Clinical features in a kindred with familial frontotemporal dementia with the P301L tau mutation

1MPAIRMENT IN CEREBELLUM FROM 1355( MITOCHONDRIAL TIENTS WITH PROGRESSIVE SUPRANUCLEAR PALSY

PA-

autoaomal S7-73).

dommant pattern of inheritance,

mean duratton

death 77 years (range 65.86). Lrrrrx

Ch Park.

David

Cornell

Mcd

Gibson.

S Alher.~. M. FIint Co11 at Burke

Bad.

Cornell

Mc,d R~seurch

Unix

Inst,

New

York, NY; Guru

White Plains,

E

NY

parkinsonism

Abnormalitie\

in energy metabolism

generative

dtseases,

mcluding

second most frequent diseax

of hyperphosphorylated

Tau protein.

superior

frontal

current


=

13). In contrast protein

carhonyl

of metabolic

In cerebrllum.

contribute wth

to cortex.

complex

modtfication.

impairment

significantly

mitochondrtal

to the pathological

The

diminished

dysfunction

lnanifestations

resultr

precede\

motor

cause degeneration

that

\tre\\.

in cerebellum

the

in PSP and may

from

patients

Prion direases, degenerative acrapie

or transmiasihle

dt\ordera

in sheep. bovine

Jnkoh diaeaae

(CJD).

(FFI)

iwform

(BHW)

significantly

alleviate\

Mental

MRI.

and EEG.

ERP

ma’s

direabe,

symptom\

State Examination eight patient\.

rerved

acupoint\.

the Si.\hrrll,oll,~(Ertra

wri\t\land

Taivi(K1

(GB

and autism. On the hai\

as having

in a systematic

mild

12346.YO)

selected according

The treatment

mvolved

Into the .Slwwrren

and 0.8

re-inwrtion

cycle wth

MMSE,

Inche\

a total

directly

a 3.day

comprirmg

break in between

pattenta significantly coordination

treatment.

imprwcd

(p
In addition.

a\

In born. acupuncture measure\

7 on two National

western

standard

blotting

by their relative

molecular

type which

with

exposure

needling

to BSE prions.

overall clmical

wxe

of PrP”’ in caws of vCJD. PrP”’ can he ohaerved

THE

effects

Background: exhthited

To date there have been at lea\t tau mutation

features

dysfunction Methods:

typical

occurring

has been 40-65 FTD

fenomic

years, duration

through

DNA.

(piO.05)

after

the

wquence

5 years

behavior,

ing has demonstrated

with

TAU

effects on

MUTATION

parkinsonism

FTD

affected

Increasing

tau mutation

and lower

motor

have neuron

the age of onset

in the proband

analysis of tau coding exonr

of a kindred

amplified

has developed

ahulia.

forgetfulness delusions,

Serial

years. with

from patient

data on the prohand and other affected relatives

impairment

ewdcnce

pathogeneri\

factor-a

wurces has

of thex

shown

were

at age 59 and

disinhihited

neuropsychometric

and test-

in domain% subserved by frontotempw

mcubated containing duction

identifymg

model

is yet

barrier,

tiwles

IN BRAIN MICROVESSELS

atrophy

dementia

elw in an

mediator\

wch

have been identified

mechanism\

in

AD,

brain

intlammatory

as interleukin

cndothrlial mediator

thi\

posing

II

IN ALZHEI-

mediators

(IL)-I,

are

IL-6,

and

tumor

the cellular

and

exprea

antnmcrobial

is to determine

evidence

is abnormal

in the levels of

work from our laboratory activated

(cationic

The ObJeCtwe of thi\ wdy

Elevated

brain, although

Preview

cells

CAP37

IL-lp

and

d&ease (AD).

in the AlLheimer

factors have not hecn identified.

of neurodegrnerattvc

lipopolysaccharide. the

homogenized

the

protein.

if production

media

i\

and intaferon-y

quantitated

by

in the microvasculaturr

oi

dtseuse (1~~7). or with

and lysates prepared to determine

In

M~crover.wl~

an mflammatory

(stimulated

ELISA.

in AD.

condition\).

addition,

cell-zsociated

media of both AD and control i\

significantly

Stimulation IL-lb

Al/heimer

m

AD

IL- I p pro-

microvewels

IL-l

However,

microvessels

control

the innammatory

cocktad

or AD

vessels. An

analyses

reveals

no detectable

by

AD

vessels.

These

by the microvasculature mediators brain.

contributes

data m AD,

IL-lb

in

of microvessel

in control an

vessel\

upregulation

and suggest that vasculx

to the mflammatory

mechanisms

by

in the IL- I p vessels.

does not signtficantly

examinatwn

demonstrate

than

are

p production

under basal conditions.

in control

blot

expression

microvessels

higher

of vessels with

levels

Western

(piO.02)

are

cocktail

Western blot analysis. The data indicate that there are detectable levels of IL-lp

mtlammatory

minmxd

developed

mflammatory

cell 101s in Alzheimer’s

are iwlated

in

hlfir~ntalhltrmporal

with

As no animal

of vCJD prions.

for 4 hours in media (basal conditions)

progre”\ive

ha\e

for

in

represent the super-

from the cortices of AD patients (n= I I) and age-matched

Ten

atrophy

that

without

where.

conical

presumably

Microvessels controls,

\trtkinp

generation\

which

be useful

and

mediator

production

three

implicates

on their wrface.

Senal magnetic resonance imaging scan\ of the hraln have shown over

PrP”‘ may

assay we

nervous

the soluble inflammatory

ml neural network\.

tndividual\

blotting

the central

in the absence of a transtmsston

tranwission

of neuronal

multifunctional

in whom

relatives

of disease 4-10 years, and age of death 45-75

and ob\el\ions/compulsions.

progrwive

familial

all

For most of the kindred\.

Result% The proband developed

suhwquent

inappropriate

FTD,

Almost

with

the

after the treatment

therapeutic

PXllL

I6 kindred< wth

identified.

frequently.

the P3OlL

All antemortem

gathered end analyxd. over

of

Par Ia\

We identified

familial

has been

or inherited

is different,

PrP”’ patterns were obtained

on the PrPSC type.

priow

IL-lp IS ELEVATED MER’S DISEASE.

I7kDal

the P3OlL

from

tissue specific

Imposition

~numerous intlammatory

WITH

iatrogenic

of vCJD

and it\

Disease.

DEMENTIA

in tonsil tissue taken at

a sensitive weam

in tissue

ttssuea studied.

il seven-day

FEATURES IN A KINDRED WITH FAMILLAL PRON-

TOTEMPORAL

Using

qome of the lymphoreticular

of iatrogenic

from other human

4 PrP”‘). We have recently

and not sporadic,

only

systems. Intriguingly,

for

In humans,

and has been

sy?tetn. Here we extend our study of the tissue

\how

of tissue-specific

can he to give a

ditease<. in I996

can he distinguished

strain type (type

distribution

necro\i\

CLINICAL

of the lymphoreticulw

fragment\

f(,r the AlLheimer’s

improvement

treatment has shown significant

of thae

that the pathogen&s

indicatmg

protease treatment

PrP”

PrP”’ type (type 4t) can be obxrved

dixase,

ri\k

Upon

resulting

human

lymphoreticular

from PrP’ by Its detergent

was first recognised

vCJD

by its unique molecular

priori

are

for each

testing

Using the

Checklist

The

of vCJD

that

Creutzfeldtfaawl fa~~tlial

which can he separated and analysed

autopsy or by biopsy from caw

mvolvement

m cattle,

rnas~i and ratio of the PrP glycofotms

disease (vCJD)

potential

Patients received

the overall

VARIANT

are a group of new,-

(BSE)

can he used in the classification

>0.5

the needle

methods.

molecular

immunoassay

The

IN

disease (GSS).

to protease degradation.

wing

classified

\en\itive

for a total of thirty

Symptoms

network\.

form of the host encoded prion protein (PrP”)

K. PrP”’ fragments are obtained

fme finger turning ot inches directly

encephalopathy

wtth proteinaw

for bioassay of vCJD

(p
a\

01

may

animals. These diseases Include

and

which can be distinguished

rwstance

availahlc

day\.

well

of the Alzheimer‘s

Eight

on ~mensures of verbal orientation

using the TCM-

Disease. patients showed a significant (p
into the 7irw.

of 30 mmutes.

after every ten minutes of needle therapy.

treatment motor

for

Al/hei-

treatment.

to the China

0.5 inches at an angle into the Si.shcwXumg.

lasted

to moderate

acupuncture

the needle inxrted acupoint

data from the CT,

6. four points on the scalp), Shrwnen(HT

3 on two feet) were

Standards on Acupoints

brush handwriting

along with clinical

diagnosed

as subject\

that Chmese

in xhirophrenia

(MMSE),

cortical

PRP”

encephalopathies

both humanr

cellular

(PI@“)

and partial

shown that a di\tinctwe

of the Mmi

mutation

and kuru in humans. One of the central features of prion dwases

to an abnormal insolubility

\pongiform

spongiform

of the normal

lmked

found

this

cerebral

Gerrtmann~Strausale~-Sheinker

the conversion

priori dtxaaes

recently

of the frontotemporal

affecting

variant CreutLfeldt-Jakoh

(2000)

but rare existence

cuggata

TISSUE DISTRIBUTION OF CREUTZFELDT-JAKOB DISEASE.

p3iJ

mwmnia

PSP.

and his collaborator\

of FTD

dysfunction

was not nitration

ruggat

oridative

a

ACUPUNCTURE ENHANCEMENT IN CLINICAL SYMPTOMS AND COGNITIVE-MOTOR ABILITIES OF THE ALZHEIMER’S DISEASE PATIENTS

Kao

The consistency

neuron

in the

stress i\ region-specific

observed

lower

tau

than most and

control hrams

in cerebellum

present

or

No

with the other reported P3OIL

the ages of onset and death are higher

of disease is much longer.

parkinsoniym

ancestry.

of this kindred.

levela. The

stress. such tt\ tyro\ine

and oxidative

although

in any member

of a

with PSP. This paralleled

in KGDHC

duration

preferentially

(KGDHC)

hy malondialdehyde

was alw

the decline

Parkinson’s

This kindred shares many similaritiea

kindreda.

and mean age of

IS of French and Canadian

tangles consisting

dehydrogenase

by the increase in marker7 of oxidative

general

interaction brain.

with

is the

we showed decreased activities

assewzd

that KGDHC

PSP

from patienta with PSP (n = 14). compared to age-matched

accompanied or

\tres\

many neurode-

(PSP).

associated

cortex from the patxnts

increase in tissue oxidative

(n

Previously.

a-ketoglutaratr

marked

ccrehellum

disorder

palsy

by abundant presence of neurofibrillary

enzyme complex,

in post-mortem

stress accompany

supranuclear

cause of neurological

It is characterized

mttochondrial

and oxidative

progressive

I5 yeara (range 8-21)

The ktndred

or motor neuron disease has occurred

Conclusionr: mutation

with the mean age of onset 62 years (range

from onset to death

affect

lysates by but strong of

IL-I

production

B of

at work in the