Tauopathies A contemporary way to consider a set of neurodegenerative diseases based on their molecular signature John Growdon, M.D.

Neurofilament tangles are composed of paired helical filaments in AD, and straight filaments in conditions such as PSP. Electron microscopy of neurofilament fibers, labeled by polyclonal anti-tau.

Tau Protein A microtubule associated protein largely localized to neuronal axons Important biological role in stabilizing microtubules and thereby aiding neuronal structure and axonal transport Hyperphosphorylation of tau at specific serine & threonine epitopes impairs it normal function; this process either leads to neuronal dysfunction & death, or is a marker of neuronal death.

Tauopathies: Clinical Diseases Alzheimer’s disease Dementia pugilistica Guam ALS/PD Pick Disease Argyrophilic grain dementia Nieman-Pick, type C SSPE PSP MSA Corticobasoganglionic degeneration FTDP-17 Postencephalitic PD Autosomal recessive PD

History of LT born: 6/26/05 died: 11/16/ : 72 y.o. woman with subtle onset of difficulty finding words in speaking. 1980: MGH examination. No focal neurologic signs. Speaking greatly impaired with anomia & circumlocutions (pen=“something you write with”); intact memory; no apraxia; preserved personality; independent ADLs. BDS = : worsening expressive language; sings better than she speaks. Recent onset of apraxia. Stopped driving a car. Sweet personality. BDS = : expressive & receptive aphasia. Withdrawn personality with apathetic mood. BDS = : mute, but occasional non-verbal communication. No housework, but still cares for personal hygiene.

ICD-10 Diagnostic Criteria for Pick’s Disease 1. Dementia. 2. Slow steady deterioration. 3. Two or more of the following: a. Emotional blunting b. Apathy or restlessness c. Coarsening of social behavior d. Aphasia 4. Relative preservation of memory & parietal-lobe functions.

Caregiver Report of Initial Symptoms in Pick Disease (PiD) and Alzheimer Disease (AD) Patients: Mean Prevalence (%) Symptom PiD n=34 AD n=78 Memory p<0.001 Speech 29.4 p< Use of objects Socializing Personality 53.3 p= Irritability/aggressiveness Reasoning Sense of direction Vision

Mean Cognitive Test Scores (+/- SD) at Initial Examination for PiD, AD, and Normal Control Subject (NCS) Groups Test PiD AD NCS NYU Immediate Recall 3.1 (2.7) 2.5 (1.9) 8.4 (3.1) NYU Delayed Recall 2.3 (3.1) 0.7 (1.3) 7.8 (3.2) Geometric Figure Recall 4.0 (3.6) 2.2 (2.9) 7.2 (2.6) Benton Visual Retention 9.2 (3.0) 8.3 (2.8) 11.9 (1.7) Boston Naming 24.6 (9.7) 25.8 (9.1) 37.1 (5.0) Stroop Color Naming 13.3 (10.1) 11.2 (7.6) 29.3 (10.9) Luria Mental Rotation 8.1 (1.9) 6.0 (2.8) 8.3 (2.4) Picture Arrangement 5.9 (4.3) 4.4 (3.1) 10.5 (5.1) NCS scores were significantly superior to AD scores on all tests (p<0.05), and to PiD on all tests (p<0.05) on all tests except the Luria. PiD scores were significantly superior to AD scores on the NYU Delayed Recall and Luria tests (p<0.001).

Cognitive test scores over time: AD open circles; Pick black circles

As judged by global measures of dementia severity, PiD (black circles) progresses faster than AD (open circles).

Clinical Aspects: PcD vs. AD Initial Symptoms: Personality change & language impairments are more commonly reported in PcD; memory loss reported in both, but was more common in AD. Cognitive Tests: PcD superior to AD in explicit memory & visuospatial functions. Over time, dementia worsened in both. PcD dclined more rapidly than AD on language tests and measures of global dementia severity.

Alzheimer’s disease is more prevalent than Pick’s disease At the Massachusetts General Hospital between 1985 and 1996, 63% of the patients examined in the Memory Disorders Unit had a clinical diagnosis of AD. During the same period of time, only 2% of the patients had a clinical diagnosis of Pick’s disease. Of autopsied cases (n=696), 52% had AD and 3% had Pick’s disease.

Six tau isoforms that are expressed in human brain: alternatively splicd exons 2,3 & 10 are shown in white; black bars indicate the microtubular-binding repeats.

Electrophoretic tau profiles distinguish AD from Pick’s disease (PiD). Characteristic western immunoblots using phosphorylation-dependent monoclonal antibodies. In AD, all isoforms are phosphorylated; in PiD, only 3R isoforms. MGH cases, courtesy of Andre Delacourte

Do defects in alternative exon 10 splicing of the tau gene underlie Pick disease? Missense mutations and splice variants of tau, many near exon 10, account for hereditary FTDP- 17, a condition similar to Pick. Antibodies to exon 10 fail to immunostain Pick bodies. Mostly 3R tau (55 & 64 kD bands) in Pick. Vulnerability to 3R tau, or altered 3R:4R ratio, in frontal & temporal cortices may account for the regional distribution of degeneration in Pick.

Frontotemporal Lobar Degeneration Pick’s Disease Frontal Lobe Dementia +/- ALS Primary Progressive Aphasia Semantic Dementia FTD with Parkinsonism linked to chr. 17 Corticobasalganglionic Degeneration

History of Mr. GSC born: 3/17/26 died: 1/27/ : Insidious onset of difficulty arising from a chair. 1982: Hypophonia. 1985: Postural instability, with falling backward. Hip fracture. 1986: Difficulty focusing eyes and looking down when reading a page in a book. 1989: MGH Examination. Slow fractionated saccades; 3 mm vertical gaze. PD stage 3 stigmata: akinesia, limb rigidity, en bloc turns. BDS = 2 (normal). 1991: Absent vertical saccades. Blepharospasms. Dsyphagia. Micrographia. 1992: Neck rigidity. Dysarthria. Requires assistance to stand; multiple falls with fractured collarbone. Stage 4 PD. 1993: Eyes fixed…no volitional movement but intact oculocephalic reflex. Fell with resultant skull fracture.

NINDS-SPSP Criteria for Dx PSP Gradually progressive disorder. Onset at age 40 years old or later. Either vertical supranuclear (up or down) gaze palsy or Both slowing of vertical saccades and prominent postural stability with falls in the first year on disease onset.

Supportive Criteria for Dx PSP Symmetric akinesia or rigidity. Abnormal neck posture, especially retrocollis. Poor or absent response of parkinsonism to levodopa therapy. Early dysphagia and dsyarthria. Early onset of cognitive impairment, including at least 2 of these: apathy, decreased verbal fluency, impaired abstract reasoning, & utilization behavior.

Memory is less affected in PSP than in classic dementing illnesses such as AD

Clinical Characteristics of PSP Patients and Separate Groups of Normal Control Subjects (NCS) Studied with Cognitive Tests & SPECT Subjects Age, yrs. Duration, yrs. H&Y stage PSP n= NCS- SPECT n= na na NCS-Cognition n= na na

Cognitive Test Scores of PSP Patients and Normal Control Subjects Cognitive Test PSP Control Subjects Delayed Story Recall 5.8 (3.0) 8.3 (2.5) Boston Naming 33.5 (2.3)** 38.2 (3.9) Verbal Fluency “S” 4.1 (2.2)*** 18.8 (7.0) Stroop 39.9 (23.7)*** (9.0) Raven’s Matrices 23.6 (5.2)*** 32.5 (3.3) Picture Arrangement 4.0 (2.8)** 11.4 (4.5) ** = p<.01 ***= p<0.001

Thalam Alzheimer (1/1) Alzheimer (Wat) (1/5)  Gel 8-15 %  Load: 20µL  AD2 at 1/ e  Quantification of pathological tau proteins :.:. Cere bellum Cortex Temporal Cortex Frontal Cortex Frontal Cortex Central Cortex Occipital White matter Cortex Central Caudate nucleus Tau doublet at 69 & 64kD that is characteristic of PSP MGH case, courtesy of Andre Delacourte In PSP, aggregated filaments are largely hyperphosphorylated tau 4R isoforms encoded by exon 10

The Search for Genetic Causes of PSP: 2004 Update 1. Hyperphosphorylated 4R tau in tangles 2. The tau gene A0 allele (a dinucleotide repeat in the intron following exon 10) is over represented in PSP. 3. The tau H1 haplotype has high sensitivity (98%) but only modest specificy as a marker for PSP 4. There are rare families with atypical PSP apparently caused by mutations in the tau gene. 5. Mutations in the tau gene have not been found in most sporadic PSP cases. 6. Some tau smoke, but no fire…more to follow!