Dementia Notes

CSF profiles and variant dementia

2012-01-18T16:54:00.000-08:00

Neurology 2012; 78:47 -54

CSF profiles of tau and abeta are extremely effective differentiating some dementias but not others. Markers were t(total) tau, p (phosphorylated) tau, and Abeta42 in CSF. " AD profile" of markers was seen in AD, but also in many autopsy proven cases of DLB, CBD, FTLD and VaD (about 30-50 % of respective types of dementia patients had :AD profile." Psychiatric patients and those with subjective complaints of memory loss had normal CSF results. PSP patients had normal results also. CJD patients had very high t tau and normal p tau

Brain reserve, education and Alzheimer's disease

2011-11-29T15:32:00.001-08:00

The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer's diseases; Murray AD, Staff RT, McNeil CJ, Salarirad S, Ahearn TS, Mustafa N, Whalley LJ; Brain (Nov 2011)

The cognitive reserve hypothesis explains the disparity between clinical and pathological phenotypes and why, in two individuals with the same extent of neuropathology, one may be demented while the other remains cognitively intact. We examined the balance between brain magnetic resonance imaging measures of the two most common pathologies associated with brain ageing, cerebrovascular disease and Alzheimer's disease, and parameters of cerebral reserve in well-characterized participants born in 1936, for whom childhood intelligence is known. Brain magnetic resonance imaging was carried out at 1.5T using fluid attenuation inversion recovery and T(1)-weighted volumetric sequences in 249 participants. Cerebrovascular disease was quantified by measuring brain white matter hyperintensities on fluid attenuation inversion recovery images using Scheltens' scale and Alzheimer's disease was measured from volumetric data using FreeSurfer to extract whole brain volume and hippocampal volumes in turn. The effect of these measures of brain burden on life-long cognitive ageing from the age of 11 to 68 years was compared with the effect of educational attainment and occupational grade using structural equation modelling. Complete brain burden and reserve data were available in 224 participants. We found that educational attainment, but not occupation, has a measurable and positive effect, with a standardized regression weight of +0.23, on late life cognitive ability in people without cognitive impairment aged 68 years, allowing for the influence of childhood intelligence and the two most common subclinical brain pathological burdens in the ageing brain. In addition, we demonstrate that the magnitude of the contribution of education is greater than the negative impact of either neuropathological burden alone, with standardized regression weights of -0.14 for white matter hyperintensities and -0.20 for hippocampal atrophy. This study illustrates how education counteracts the deleterious effects of cerebrovascular disease and Alzheimer's disease and highlights the importance of quantifying cognitive reserve in dementia research.

Blogger note: Education is known to be very important in Alzheimer's development, but is now more important than pathology? I agree that it affects dementia research but might do so because education affects performance on tools used in dementia research, more than the biologic process of disease. One could conclude, equally valid-ly, that this proves we need new tools to measure Alzheimer's that are less reflective of educational attainment.

Vitamin D and risk of cognitive decline in elderly persons

2010-07-20T08:40:00.001-07:00

Llewellyn DJ, Lang IA, Langa KM, Muniz-Terrera G, Phillips CL, Cherubini A, Ferrucci L, Melzer D; Archives of Internal Medicine 170 (13), 1135-41 (Jul 2010)

BACKGROUND: To our knowledge, no prospective study has examined the association between vitamin D and cognitive decline or dementia. METHODS: We determined whether low levels of serum 25-hydroxyvitamin D (25[OH]D) were associated with an increased risk of substantial cognitive decline in the InCHIANTI population-based study conducted in Italy between 1998 and 2006 with follow-up assessments every 3 years. A total of 858 adults 65 years or older completed interviews, cognitive assessments, and medical examinations and provided blood samples. Cognitive decline was assessed using the Mini-Mental State Examination (MMSE), and substantial decline was defined as 3 or more points. The Trail-Making Tests A and B were also used, and substantial decline was defined as the worst 10% of the distribution of decline or as discontinued testing. RESULTS: The multivariate adjusted relative risk (95% confidence interval [CI]) of substantial cognitive decline on the MMSE in participants who were severely serum 25(OH)D deficient (levels<25 nmol/L) in comparison with those with sufficient levels of 25(OH)D (>/=75 nmol/L) was 1.60 (95% CI, 1.19-2.00). Multivariate adjusted random-effects models demonstrated that the scores of participants who were severely 25(OH)D deficient declined by an additional 0.3 MMSE points per year more than those with sufficient levels of 25(OH)D. The relative risk for substantial decline on Trail-Making Test B was 1.31 (95% CI, 1.03-1.51) among those who were severely 25(OH)D deficient compared with those with sufficient levels of 25(OH)D. No significant association was observed for Trail-Making Test A. CONCLUSION: Low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied over a 6-year period, which raises important new possibilities for treatment and prevention.

Treating Neuropsychiatric Symptoms in Dementia With Lewy Bodies: A Randomized Co

2010-07-20T08:30:00.001-07:00

Culo S, Mulsant BH, Rosen J, Mazumdar S, Blakesley RE, Houck PR, Pollock BG; Alzheimer Disease & Associated Disorders (Jul 2010)

Sensitivity to psychotropic medications presents a therapeutic challenge when treating neuropsychiatric symptoms in patients with dementia with Lewy bodies (DLB). We compared under randomized, double-blinded conditions the tolerability and efficacy of citalopram and risperidone in the treatment of behavioral and psychotic symptoms in patients with DLB and Alzheimer disease (AD). Thirty-one participants with DLB and 66 with AD hospitalized for behavioral disturbance were treated under randomized, double-blind conditions with citalopram or risperidone for up to 12 weeks. Neuropsychiatric symptoms were assessed with the nursing home version of the Neuropsychiatric Inventory (NPI) and the Clinical Global Impression of Change (CGIC). Side effects were measured using the UKU Side Effect Rating Scale. A significantly higher proportion of participants with DLB (68%) than with AD (50%) discontinued the study prematurely. Discontinuation rates were comparable in DLB participants treated with citalopram (71%) or risperidone (65%). However, participants with DLB randomized to risperidone experienced a higher overall burden of side effects. Scores on the NPI and the CGIC worsened in DLB participants and improved in those with AD. Most patients with behavioral disturbances or psychosis associated with DLB tolerate citalopram or risperidone poorly and do not seem to benefit from either medication.

donepezil and apathy

2010-07-13T06:45:00.001-07:00

Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease; Waldemar G, Gauthier S, Jones R, Wilkinson D, Cummings J, Lopez O, Zhang R, Xu Y, Sun Y, Knox S, Richardson S, Mackell J; International Journal of Geriatric Psychiatry (Jul 2010)

OBJECTIVE: To determine whether donepezil treatment (10 mg/day over 24 weeks) is associated with delayed emergence of apathy in patients with mild to moderate Alzheimer's disease (AD) and to explore relationships between donepezil's effects on apathy and other Neuropsychiatric Inventory (NPI)-measured behavioural symptoms. METHODS: Two randomised, double-blind, parallel-group, placebo-controlled studies that met prespecified criteria and were sufficiently similar to allow data pooling were derived from all donepezil AD clinical trials. Patients scoring from 10 to 26 on baseline Mini-Mental Status Examination were included. A clinical milestone for apathy and other NPI items was defined as the first emergence of a composite score (frequency x severity)>/=3. Differences in time to event (i.e. milestone) between donepezil- and placebo-treated groups were assessed using the Kaplan-Meier method and log-rank test. Shift tables were constructed to evaluate clinical milestone status for apathy and other NPI items at baseline and endpoint, and were analysed using the Cochran-Mantel-Haenszel (CMH) test, stratified by baseline status. RESULTS: Of all NPI items, apathy had the highest proportion of subjects scoring>/=3 at baseline. Donepezil was superior to placebo on both apathy milestone analyses (time-to-event log-rank test and shift table CMH test, p = 0.01). Aberrant motor behaviour demonstrated similar benefit. CONCLUSIONS: Donepezil treatment appears to have resulted in a significant reduction over 6 months of the emergence of apathy in patients with AD. These data suggest that a prospective clinical trial in patients with early AD that includes apathy as a primary outcome measure may be warranted. Copyright (c) 2010 John Wiley&Sons, Ltd.

Cholinesterase inhibitor minutiae

2010-06-13T11:46:00.000-07:00

1. oral donepezil is not affected by food, unlike rivastigmine and galanthamine
2. donepezil has 3-5 hours to peak onnset v. 0.5-1 for galanthamine and rivastigmine (oral) and 8-10 hours for rivastigmine patch
3. serum half life is 70-80 hours for oral donepezil, 5-7 hours for galantamine, 2-8 hours for oral rivastigmine, 3-4 hours for rivastigmine patch and 60-80 hours for memantine

GOVERNMENT REPORT ON RISK FACTORS FOR ALZ DISEASE

2010-05-03T18:52:00.001-07:00

http://www.ahrq.gov/downloads/pub/evidence/pdf/alzheimers/alzcog.pdf

UPSHOT

GOOD: PHYSICAL ACTIVITY, COGNITIVE ENGAGEMENT

BAD; SMOKING, E4 ALLELE, DIABETES,HYPERTENSION

LONG REPORT IF YOU WANT DETAILS.

Frontotemporal dementia- clinical pearls

2010-02-10T06:22:00.000-08:00

1. Frontotemporal dementia is a clinical term, frontolobar degeneration is a pathologic term

2. Preservation of memory, ability to keep track of day events, timing of spouse coming to and leaving home, and lack of getting lost (intact visuospatial) are characteristic, as is young age at onset (is second most common presentation before age 65, third after).

3. FTD-bv is more common than FTD-lang presentation. See other post for criteria. Presentation of FTD-bv includes difficulty with modulating behaviors (disinhibition, perseveration, lack of initiative), personality change, emotional blunting and loss of insight. Language presentation can be a problem with expression and naming, or word meaning (semantic dementia). Later, dementia becomes more global. Patients have frontal lobe release signs and in some cases, evidence of MND or Parkinson's.

4. Web resources
www.ftd-picks.org
www.aphasia.org

MAPT and types of tau

2009-12-25T19:39:00.003-08:00

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

2009-12-25T19:39:00.001-08:00

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

2009-12-20T19:09:00.000-08:00

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

2009-12-20T18:48:00.000-08:00

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

2009-12-07T13:52:00.000-08:00

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

2009-11-30T07:34:00.000-08:00

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

2009-11-29T11:42:00.000-08:00

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

2009-11-28T09:31:00.000-08:00

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 biomarkersand cognitive profiles in Alzheimer disease (AD).

Methods: We included 177 patients with AD. Digit Span, VisualAssociation 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, andtau phosphorylated at threonine 181 (p-tau) were measured. K-meanscluster analysis was performed with the three biomarkers toobtain three clusters. Multivariate analysis of variance forrepeated measures was performed with CSF cluster as between-subjectsfactor, neuropsychological z scores as within-subjects variable,and age, sex, and education as covariates.

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

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

Politics of health care reform distort reality

2009-11-28T08:17:00.001-08:00

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

2009-11-27T17:12:00.001-08:00

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

2009-11-27T12:57:00.001-08:00

Benton Visual Retention Test

Complex Figure Test Copy

Trails A

Functional Reach Test

from Neurology 2009 Feb Dawson et al. (Iowa)

lbd PEARLS

2009-11-09T09:19:00.000-08:00

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

2009-11-09T09:14:00.000-08:00

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

2009-11-09T09:07:00.000-08:00

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

2009-10-17T16:21:00.001-07:00

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

2009-06-06T10:14:00.000-07:00

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

2009-03-16T11:43:00.000-07:00

Kokmen Short test of mental status

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

A Good Credit Score is 700 or Above. See yours in just 2 easy steps!

Predictors of bad driving in AD

2009-02-26T12:26:00.000-08:00

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.

VGKC autoantibodies mimicking CJD

2008-06-01T13:39:00.000-07:00

Tan KM, Lennon VA, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 2008; 70: 1883-1890.

VGKC antibodies have been described in a variety of patient types, and may present with a symptom c0mplex including cognitive impairment and myoclonus, mimicking Creutzfeld-Jacob disease, which is untreatable. Some cases of VGKC may be treatable with IVIG or other anti-immune strategies.

Paraneoplastic VGKC have been identified as paraneoplastic antibodies in neuroendocrine tumors (including small cell lung cancer), retinoblastoma, oligodendroglioma, melanoma, leiomyosarcoma, and hematologic malignancies. They are also seen as markers of neuromyotonia, Morvan's, epilepsy, limbic encephalits, and dysautonomia with hyperhidrosis and GI dysmotility. Animal passive transfer experiments suggest pathogenicitiy. IVIG and plasma exchange are beneficial.

Among 80 patients in this Mayo Clinic series, was usually an inflammatory or neurodegenerative disease. 11 were correctly thought to have autoimmune encephalopathy, 10 with CJD, 5 with viral encephalitis, 3 with recurrent TGA, 4 with psychiatric (anxiety disorder/panic attacks/ conversion disorder). Examination showed frontosubcortical involvement, pesonality change, executive dysfunction, disinhibition, visual hallucinations (10%), agitation or depression. Short term memory impairment, with 58 % having some form of seizure disorder (all types seen) . Cranial nerve involvement was seen in 19 % including diplopia (not MG associated), dysarthria, dysphagia, vision loss, hemifacial spasm, hyperphagia, hyponatremia, EPS, cerebellar ataxia, recurrent ON without NMO antibodies, myoclonus, hypersomnia, autonomic dysfunction. MRI's showed abnormalities in bilateral hippocampi, CN head, splenium , frontal lobe, or multifocal suspicious for CJD. MRI improved partly or wholly. SPECT, EEG, CSF generally or often abnormal. 47% had documented neoplasia, of whom 76 % were smokers, and VGKC preceded diagnosis by five or more months.

Coexisting antibodies included ANNA-1, PCA2, amphiphysin IgG, CRMP 5 IgG with ultimate diagnosis of 5 small cell lung CA, three thymic CA, four prostate adenoCA, Becelllymphoma, CLL, mycosis fungoides, 3 head and neck CA, one colonic adenoca. There also were benign neoplasia including 5 pituitary adenoca, one adrenal, one colonic, one parathyroid, one renal oncocytoma, one gastric leiomyoma. Other AI disorders were Hashimoto titers in 15, endocrine pancreas in 8, and pernicious anemia. 89 % improved with treatment, half dramatically so, including 8 of 10 with initial misdiagnosis of CJD. These included six patients with increased 14,3,3 or NSE, 5 of whom improved remarkably.

Changing the trajectory of cognitive decline?

2008-05-12T18:20:00.000-07:00

Albert, MS. Clinical implications of basic research. NEJM 2007; 357:502-503.

This brief article describes recent findings in mouse models of cognitive loss. An enriched environment, containing many objects a mouse can explore, enhances learning and memory. Hippocampal neurogenesis is increased but not olfactory bulb. A model described by Fischer et al (Nature 2007) correlates with histone acetylation. Histone deacetylase (HDAC) inhibitor injections also facilitates memory. Histone acetylation is associated with synaptic plasticity.

Capgras syndrome and its relationship to neurodegenerative disease

2008-02-09T09:51:00.000-08:00

Joseph KA. Arch Neurol 2007;64:1762-1766.
Capgras s is delusional belief that a person has been removed and replaced by an impostor (husband, wife, etc.) In a review of 57 instances (Mayo Minnesota) 38 had neurodegenerative disease usually Lewy body disease. 100 % of those with LBD had visual hallucinations too compared to only one with AD. In younger patients CS occurred in the context of paranoid schizophrenia, schizoaffective disorder, methamphetamine abuse, and immediately after massive infarctions not in any one distinctive area.

Antiinflammatories, APOE status and dementia risk

2008-02-09T08:51:00.000-08:00

Szekely CA, Breitner JCS, Fitzpatrick AL et al. NSAID use and dementia risk in the cardiovascular health study. Role of APOE and NSAID type. Neurology 2008; 70:17-24.

3229 subjects aged 65+, free of dementia were analyzed. Use of NSAID's led to lower dementia risk (did not matter which AED). Acetominophen did not prevent dementia. Risk reduction was present only among subjects having an APOE4 allele . A contoversy exists regarding the use of particular NSAID's (ie ibuprofen but not naproxen due to AB 42 lowering effect) but there was not advantage seen in this study.

Blogger comment:
Back to screening first degree relatives of Alz patients to prevent their risk of developing disease and advising them. We have a rationale for measuring APOE status in these patients (which has been missing for 15 years). Mechanisms, counselling, etc. needs to be put into place first.

The natural history of cognitive dysfunction in late onset GM2 gangliosidosis

2008-02-03T11:35:00.000-08:00

Frey LC, Ringel SP, Filley CM. Arch Neurol 2005;62:989-994

Comment-- As one my mentors warned, pediatric diseases show up in adults and we need to diagnose them. This is the "adult form" of Tay Sachs disease. Late onset GM2 gangliosidosis (LGG)has late onset (adolescents and young adults), has a prolonged disease course, comparably late onset of neurologic dysfunction, and affects a significant minority of patients who are not of Ashkenazi Jewish descent.

Case one was a 46 year old Ahkenazi Jewish woman who had required special tutoring and was "emotionally immature." She showed emotional lability, aggressiveness and visual hallucinations. She had dysarthria, poor recall on memory tests, muscle atrophy and fasciculations, appendicular ataxia, and dysmetria, diffusely brisk reflexes and upgoing toes. EMG/ muscle biopsy done at age 13 showed diffuse denervation. She had a FSIQ of 93 at age 10, and 70 at age 20. CT showed cerebellar atrophy. Hex A level at age 20 showed partial deficiency (20.3 % residual WBC hex A).

Case 2 was sister of case one. She was learning disabled, weakness and ataxia, multiple psychiatric hospitalizations for psychoses, responsive to phenothiazines and lithium. She had partial hex A deficiency (20 %). She had supranuclear gaze palsy, tongue fasciculations, diffuse weakness, brisk reflexes, and flexor plantar responses. She had abnormal executive function, as detailed in Trailmaking Tests A and B and memory.

Case 3 was a 30 yo woman who had come to attention with deteriorating schoolwork in second grade. At age 25 she had a confusional state and profound abulia. She was briefly given AED's. MMSE was 27/30. She had limited upgaze, mild neck flexor weakness, diffuse limb weakness, brisk reflexes with bilateral Babinski signs, mild CT atrophy, slow RAM's, EMG showed abnormal spontaneous activity and decreased motor unit amplitude.

Review of 62 patients-- 2/3 were Ashknenazi Jews, 82 % LMN signs, and 69 % cerebellar signs, were seen. Mean hex A ranged from 0-48 %. 44 % were described as having cognitive dysfunction. 38 % of patients were cognitively stable, and 62 % had progressive cognitive loss.

Cognitive impairment in familial ALS

2008-02-03T08:17:00.000-08:00

Wheaton MW, Salamone AR, Mosnik DM et al. Cognitive impairment in familial ALS. Neurology 2007; 69:1411-1417.

Background. 51 % of patients with sALS have mild cognitive impairment, esp. executive function and memory. A subset, 15 % have more sever impairments with features of FTD. Over 60 % of patients had some cognitive impairment, either moderate or severe, generally unrelated to motor variables.

Binge eating in FTLD

2008-02-03T07:46:00.000-08:00

Neurology 2007; 69: 1424-33 and editorial 1389-1390. Article by Wooley et al, editorial by Murray Grossman

FTLD patients binge eat, especially sweets, even when stated that they are full. Investigators found significant atrophy in ventral insula, rostral orbital frontal, and striatum of right hemisphere among six binge eaters. Interestingly other frontal lobe abnormalities on neuropsychological tests were not found. Also they did not gain weight, leading Grossman to question whether the eating was a form of L'Hermitte's environmental dependency.

Dementia mimicking FTD with striatal hypermetabolic

2007-12-02T18:32:00.000-08:00

state and responsive to steroids.

Leger GC,Johnson N,Horowitz SW , et al. Dememtia like presentation of striatal hypermetabolic state with antistriatal antibodies responsive to steroids. Arch Neurol 2004; 61: 757-757.

Case presentation of a 48 year old woman with a one year history of progressive changes in pesonality and attention, originally diagnosed with a frontal dementia. PET showed a hypermetabolic lesion in the left striatum and plasma antistriatal antibodies were found. Treatment with corticosteroids resulted in a return of her premorbid state. PET scan and titers of antibody resolved. the differential diagnosis in this case was Syndenham's chorea and theantiphospholipid antibody state.

the phenotype of Sydenhams is usuallykids with onset of chorea, facial grimacing, hypotonia, and loss of fine control. Elevated ASO titers are present. Mood changes and OCD behavior may occur. Epitypes of IgM ASO titers cros react with striatum. It typically is self-limited and immune modulation may be useful. SLE occassionally occurs.

Dementia in women preceded by weight loss

2007-12-02T12:24:00.000-08:00

Knopman DS et al. Incident dementia in women is preceded by weight loss by at least a decade. Neurology 2007; 69:739-746.

Data is mixed. Weight loss isnoted at diagnosis, but obesity is a risk factor. Weight loss progresses with dementia. The Rochester Epidemiology project. Women began to lose weight 11-20 years prior to onset of dementia.

Progressive supranuclear palsy.-parkinsonism

2007-12-02T12:01:00.000-08:00

Kaat LD, Boon AJW, Kamphorst W etal.,Frontal presentation in PSP. Neurology 2007; 69:723-729

Diagnostic accuracy is poor (70 % initial misdiagnosis, 20 % terminal misdiagnosis). International criteria include falls in first year and vertical supranuclear palsy. PSP parkinsonism is a phenotype with assymmetric onset, tremor, levodopa response and longer disease duration. (see Williams DR et al. Brain 2005). A different phenotype of PSP is behavioral changes with impaired executive functions that may overlap FTD.

Clinical signs that were significant were abnormal score on the Thurstone (word fluency) with results often less than 3 or 5; applause sign in 72 % (http://neurologyminutiae.blogspot.com/search?q=applause+sign), and 85 % were abnormal when detailed cognitive evaluation was performed. These included especially abnormal executive functions, mental slowing, memory disturbance and change in personality.

Unreliable: dyskinesia, cortical sensory loss, dystonia and and cerebellar signs (all < 3 %). The most common misdiagnosis was FTD. Urge incontinence was both significantly higher (2x) than PD and with increased mortality, as was older age. Phenotype did not affect survival. Both had median survival around 8 years. Article suggests importance of Thurstone and personality changes (applause sign) increase the sensitivity of diagnosis.

Dementia with LB and PDD. Can MRI make difference?

2007-12-02T11:49:00.000-08:00

editorial Seppi K, Rascol O. Dementia with lewy bodies and Parkinsondisease with dementia. Can MRI make the difference? Neurology 2007; 69: 717-718 (editorial) and aricle
Beyer MK, Larsen JP, Aarsland D. Gray matter atrophy in Parkinson disease with dementia and dementia with Lewy bodies. Neurology 2007; 69: 747-754.

Article shows DLB had more cortical atrophy than patients with PDD especially in temporal, parietal and occipital lobes. The editorial cites the clinical rule, that if dementia occurs within 12 months of the PD, its DLB, but if more than that, its PDD.

Neuropathology is not always different as both conditions share widespread ubiquitin, alpha synuclein positive neuronal inclusion LB. The editorial cautions that the issue remains unsettled whether DLB and PDD are one or two diseases.

Alz disease and Mediterranean diet

2007-11-03T16:35:00.000-07:00

Scarmeas N, Luchsinger JA, Mayeux R, Stern Y. Mediterranean diet and Alzheimer's disease mortality. Neurology 2007; 69:1084-1093.

editorial Galvin JE Pass the grain and spare the brain. Neurology 2007; 69: 1072-1073.

Article states that consuming M diet, consisting of a high intake of cereal, legumes, vegetables, fruits, and fish, with a high unsaturated fatty acid, eg., olive oil is associated with a low intake of saturated fats , dairy products, meat and poultry. moderate wine is consumed with meals.

Adherence to the diet was associated with a lower mortality with a positive dose response effect. Adherence inthe highest tertile led to a 73 % risk reduction and average extra survival or nearly four years. It prevents death from ANY cause. Other studies have shown that exercise and mental stimulation also delay mortality.

Dementia, estrogens after oopherectomy

2007-11-03T16:19:00.000-07:00

Rocca WA et al. Increased risk of cognitive impairment or dementia in women who underwent oopherectomy before menopause. Neurology 2007; 69:1074-1083.

editorialHogervorst E. Should surgical menopausal women be treated with estrogens to decrease the risk of dementia? Neurology 2007; 69: 1070-1071.

article is from Mayo Clinic in Minnesota. Surgical menopause increases the risk of dementia or cognitive impairment by 45 % in a large observation followup trial. With unilateral surgery before age 41, there was double risk, before age 34 there was four times risk, for bilateral surgery before age 46 without treatment there was 82 % increased risk, but if estrogens were given till age 51 (natural menopause age) the risk for dementia was not significant. After age 51, the effects of estrogens were not protective against dementia. A prior study showed a benefit in patients up to age 58 with bilateral surgery. Editorial emphasizes that the effects of treatment are beneficial only for a short period of administration of drug (3-12 months). Estrogens are not indicated for this purpose in women above age 60. The author of the editorial proposed to investigate genetic polymorphisms in women with AD which are associated with altered sex steroid metabolism and synthesis, especially CYP 1B1 (Leu432) and COMT Met/Met to explain why some older women have an increased risk of AD when they receive HRT for a longer period of time.

Criteria for Sporadic CJD

2007-05-02T14:25:00.000-07:00

WHO 1998

1. Progressive dementia with any 2 of (myoclonus, pyramidal/EP, visual/cerebrellar/akinetic mutism)

AND

2, typical EEG and/or if 2 year duration + CSF 14,3,3

AND

3. Routine evaluation shows no other diagnosis

UCSF Modified

Rapid Cognitive Decline with any 2 of following: myoclonus, pyramidal/EP, visual, cerebellar, akinetic mutism, other focal cortical signs

AND

typical MRI and/or EEG

Comments of MRI on CJD: 91 % sensitive and 93-95 % specific. Findings include abnormal FLAIR and DWI in cortical gyri (ribboning) especially in CN, PUT and THAL. Only one form of CJD-- the MM2 subtype may not always show the DWI and FLAIR changes. vCJD shows "pulvinar" sign in thalamus.

Reviewing Geschwind's lecture and handout, the most useful table was the "lab finding not consistent with CJD". They include normal DWI and FLAIR, FLAIR without corresponding DWI abnormalities, abnormal contrast enhancement, leukoencephalopathy or significant white matter abnormality not attributable to another condition, mass effect or edema, CSF pleocytosis, CSF protein > 100, or elevated IgG index.

Clinical finding not typically found in CJD included early seizures, significant GI distress, ataxia without cognitive impairment, cranial neuropathy, acute stroke like onset weakness, and chorea. By contrast, aphasia, neglect and other "cortical" findings are common.

Body CT/PET can be considered for cases of possible paraneoplastic syndrome. Sarcoid also can be discovered.

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HIV dementia notes (talk A Nath AAN 2007)

2007-05-02T13:25:00.000-07:00

1. Post Haart, HIV dementia is seen at higher CD4 counts and the nadir CD4 count is more important than present count.

2. Host genetic factors are important in the development, including genetic mutations in the promoter region of monocyte chemoattractant factor 1 or its receptor CCR2 and TNF alpha.

3. Cognitive slowing and apathy are well known signs. Gait disturbance, bradykinesia, falls, loss of dexterity, and frontal release signs are also well known. Less well known is mania in 5 %, or accompanying myelopathy and symmetric peripheral sensory neuropathy.

4. Distinguishing HIV dementia from effects of drug abuse is important since the latter is unlikely to respond to HAART. Differentiating from effects of HCV is also a challenge especially as HAART drugs are metabolized hepatically.

5. There is increased incidence in older patients and apo E4 alleles and thus an interaction with Alzheimer's disease which can also present in older patients, albeit faster in some cases than it would have otherwise.

6. IRIS patients may have features similar to JC virus and PML but without JC virus detectable in brain or CSF, and IRIS patients may respond partially to steroids.

7. Potent antiretrovirals with 3 or more highly penetrant drugs are the standard of care for most cases of HIV dementia. Highly penetrant drugs include D4T, AZT, ABV, EFV, NVP, IDV.

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Natural history of primary progressive aphasia

2007-04-22T15:23:00.000-07:00

Rhun EL et al.Neurology 2005; 65:887-891.
49 patients were diagnosed (France). median age at onset was 62. First visit median age 66. Impaired ADL's occurred within 7 years. 75 % eventually met diagnostic criteria for FTD, 14 % for LBD, 8 % for CBD, 60 % died after median 7 years.

Primary progressive aphasia

2007-04-22T08:39:00.000-07:00

Review article Mesulam M-M. Primary progressive aphasia- a language based dementia. NEJM 2003;349-1535-42
Salient points
1. Language only disorder can be present for up to 14 years, or if other deficits are present the language deficit is "salient feature." Complex hobbies such as gardening, sculpting, painting may remain intact. One patient flew his airplane.
2. Differentiate from pure progressive dysarthria or phonologic disintegration (disruption of the formation of words rather than their use); from AD; from FTD with or without AD.
3. "Semantic dementia" refers to patients with a combination of impaired word comprehension and impaired recognition (agnosia) of faces and objects.
4. Clinical picture may vary. "Some patients cannot find the words to express their thoughts. Others cannot understand the meaning of words either seen or heard. Still others cannot name objects. The language can be fluent or nonfluent. (whereas) ...in Alzheimer's disease it is almost always fluent." Some patients may have preserved ability to write language.
5. Anomia is almost always first, later patients may develop agrammatism or develop comprehension problems almost to the point of mutism.
6. Functional imaging has shown greater activation of traditional nonlanguage areas (compensatory areas) during the performance of language tasks.
7. E4 allele is not associated with ppa
8. Chromosome 17 carries the tau gene and is linked to frontotemporal lobar atrophies (Picks or dementia without distinctive histopathology). PPA and frontal lobe dementia may represent anatomically distinct manifestations of a unitary spectrum of degenerative brain diseases. A specific haplotype *H1) of tau gene is overrepresented in patients with the sporadic form of PPA.
9. Pathology of FT degeneration is lobar atrophy, neuronal loss, ubiquitin positive inclusions, tauopathy, occassionally taking the form of Pick bodies.
10. A recent report of 3/4 sibs and 0/12 members of parental generation affected raises the possibility of an aut recessive form of tau-opathy.
11. Voice synthesizers and other technology based devices are useful.

Wernicke encephalopathy after bariatric surgery

2007-03-29T08:17:00.000-07:00

Singh S and Kumar A. Neurology 68; 807-811 . 2007. Clinical description. review of the literature. 27 cases were found. Most had vomiting as a risk factor, presented with the clinical triad of confusion, ataxia and nystagmus, and had a peripheral neuropathy at a median of two months. Most cases occurred at 4-12 weeks. Other neurologic findings included optic neuropathy, seizures, papilledema, deafness, asterixis, eating avoidance and weakness. Prevalence is around eight percent. Some of the patients had hyperintense signal in the periaqueductal gray and dorsal thalamus. Serum thiamine levels and transketolase levels were variably low. Most patients recovered completely with intravenous thiamine. The pathology has been attributed to thiamine deficit, but that is debated. The amblyopia resembles Leber's and tobacco amblyopia. The deafness may be thalamically based. Vasogenic edema due to free radical production and NMDA mediated neuronal injury may be at fault. In Brazil, the presence of thiaminase in river fish has been attributed. MRI is 53 % SENSITIVE AND 93 % SPECIFIC for the diagnosis. Gastroscopy is prudent to evaluate for stasis.

Semantic Dementia Lesions

2007-02-03T20:45:00.000-08:00

Davies RR, Hodges JR et al. The pathologic basis of semantic dementia. Brain 2005; 128:1984-1995

18 cases with semantic language deficit and associative agnosias and sparing of other aspects oo cognition. 10 men, 8 women, mean onset age 58 mean age of death 68. 8 patients had behavioral disorder including disinhibition, apathy, reduced empathy, stereotypic behavior. Pathologically, 16 had FTD, 13 ubiquitin positive 11 in cortex 2 i inferior olive only; 3 had Picks disease in dentate gyrus, 2 had AD.

Most cased were ubiquitin positive and tau negative. Cases suggest an intriguing overlap with MND

Frontotemporal dementia syndromes

2007-02-03T20:21:00.000-08:00

Kertesz A et al. The Evolution and Pathology of Frontotemporal dementia Brain 2005 128;1996-2005

Pathology varies. It can include balloon neurons (corticobasal ganglionic degenerations), microtubular tau (50%) and inclusions that are tau negative and ubiquitin positive (50-60 %) also called MND type inclusions. Another group lacks the above and are called dementia lacking distinctive histology. Pick disease has ntracytoplasmic neuronal inclusions, Pick bodies with specific staining in tau in the fascia dentata, hippocampus and cortex.

The clinical phenotypes are FTD-BV (behavioral variant) with loss of behavior and personality; PPA (primary progressive aphasia) with anomia, logopenia and nonfluent speech; corticobasal ganglionic degeneration with unilateral rigidity, apraxia/alien hand and late cognitive change; PSP with vertical gaze palsy, axial rigidity and pseudobulbar palsy with overlap syndromes also.

Of 60 autopsied, 32 had FTD BV, 22 had PPA, 4 had CBGD, 2 had PSP; autopsies however showed MND type inclusions in 18, CBGD in 12, PSP in 3 , Picks in 6, and DLDH in in 6, AD in 10, 5 others showing 1 each of LBD/AD, LBD, Binswanger's d, GSS, and undetermined.

Tau negative pathologies were most likely MND type inclusions, DLDH, and presented with FTD-BV. But PPA, CBGD and semantic dementia appeared.

Tau positive pathology appeared in CBGD, PSP and Picks and presented with PPA CBDS or PSP

Wernicke's encephalopathy

2007-02-03T14:12:00.001-08:00

Acute neurologic disorder with the triad of opthalmolegia, ataxia, and confusion, due to thiamine (B1) deficiency. Its probably more common than recognized. Neuroopthalmologic findings are usually horizontal and/or vertical gaze palsy with bilateral abduction deficits, and often, upbeat nystagmus. Mental status changes may be mild. MRI abnormalities may be seen in up to half of patients imaged within two weeks of symptom onset. It may be confirmed by lab testing of erythrocyte ketolase activity. Treatment is 100 mg of thiamine given iv or im with resolution of the symptoms promptly, prevention of Korsakoff's amnesia. MRI deficits may take several days to improve

14,3,3 protein in CJD

2007-02-03T13:39:00.001-08:00

Castellani et al. (Case Western Reserve, Italy) studied 90 patients with CJD. IN addition to neurologic deterioration and spongiform deterioration of the brain in sCJD, there is accumulation of proteinase K resistant prion protein (PrP-sc). Most cases are sporadic without prion protein gene (PRNP) or exposure to exogenous prions. The authors classify sCJD based on electropheretic motility of K resistant PrP-sc. Type I sporadic CJD patients are homozygous methionine at codon 129 (sCJDMM1) with phenotype of advanced age, rapid dementia and periodic sharp waves on EEG. sCJDMV1 also has classic phenotype and the two classic forms together account for 70 % of sporadic CJD. The alternate types have a younger age at onset (CJDVV1) ataxia at presentation (sCJDMV2 and sCJDVV2),a slower course and a lack of periodic sharp waves on EEG. The study looked at the sensitivity of 14,3,3 for the different types of sCJD and found an overall sensitivity of 87 %, with 94 % sensitive in classic forms and 57-84 % in nonclassic forms of CJD. Nonclassic presentations are harder to diagnose as they have such symptoms as vertigo, hemianopsia, gait difficulty, and hallucinations. Other tests for CJD include NSE (neuron specific enolase and atu tau protein in CSF). Periodic sharp waves are only present half the time and only the in the midstages of the disease. Nomenclature for the nonclassic forms has included the Heidenham variant (visual symptoms predominate) and Brownell-Oppenheimer variant (cerebellar ataxis is presenting sign). Two other studies in the same issue looked at MRI in sCJD. Shiga et al. looked at 24 cases of 26 that had abnormalities on diffusion weighted imaging (DWI) 3 in striatum,esp caudate, 10 linear lesions in cortex, and 11 in both. 12.5 percent of controls were false positives. In yet another study in same issue, Meissner et al. found that MRI basal ganglia hyperintensity on T2 images are seen in most MV2 cases (variants that may have normal 14,3,3 testing). There was no correlation with basal ganglia abnormality on MRI and eps symptoms. Most patients, whether atypical or not, will have abnormalities on MRI or 14,3,3, testing or both.

14,3,3 protein

2007-02-03T13:36:00.000-08:00

Drugs for prion disease

2007-02-03T13:34:00.001-08:00

Korth C, Peters PJ Emerging pharmacotherapies for Creutzfeld-Jakob disease. Arch Neurol 2006;63:497-501. Neurological review. Antibodies are protective and heterocyclic small compounds have been proposed as antiprion drugs, leading to clinical trials. Notes from intro-- Variant CJD lasts longer, has younger onset, more psychiatric symptoms, occurs because of the lack of a bovine-human species barrier (which exists with humans and sheep), and concern exists about blood transfusions,organ donations in affected individuals. CJD occurs as sporadic, genetic, and infectious disease. PrP derives from a gene that is expressed by most cell types in the body, but especially CNS and lymphatic organs. After synthesis, PrP(c) (or cellular) is modified postranslationally to receive 2 N linked carbohydrate side chains and a glycosyl phosphatidylinositol membrane anchor, then is sent to the plasma membrane, where it sorts into cholesterol rich detergent resistant membranes (DRM) domains or so called lipid rafts. Membrane anchored PrP can adopt a pathological and infectious conformation PrP(Sc) (scrapie) by a mutation in its amino acid sequence either due to germline or somatic mutation. Once sufficient amount of PrP (sc) is present ("infectious dosage") normal PrP molecules are induced to adopt the PrP(sc) conformation. Cofactors like protein "x" may be essential. Once cascade starts, signal ensue that lead to neuronal death, and pathological hallmarks including plaques and vacuolation. Malluci et al (Science , 2003) showed that knocking out PrP during inoculation of prions, but before replication,could prevent/reverse vacuolization and halt neurological symptoms. Treatment ideas include 1. gene silencing by small RNA interfering targets of PrP expression. 2. Protecting/shielding PrP(c) from conversion by antibodies is proved in animals, but has the problem of constructing an antibody than can cross the blood brain barrier. 3. Destabilizing DRM which is needed for PrP conversion. Possibly statins or quinacrine. 4. Find a competitor to binding on the enzyme "x" which has yet to be identified, which may be necessary to conversion of PrP and misfolding. 5. Inactivating/shielding Prp(sc) so that it is conversion incompetent. Polyanions such as Congo red, dextran, heparin sulfate, and pentosan polysulfate. Pentosan polysulfate is used for cystitis and can be tried, especially if given intrathecally. 6. Conceptually, increase the degradation of the misfolded protein, which has a half life of 28 hours, but unfortunately, the degrading proteins are now unknown. 7. Preventing the neurotoxic effects of PrP(sc), but not known how. Heterocyclic antiprion compounds were identified in cell cultures including phenothiazine and acridine derivatives (quinacrine). Quinacrine was 10x more active than chlorpromazine.

Early signs of GSS syndrome

2007-02-03T13:30:00.001-08:00

Arata H. et al. Early clinical signs and imaging findings in Gerstmann-Straussler-Scheinker syndrome (Pro102Leu) There are seven types of inherited prion disease,of which the above is but one accounting for about 28 % of cases. Classic signs of GSS102 are cerebellar signs and slowly progressive dementia, but the ataxia occurs late. Early findings in 11 patients (9 families) are described, including mild gait disturbance, dysesthesias and hyporeflexias of the legs, dysarthria and truncal ataxia and 9/11 had proximal leg weakness. None were demented early. MRI/EEG were normal with abnormal SPECT scans. NCS/EMG were normal. On initial exam only three patients had mild limb ataxia and three others had mild nystagmus. Several were seen/operated for lumbar disease. Two tested had increased 14,3,3, protein in CSF. The problem with orhtopedic referrals was transmission of the disease.

Hashimoto's Encephalopathy by other names

2007-01-31T18:48:00.000-08:00

Chong Jy and Rowland LP. What's in a NAIM? (editorial) Arch Neurol 2006 63:175-176

Hashimoto's encephalopathy (named by Lord Brain) is also called by "steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT)" or "nonvasculitic autoimmune meningoencephalitis (NAIM). CJD may present identically except without steroid responsiveness.

TGA Mechanism

2007-01-29T07:54:00.000-08:00

Bartsch T et al. Brain 2006;129:2874-2884. Selective affection of hippocampal CCA-1 neurons in patients with TGA without long term sequelae.

71 percent occurred after physical exertion, stress, Vasalva, or postural changes, most in the morning or afternoon. Of 41 patients, 29 had 36 DWI lesions and corresponding T2 lesions in hippocampus 48-72 hours after , almost all (34/36) in CA1 secotr, one in CA3 sector and one in cornu ammonis. Left sided lesions favored 20-16 with episodic verbal deficits seen in those tested acutely and visuospatial deficits in those with right sided lesions tested acutely. MRI lesions did not persist.

A hypoplastic transverse sinus with slight left sided predominance was seen in 88 %

Neurologic cosequences of starvation

2007-01-29T07:47:00.000-08:00

Basoglu M et al. Neurological consequences of prolonged hunger strike. Eur J Neurol 2006; 13; 1089-1097.

Extensive studies were carried out of Turkish hunger strikers. Patients typically developed gaze evoked nystagmus (vertical in 9/41), limb ataxia in 3, and lateral rectus palsy in 14. All had muscle atrophy but only 11 were demonstrably weak. 15 had paresthesias, and 17 had abnormal vibratory or position sense. All patients were treated with thiamine when they reached the point of confusion. Nystagmus and ataxia resolved, sensory function normalized, but anterograde and retrograde amnesia remained in all.

Michael Rubin commented that although Wernicke-Korsakoff s. was diagnosed in all, osmotic myelinolysis with shift from normonatremic to hypernatremic state was reported in an Algerian hunger striker (Neurology 2005; 64;574-5).

CATIE-AD study

2007-01-29T06:51:00.000-08:00

Schneider LS etr al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. NEJM 2006; 355:1533-1538.

Design 421 patients with average MMSE 15 enrolled at 42 sites. Subjects were randomized to placebo, 5.5 mg/d olanzepine, 1 mg/day risperidone, or 56.5 mg/day of quetiapine. Endpoint was the time until the physician switched the medication. Results were not significantly different in the various groups except on minor measures. AE's included higher eps in patients receiving risperidone or olanzepine, and sedation with olanzepine and quetiapine (more than risperidone). Cognitive disturbances were higher in patients on olanzepine (7%) and increased agitation in those getting quetiapine.

In Neurology Alert, Norman Relkin comments that treatment of psychosis in AL is not a matter of writing a drug, but looking at all drugs, precipitants, sleep wake cycle and nutrition, supportive environment and caregiver education, none of which were controlled for. The study did not show the antipsychotic drugs were ineffective, just that they have risks as well. The lay press has misinterpreted the results.