Tauopathies 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 tau protein. 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 • Frontotemporal dementia eases with either 3R tau, 4R tau, or pulmonary emboli.9 with parkinsonism 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 near ly half of patients by the time of tauopathy 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