metabo- posed by the National Institute of

6•The Canadian Review of Alzheimer’s Disease and Other Dementias Diagnostic Criteria for Tauopathies

Neurological Disorders and the Society for Progressive Supranuclear Palsy Table 3 (NINDS-SPSP) in 1996 and are listed in Proposed Criteria for the Diagnosis of CBD25 Table 2.9,23 In the table, the core features list the onset of PSP after 40 years of Core features age, falls within 12 months of diagnosis • Insidious onset and progressive course of the disease and vertical supranuclear • No identifiable cause gaze palsy. The exclusion criteria are • Cortical dysfunction as reflected by at least one of the following: important because they provide the − focal or asymmetric ideomotor apraxia specificity for the diagnosis. The sup- − alien limb phenomenon portive criteria are there to remind the − cortical sensory loss physician of important features associat- − visual or sensory hemineglect ed with PSP, but they are neither essen- − constructional apraxia tial nor sufficient for the diagnosis. − focal or asymmetric moclonus − apraxia of speech nonfluent aphasia Corticobasal Degeneration • Extrapyramidal dysfunction as reflected by at least one of the following: CBD was first described by Rebeiz, − focal or asymmetric appendicular rigidity lacking prominent Kolodny and Richardson in 1967 as a and sustained levodopa response progressive asymmetrical akinetic-rigid − focal or asymmetrical appendicular dystonia syndrome with apraxia that they called Supportive investigations “corticodentatonigral degeneration with neuronal achromasia.”24 Since then, a • Variable degrees of focal or lateralized cognitive dysfunction, with relative preservation of learning and memory, on neuropsychometric confusing terminology has been used to testing describe this disease. The current term • Focal or asymmetric atrophy on CT or MRI, typically maximal in is “corticobasal syndrome” (CBS) when parietofrontal cortex referring to the clinical constellation of • Focal or asymmetric hypoperfusion on SPECT, typically maximal in symptoms to be described below, and parietofrontal cortex ± basal ganglia ± thalamus CBD when the histopathological dis- ease is confirmed. Adding to the confu- sion, clinical and pathological hetero- ent in all patients, other movement dis- nosis with additional impaired posi- geneity and overlap with other disorders orders in 89%, and higher cortical dys- tion sense and two-point discrimination. is not unusual. CBS has been associated function in 93%. The most common Although CBD is considered by with a number of pathologies other than parkinsonian sign was rigidity (92%), many a movement disorder, it often CBD, including Alzheimer’s and Pick’s followed by bradykinesia (80%), gait presents first with cognitive dysfunc- disease, PSP, and Creutzfeldt-Jakob dis- disorder (80%), and tremor (55%). tion. Neuropsychological testing typi- ease. Although CBD presents most Other movement disorders were dysto- cally reveals impairment in attention, commonly as CBS, it may also follow nia in 71% of patients and executive function, verbal fluency, clinical diagnoses of dementia (not oth- in 55%. Higher cortical dysfunction language and visuospatial functioning, erwise specified), progressive aphasia, included dyspraxia (82%), alien limb with asymmetrical apraxia. Learning and FTD.25 (42%), cortical sensory loss (33%), and memory are generally spared.28 Clinical findings. Core clinical and dementia (25%).25-27 Investigations. Structural neu- findings in CBD are progressive asym- Apraxia typically begins in one roimaging (mostly with MRI) usually metrical rigidity and apraxia with other limb and spreads to other limbs within reveals strikingly asymmetric cortical findings suggesting cortical (alien two years. The presence of an alien atrophy, predominantly involving limb, cortical sensory loss, myoclonus) limb, historically associated with frontoparietal areas contralateral to and basal ganglionic (bradykinesia, CBD, occurs in only 50% of patients, the clinically most affected side. dystonia, tremor) dysfunction. and is described as having “a mind of Atrophy of the middle or posterior In a clinicopathological study of its own.” Cortical sensory loss is man- segment of the corpus callosum may CBD, parkinsonian features were pres- ifested by agraphestesia and astereog- also be seen. Signal changes in the

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tia characterized by memory distur- Table 4 bances and personality changes simi- Comparison of CBD and PSP30 lar to mild AD. Parkinson’s disease complex of Guam (PDC of Guam) is a Characteristics PSP CBD disease that appears in the fifth or sixth Parkinsonism Symmetric-axial Asymmetric-distal decade with parkinsonism and frontal Levodopa response Initial ? Absent dysexecutive dementia.3 Cognitive disturbances Frontal Lateralized Treatment. No specific treatment is Psychiatric disturbances Apathy Depression currently recommended for these Postural instability Early (within 1 year) Present pathologies. The supportive approach Pyramidal signs Late (bilateral) Unilateral/bilateral is favored, which includes physical and Contracture Late Early occupational assessments, and speech 26 Myoclonus and apraxia Absent Unilateral-bilateral therapy as needed. A trial of lev- Saccades latency Normal Increased odopa is often attempted, but the effect Saccades speed Slow Normal is usually modest and short-lived for PSP and CBD. Saccades Vertical > horizontal Vertical = horizontal CT scan Brain stem/midbrain Asymmetric-unilateral atrophy frontoparietal atrophy Are Tauopathies Distinct MRI Frontal and midbrain Asymmetric-unilateral Diseases? atrophy; T2 signal frontoparietal PSP and CBD have been presented here increase in midbrain and as distinct entities to facilitate diagnosis globus pallidus atrophy and comprehension of these complex pathologies. However, in the current lit- erature, recent findings challenge this putamen as well as subcortical hyper- has been validated formally. For a com- traditional nomenclature. So-called intensities in motor and somatosenso- parison of CBD and PSP, see Table 4. “splitters” and “lumpers” have emerged ry areas have been described. from this debate. Kertesz recommends Functional imaging studies such as Other Tauopathies that these diseases be considered as a blood flow (SPECT) or glucose metab- Alzheimer’s disease. As seen in Table spectrum of presentations of the same olism (PET) tend to parallel and pre- 1, a number of neurodegenerative disor- disorder called “Pick complex” because date the atrophic changes seen on ders are associated with tau pathology. of their common pathology.32 Others MRIs, with additional losses in the AD is not mentioned in the Table, but support the notion that these disorders basal ganglia. There is, however, no the disease is associated with an accu- must be considered as different syn- defined biomarker that can clearly dis- mulation of both tau and amyloid beta. dromes because of their fundamental tinguish CBD from other causes of Therefore, it is not strictly a “tauopathy.” clinical particularities. Research is ongo- CBS. Electrophy siological studies can In addition, tau accumulation is thought ing to try to resolve the debate.33 be used to help diagnosis, especially in to follow and is probably a consequence So why should clinicians even characterizing the myoclonus.29 of amyloid beta related toxicity.31 learn these molecular distinctions and Neuropathology. Balloon-shaped Frontotemporal lobar degenera- classifications? We would argue that neurons and prominent diffuse corti- tion. Tau pathology accounts for about developments in the molecular under- cal glial tau pathology are found at 50% of all cases of FTLD. The majori- standing of tau dysfunction are likely neuropathology. ty of other cases are tardopathies. They to lead to targeting tau specifically in Diagnostic criteria. Proposed diag- are discussed in other reviews within the next decade. When that occurs, it nostic criteria were elaborated in 2003 this issue. will be essential for clinicians to by Boeve as listed in Table 3.25 Rare and uncommon tauo pathies. understand the molecular neuropathol- However, no set of diagnostic criteria Argyrophilic grain disease is a demen- ogy of these syndromes.

8•The Canadian Review of Alzheimer’s Disease and Other Dementias Diagnostic Criteria for Tauopathies

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