MAPT and types of tau

Patients with MAPT all have neuronal or glial tau inclusions, but phenotype can vary even among relatives with the disease.  Types include s Picks, s CBD, s PSP and s AGD. 

 

Tau is divided into 3-tau and 4-tau depending on the number and type of binding sites available.  3Repeat tau is associated with Picks, and 4R tau is associated with CBD, PSP, AGD whereas AD has isoforms of both 3rtau and 4r tau. Thus the neuropathologic diagnosis depends not only on immunostaining but also genotyping of MAPT.

 

Phenotypes of patients with progranulin mutation are varied and include CBD, AD, MCI, PDD, DLB, FTD+/- Parkinsonism and progressive aphasia syndromes.

 

Genetically, all PRGN mutations cause premature termination codons, This induces nonsense mediated decay or true haploinsufficiency.

Dementia classifications-- rapid FTD's, by abnormal protein

Frontotemporal dementia subtypes and genetics-- rapidly progressive subtypes

1. FTD and parkinsonism due to mutation on chromosome 17 on gene encoding microtubule associated protein tau (MAPT)= FTD17MAPT

2. FTD and parkinsonism due to mutation on chromosome 17 on gene encoding progranulin (PGN)=FTD17PRGN

3. FTD and frontal lobar degeneration due with ubiquitin and TDP-43 positive inclusions=FTDUTDP43

4. FTD and frontal lobar degeneration due with ubiquitin and TDP-43 negative inclusions=FTDU-TDP43

5. Neuronal inclusion body dementia

6. Dementia lacking distinctive histopathology (DLDH) (except gliosis and neuronal loss)-- may also be included in rubric of FTD

By protein

Amyloidopathies--

1.Alzheimer's disease,

2. Down's syndrome

Tau-opathies-

1.-Picks disease (sporadic and familial);

2. corticobasal degeneration (CBD) (sporadic and familial);

3. progressive supranuclear palsy PSP (sporadic and familial);

4. Argyrophilic grain disease (AGD) (sporadic and familial);

5. multisystem tau-opathy (sporadic and familial);

6. FTD-17-MAPT;

7. Alzheimer's disease

Synucleinopathies

1.Lewy body disease * (also PDD, DLB, PD) sporadic and familial

2.Multiple system atrophy (rarely associated with dementia)

3. Pure autonomic failure

Huntingtin

1. Huntington's disease

Alpha internexin

1. Neurofilament inclusion body disease (NIBD)* =neuronal intermediate filament inclusion disease (NIFID)

TAR 43 binding protein (TDP 43)

1. FTLD-u-TDP43 * aka a) FTD with ITSNU (inclusions, tau and synuclein negative, with ubiquitin) b) FTLD with MND (motor neuron disease inclusions) c) MNDID motor neuron disease inclusion dementia

2. FTD 17 PRGN

Protein unknown

1. FTLD-u (TDP43 negative inclusions)*

2. DLDH*

* evolve to death within 3 years*

non sporadic or v CJD cases

There are more than 40 mutations, and most patients do not have a family history (although they may have a history of Alzheimer's or Parkinson's diseases). v CJD occurs in younger patients, mean age 28, longer duration (14 months) and is typically acquired in England or France rather than the US. The pulvinar sign is seen on T2 images Pulvinar brighter than PUT). EEG is abnormal only late in disease. Psych prodrome may occur and diagnosis can be made by tonsillar or brain biopsy. V CJD is transmissible by blood transfusions. Website pertaining to is found at: http://www.cjd.ed.ac.uk/criteria.htm/#vCJD .

CJD Prion disease criteria

UCSF modified criteria (Geschwind)
Rapid cognitive decline with any two (2) of
1. Myoclonus
2. Pyramidal/EP
3. Visual
4. Cerebellar
5. Akinetic mutism
6. Other cortical signs (aphasia, apraxia, acalculia, etc.)

and
1. typical MRI or EEG
2. No other disease that adequately explains diagnosis.

Competing criteria: Master's, WHO criteria see AAN syllabus 2009
14,3,3 positivity is included in WHO criteria but not UCSF modified criteria

More information:
1. CSF tests are markers of rapid neuronal injury, not diagnostic. The 3 tests most used are 14,3,3,; NSE; total tau (greater than 1200). The sensitivity and specificity of the 3 tests are, respectively, sensitivity: 53,63,69; specificity: 69, 86, 95.

2. MRI, esp. FLAIR and DWI images, show cortical ribboning and also involves CN, PUT, and/or THAL

3. Cases lacking MRI changes may be genetic variant, consider genetic test for MM2 subtest before brain biopsy.

4. vCJD is more likely than sCJD to have "pulvinar sign" on MRI

5. Symptoms , signs, lab tests NOT found typically in CJD: seizures, GI symptoms, ataxia without dementia, CN abnormality other than mild diplopia, stroke like hemiparesis, true focal weakness, or chorea (except in GSS). Lab findings not indicative of CJD include: normal DWI/FLAIR; FLAIR without concomitant DWI abnormality; abnormal contrast enhancement; severe leukoencephalopathy; , mass effect or edema; CSF pelocytosis, protein>100 , or elevated IgG index or OCB's.

6. First symptoms in a large sCJD cohort: cognitive , 40 % (of which, memory loss 45%, executive dysfunction, 13%; dysphasia 13 %, confusion), cerebellar signs 22 % (84 % gait/balance, 12 % limb ataxia); constitutional 21 % (vertigo/dizzy 41 %, fatigue 20 %, sleep disorder 10 %).

Clinical syndromes associated with posterior cortical atrophy

Early age at onset AD spectrum. Migliaccio R, Agosta F et al. Neurology 2009; 1571-1578

Authors compared posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) and early onset AD. N= 14, 10, 16 respectively with 65 healthy controls. Voxel based morphometry showed overlapping atrophy in bilateral parietal, occipital, precuneus, posterior cingulate, posterior temporal and hippocampal areas. Group specific atrophy was also seen in right ventral occipital and superior parietal in PCA, left MTG and STG in LPA, and prefrontal cortez in eo-AD. All had higher apoE frequency and about half of each group had cortical amyloid on pathology or PET. Authors propose the disorders are all Alzheimers "spectrum" diseases with overlapping elements.