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.

CSF markers tau and p-tau and low a Beta

NEUROLOGY 2009;72:1056-1061

17 patients (10%) with low levels of Aβ1-42 and very high levels of tau and p-tau. More with moderate levels of tau were found, plus controls.

High tau and p-tau levels negatively correlated with category fluency and VAT test, not with other neuropsych tests (TMT A and B, digit span forward and backward).

bv variant of FTD

NEUROLOGY 2009;72:732-737 Sensitivity of current criteria

Consensus Criteria published in 1998 by Neary and colleagues.4

Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554.[Abstract/Free Full Text]

However, not all patients have all five core features: loss of insight, emotional blunting, impaired personal conduct, decline in social interpersonal conduct, and insidious onset. Loss of insight and emotional blunting were the ones least likely to be represented

Secondary criteria such as speech problems upt o mutism occurred in less than half.

CSF biomarkers and Alzheimer's disease

A. E. van der Vlies, MSc, N. A. Verwey, MD, F. H. Bouwman, MD, PhD, M. A. Blankenstein, PhD, M. Klein, PhD, P. Scheltens, MD, PhD and W. M. van der Flier, PhD

CSF biomarkers in relationship to cognitive profiles in Alzheimer disease

NEUROLOGY 2009;72:1056-1061

 

From : To investigate the relationship between CSF biomarkers and cognitive profiles in Alzheimer disease (AD).

Methods: We included 177 patients with AD. Digit Span, Visual Association Test (VAT), VAT object naming, Trail Making Test (TMT), and category fluency were used to assess cognitive functions. Disease severity was assessed using Mini-Mental State Examination; functional impairment was rated by Clinical Dementia Rating. In CSF, levels of amyloid-beta 1-42 (Aβ_1-42), tau, and tau phosphorylated at threonine 181 (p-tau) were measured. K-means cluster analysis was performed with the three biomarkers to obtain three clusters. Multivariate analysis of variance for repeated measures was performed with CSF cluster as between-subjects factor, neuropsychological z scores as within-subjects variable, and age, sex, and education as covariates.

Results: Cluster 1 consisted of 88 patients (49%) with relatively high levels of Aβ_1-42 and low levels of tau and p-tau. Cluster 2 contained 72 patients (41%) with relatively low levels of Aβ_1-42 and high levels of tau and p-tau. Cluster 3 was made up of 17 patients (10%) with low levels of Aβ_1-42 and very high levels of tau and p-tau. No differences between clusters on age, sex, education, APOE genotype, disease duration, functional impairment, or disease severity were found. Patients in cluster 3 performed worse on VAT, TMT-A and -B, and fluency.

Conclusions: Clusters of CSF biomarker levels are related to cognitive profiles in Alzheimer disease. A subgroup of patients with extremely high CSF levels of tau and tau phosphorylated at threonine 181 shows a distinct cognitive profile with more severe impairment of memory, mental speed, and executive functions, which cannot be explained by disease severity.

Politics of health care reform distort reality

The October 29, 2009 issue of the New England Journal of Medicine contains four separate articles on health care issues which, if taken in their entirety, represent the absurdity to which the health care debates in the United States have gone.

The first article-- the best of the four-- describes how much FDA information never reaches clinicians (1). Clinicians and the public rely on the Food and Drug Administration (FDA) for drug and product approvals and denials, and for disseminating accurate information about drugs in their product inserts. I learned that the lengthy, often poorly written and weakly summarized debates about drugs are posted publicly at www.accessdata.fda.gov/scripts/cder/drugsatfda/. The authors cited glaring examples of critical information that somehow was not included in the product labels. Zometa (zoledronic acid, Novartis), used to treat hypercalcemia of malignancy, at the 8 mg dose, caused more renal toxicity and death than the 4 mg dose and was no more effective. Nonetheless, the labelling suggested using the higher dosage "in refractory cases." The product label did not mention increased mortality at the higher dose.

Lunesta (eszopiclone, Sepracor), sold 800 million dollars last year with the help of a direct to consumers marketing campaign. Yet the efficacy data, buried on page 306 of 403, shows patients slept 15 minutes earlier and 37 minutes longer than placebo, with no clinically meaningful improvement in next day alertness or functioning. Similarly, Rozerem (ramelteon), another approved sleep drug, caused younger adults to fall asleep 14 minutes earlier, and older ones 7 minutes earlier, with no improvement on subjective assessments of sleep quality.

The very next article details ways the same government can "further" improve health care. Victor Fuchs (2). advocates incremental rather than radical health care reform. The first of his four proposed reforms is to eliminate employer based health care coverage tax exemptions. The purpose is to raise 200 billion dollars in new revenues, that is taxes, to make the tax system "fairer" since the tax benefit is a regressive tax. He alleges it benefits the wealthy. (Wait a minute-- my practice employs 15 people, who have relatively low incomes and have the same insurance I have. A biller who had breast cancer last year would never have gotten treatment without our comprehensive health insurance). This would allow the creation of insurance exchanges, the second idea, that would, using Fuchs' words, be not as "generous" to "consumers" (actually, sick patients) as the private plans they replace. Supposedly, these exchanges would decrease "broker" costs.

The third, chilling suggestion of Fuchs is the appointment of an "expert" commission to devise changes to the ways Medicare reimburses providers. Fuchs cites "special interests" as blocking the "public good," as a charged way to rally the troops. Again, citing my own practice, with 50 % overhead, a 10 % payment cut equals a 20 % loss of income. Could it be, that by going after providers who have already been sucked dry, Fuchs will drive people out of practice, resulting in fewer providers, thereby raising the cost of care? Fuchs' final idea is an office for technology assessment that would be "quasi-independent." Of whom, I might ask.

The third article-- the last to be reviewed here- describes implementing evidence based medicine in Washington state (3). The state has total authority, except where prohibited by federal statute, to use evidence based methods to assess drugs, devices, surgical procedures, diagnostic tests, imaging procedures, and medical equipment. The author decries the political "pressure" wrought by patients who testify that the benefitted from a technology the state wants to eliminate. Obscenely, the same authors equate pharmaceutical direct to patient marketing with physician "autonomy" and "financial incentive" in ordering tests.
The authors note the "challenges" of this policy, citing the example that thymectomy of myasthenia gravis, used since 1912, has never undergone a rigorous trial. This author will note a few more nonevidence based treatments: penicillin for infection, appendectomy for appendicitis, and burr holes for subdural hematomas of the brain. Are these procedures necessary? Shall the government be in a position to decide? May I be so impudent to suggest satisfaction surveys be returned for all cases of physician assisted suicide?

The assumption of evidence based medicine is that care from one can be generalized to another and is equivalent to another. Evidence is important, and can help us learn how to be better doctors. But, evidence is not the be all and end all. Sometimes doctors have to take the controls from the nurse practitioners and PhD's and make decisions that are in the best interests of the patient. The reasons may not be obvious to the lay public but may be based on sound understanding of pathophysiology. Experience and judgment, absent from these vacuous bureaucratic declarations, still are what most patients seek.

1. Schwartz LM, Woloshin S. Lost in transmission: FDA drug information that never reaches clinicians. N Engl J Med 2009; 361:1717-1720.

2. Fuchs VR. Four health care reforms for 2009. N Engl. J Med 2009; 361: 1720-1722.

3. Franklin GM, Budenholzer BR. Implementing evidence based health policy in Washington State. N Engl J Med 2009; 361:1722-1725.

HIV dementia scales

HIV dementia scale

http://www.hivguidelines.org/Content.aspx?PageID=325&guideLineID=44&guideParent=&vType=&pGuideLineID=44,

HIV modified dementia scale

http://www.hivguidelines.org/Content.aspx?PageID=326&guideLineID=44&guideParent=&vType=&pGuideLineID=44,

Mental alternation test

http://www.hivguidelines.org/Content.aspx?PageID=327&guideLineID=44&guideParent=&vType=&pGuideLineID=44,

Sloane Kettering Scale for AIDS dementia complex

http://www.hivguidelines.org/Content.aspx?PageID=328&guideLineID=44&guideParent=&vType=&pGuideLineID=44,

Apathy evaluation scale

http://www.tbims.org/combi/aes/AES.PDF

neuropsychological predictors of poor driving in Alzheimer's disease

Benton Visual Retention Test

Complex Figure Test Copy

Trails A

Functional Reach Test

 

from Neurology 2009 Feb Dawson et al. (Iowa)

lbd PEARLS

1. RBD is common and fairly specific for synucleinopathy, LBD or MSA
2. Cognitive testing not that bad, memory not that bad, visuospatial especially copying is very bad
3. Parkinson's is atypical
4. Fluctuations with Mayo Fluctuations Scale
5. Profound sleepiness during day
6. Utility of Pet scans "debated"

Semantic dementia pearls

1. Naming problems, esp anomic
2. left anterior temporal atrophy esp inferolateral
3. good delayed recall
4. homologous contralateral involvement occurs
5. positive family history dementia and ALS is common
6. Behavioral changes ubiquitous later on
7. FTLD pathology

PNFA pearls

1. slowly progressive, lifespan of 20 + years
2. check oromotor apraxia "Lick your lips" "pa-ta-ka, pa-ta-ka"
3. Otherwise normal neuropsych
4. +/- Pet may show left insular/perisylvian abnormality
5. young age 40-80
6. tauopathy like PSP or CBD
7. up-down reversals
8. normal MRI

depression scales other scales for PD, AD and MS

http://www.mhsfopcls.com/downloads/ger_dep_scl.pdf Geriatric Depression scale

http://www.ibogaine.desk.nl/graphics/3639b1c_23.pdf Beck Depression inventory- pref in Parkinson's disease

http://healthnet.umassmed.edu/mhealth/ZungSelfRatedDepressionScale.pdf Zung SRDS

Other scales

http://www.nysaaaa.org/Caregiver_Forum/CaregiverForumErieHandout09.pdf caregiver burden assessment

http://www.nationalmssociety.org/for-professionals/researchers/clinical-study-measures/mfis/index.aspx

MFIS with link to MSQLI (Connie is this different than MSQOL and how?)

http://www.nationalmssociety.org/for-professionals/researchers/clinical-study-measures/index.aspx

link to links to many clinical tools in MS research

http://www.mdvu.org/library/ratingscales/pd/updrs.pdf updrs and scwab (parkinson;s)

http://www.alegent.com/documents/Sleep_eval.pdf berlin and epworth sleep questionnaire

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/clock_drawing_test.pdf clock drawing and mini cog (= 3 word recall)

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/instrumental_activities.pdf Instrumental activities of daily livving (IADL)

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/phys_selfmain.pdf physical self maintenance scale

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/function_status_questionnai.pdf (last page is functional activities questionnaire)

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/painscales.pdf pain scale

http://www.mocatest.org/ Moca-- has links for multiple languages

http://www.neurotransmitter.net/alzheimerscales.html link to MANY Alz assessment tools, behavior and otherwise a few linked below

http://strokecenter.org/trials/scales/blessed_dementia.html blessed dementia scale

http://www.aafp.org/afp/2002/0601/p2263.html CBI, IADL, NPI

CAA with inflammation clinical characteristics

Kinnecom C et al. Course of cerebral amyloid angiopathy related inflammation. Neurology 2007; 68: 1411-1416.

CAA, amyloid angiopathy, dementia, seizures, HA, T2 hyperintensities, MRI lesions with edema, neuropath with consistent with inflammation, response to decadron, monophasic, or relapsing course.

Lesions were primarily white matter and could be unilateral. 7/12 had monophasic improvement with treatment, 3/12 relapsed, 2/12 were not responsive. Apo E4/E4 was present in 10/12 of CAA with inflammation v. 5.1 % of symptomatic CAA without inflammation.

The suspicion is that this represents inflammation against amyloid deposits and that it strikingly resembles the encephalitis seen in those given Alzheimer's amyloid vaccines.

Mental status tests Kokmen

Kokmen Short test of mental status

http://www.fpnotebook.com/Neuro/Exam/KkmnShrtTstOfMntlSts.htm

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Predictors of bad driving in AD

Dawson et al. Neurology 2009; 72: 521-527.

Lane violations were the commonest driving error/safety violation in patients.

Neuropsych measures that correlated best with safety errors were: Benton Visual Retention Test, Complex Figure Test copy, Trails A and Functional Reach Test.