2880 dementia with lewy bodies

Plenary

Session

IV

Wednesday, July 12

NELJROINFLAMMATION

Plenary Session IV

19421

2880 DEMENTIA

WITH

LEWY

Joseph

BODIES

B Rogers

Dr.,

Sun Health

IN ALZHEIMER’S

Research

Institute.

DISEASE

Sun City.

AZ

the last decade a wrtual textbook of inflammatory mechanisms has been uncovered in the Alrheimer’a disease (AD) brain. The issue now is not whether neuroinflammation occ”rs, but how significant it may be to the development and progression of the disorder. To understand this issue, the depth of the basic science data on major inflammatory pathways-including the alternative and classical complement pathways, cytokines, and acute phase reactants-must first be appreciated. From that vantage point, it may be possible to make sense of the mostly positive clinical literature that haa so far been published, and the mostly negative anecdotal results of more recent antl-mflammatay AD trials. Neuroinflammation is unlikely to be the root cause of AD, and anti-inflammatory drugs are no more likely to cure it than they do arthritis. Anti-inflammatory drugs may, however, provide a significant adjunct benefit to c”rrent therapies for AD patients, and might well delay onset in normal elderly patients at risk for the disorder. [Supported by NIA AGO7367 and the State of Arizona‘s Alrheimer’a Diaeaae Research Center].

Over Ian G McKeith,

lnstititurefor

the Health

ofthe

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upon l)ne

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Dementia with Lewy bodies (DLB) is a common cause of dementia in patients > 70 years old, only Alzheimer’s disease (AD) being more frequent. Consensus criteria for DLB identified key diagnostic features including fluctuating attentional deficits and relative preservation of episodic memory compared with AD. Persistent visual hallucinations, extrapyramidal feat”res(EPF), misidentification syndromes, depre\we symptoms, syncopal episodes and REM sleep behaviour disorder alao help discriminate DLB from AD. Age of onset is similar in the two disorders, as is mean rate of cognitive decline. Annual rate of progression of EPF (IO%)in DLB is similar to Parkinson’s disease (PD). Survival time is reduced in DLB (4Syrs) compared both with AD (8.0 yrs) and PD (lO.Oyrs). Although recent autopsy validation studies suggest that the Consensus criteria for clinical diagnosis of DLB can consistently achieve rpecificity rates > 0.9, sensitivity (the proportion of all cases that are clinically detected) is lower and more variable (0.22-0.83). Relative preservation of medial temporal lobe Ytr”ct”res visualised by CT, MRI and SPECT HMPAO may assist in the differential diagnosis from AD. Deep white matter and periventricular hyperintensities occur in both DLB and AD, reflecting similar degrees of vascular comorbidity. The recent demonstration, “sing SPECT FP-CIT, of reduced dopamine transporter activity in the putamen of DLB, but not AD patients, has potential to significantly increase diagnostic sensitivity and accuracy. Accurate diagnosis of DLB is important in order to prevent patienta being exposed to neuroleptic agents which provoke severe adverse reactions in 50%. with a 2-3 fold increased mortality risk. Post-mortem studies find sigmficantly greater cortical cholinergic deficits in DLB than in AD, due to degeneration of both sub-cortical and basal forebrain projection neurones. Cholinergic deficits in DLB are correlated with cognitive impairment and visual hallucinations, both of which have been demonstrated to improve with chohnesterase inhibition in a randomised, placebo controlled study “sing rivastigmme. Apathy, anxiety. hallucinations and delusions were the most treatment respon\ive symptom\.

19431

CNS BIOMARKERS

FOR

ALZHEIMER’S

DISEASE

Antemortem biological correlates of AD stem from discoveries in molecular genetics, measuring molecular markers of senile plaques and neurofibrillary tangles in body fluids, and detecting characteristic structural and functional abnormalities in brain with neuroimaging techniques. This presentation will examine whether any of these correlates can be used in the clinical diagnosis of AD or as surrogate outcome measures in assessing treatment efficacy. For diagnosis, a useful biomarker should have high sensitivity and specificity. This goal has proved elusive for all proposed biomarkers. For example, detecting genetic mutations that cause early-onset familial AD provides nearly 100% specificity but lest than 5% sensitivity. Therefore genetic screening cannot be recommended for routine “se, but should be limited to familier with AD onset ~50 years old. Similarly, sensitivities and specificities are inversely related for measuring A@42 and ta” in CSF even though they approach 80% in some reports. Plasma AP42 and 40 are elevated in most familial and some sporadic AD cases, but these meas”res are not widely available. Abnormalities in cerebral blood flow and glucose metabohsm are believed to reflect synaptic and neuronal degeneration and are therefore not specliic for AD, although the pattern of impairment may be characteristic of AD in > 80% of cases. For tracking progression of disease, quantitative “euroimaging of either the whole brain or specific regions such as temporal lobe str”ct”res is most accurate. Based upon serial MRI examinations, brain volume in AD decreases by about 2.3%/year compared to
Symposium:

19451

Prion Diseases

PATHOLOGY

AND PATHOGENESIS

OF PRION

DISEASES

Scrapie and Creutzfeldt-Jakob disease (CID) are characterized by vacuolar degeneration of the grey matter neuropil, accumulation of protease-resistant PrPSc, high rate of transmissibility, and involves conversion of glycolipid anchored PrPC to PrPSc. The conversion of PrPC to PrPSc and accumulation of PrPSc in nerve cells causes the clinically relevant neuropathology. 90% of the accumulated PrPSc becomes concentrated in cholesterol-nch caveolae-like domains (CLDs) of the plasma membrane. This causes depression of receptor mediated second messenger responses in vitro and argues that alterations of receptor-mediated neuronal transmirsion and trophic factor effects may underlie degeneration of neurons in viva. However, the degree of vacuolar degeneration is not directly proportional to the amount of local PrPSc accumulation. The latter argues that neuronal degeneration and death are likely complex and multistep processes. In this regard, recent studies indicate that not all neurons are equally susceptible to PrPSc. The pawalbumin subset of GABAergic neurons are the first to degenerate even though PrPSc appears to be uniformly distributed to all neurons in a brain region, and their degeneration precedes vacuolation. This raises the possibility that generalized neuronal vacuolation is caused by a combination of: (1) Loss of GABAergic inhibitory neurons; (2) subsequent overactivity of excitatory pathways; and (3) vacuolar degeneration of non GABAergic neuron populations made more vulnerable to excitatory neurotransmitters as a result of PrPSc accumulatmn.

19461

PRPyc

REPLICATION,

PROTEIN

FOLDING

AND

MISFOLDINC;

The transmissible encephalopathies including Kur”, Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy appear to be caused by a proteinaceous infectious agent or prion. I will describe theoretical and experimental studies of the prion protein that help to explain how one disease can present in infectious, sporadic and Inherited modes and how a protein can “replicate” in viva Current work suggests that the transmissible encephalopathies are diseases of protein folding where the tertiary structures of the normal cellular isoform, PrPc, and the disease causing isoform PrPs’, are distinct while their covalent str”ct”res are identical. Work on peptides refolding into P-rich confomuttions that initiate neuropathology in transgenic models of prion diseases as well as work on the design of small molecule inhibitors of priori replication will be diwussed.