Semantic Dementia Lesions

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

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

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

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

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.

Drugs for prion disease

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

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.