The Role of Supplemental Antioxidants in Preventing Memory

Loss

Andrew McCaddon MD

19th March 2011

> 9,000 patients

4 full-time GP’s

≈ 10 new dementia cases pa

40+ established dementia

Homocysteine - mechanisms

Why IS homocysteine raised?

Case Studies

CBS

Cysteine

Cystathionine

Serine

Transsulfuration Pathway

THF

Methyl-THF

Methylene-THF

Serine

Glycine Methionine

SAM

SAH

Homocysteine

MS B12

Acceptor

Methylated Acceptor

ATP

Methionine Cycle

Folate Cycle

MTHFR

Glutathione

Dietary protein

Hypomethylation

DNA damage

Excitotoxicity AD pathology

Apoptosis

Vascular damage

Why is homocysteine raised in mild

cognitive impairment and dementia?

McCaddon et al Biological Psychiatry 2003 (53): 254-260 Box & Whisker Plot: CYSTEINE

Mean ±SE ±1.96*SE ALZ CON

DIAG

105

110

115

120

125

130

135

140

145CY

STEI

NE

(50 AD patients v 57 controls)

Cysteine

CBS

Cysteine

Cystathionine

Serine

Transsulfuration Pathway

THF

Methyl-THF

Methylene-THF

Serine

Glycine Methionine

SAM

SAH

Homocysteine

MS B12

Acceptor

Methylated Acceptor

ATP

Methionine Cycle

Folate

Cycle

MTHFR

Glutathione

Could ↑Hcy reflect oxidative stress?

Glutathione McCaddon et al Biological Psychiatry 2003 (53): 254-260

Limited pathways to remove homocysteine in the brain The major pathway is impaired by oxidative stress

Inflammation Oxidative Stress

SAM

SAH

Homocysteine

Methyl-THF

THF

Methionine

CH3

Co III

DMB

MS

Co I

DMB MS

Co II

DMB

MS

Oxidative Stress

Increased Hcy

NAC

Homocysteine B-

vitamins

NAC

Why NAC?...

Safe, and orally bioavailable

Antioxidant in and of itself (via SH group)

Cysteine precursor Increased GSH

Lowers Hcy Urinary excretion

Oral NAC (600 mg daily) added. 1/12 later “..livelier and happier” MMSE improved to 25/30; regained ability to recall 3 objects

Mild cognitive deficits (27/30 on MMSE) Diagnosis? ‘Age-associated memory impairment’

70 yr old lady 1 yr H/O ST memory loss Controlled hypothyroidism

MMSE fell to 22/30. Borderline low B12 (195 ng/L) and folate (4.6 µg/L) Elevated tHcy (16.5 µmol/L) Low glutathione (2.1 µmol/l)

Commenced monthly im OH-B12 (1 mg) and oral folic acid (5 mg)

BUT cognitive function unchanged over 6/12 (21/30 on MMSE)

Memory declined over next 3 yrs - Forgot to convey messages to husband Inappropriate questions - enquired after deceased friends

Continued on this Tx for last 3 years; scored 27/30 on most recent MMSE

Now on AchE inhibitor in addition to B vitamins and NAC

71 yr old retired telecom engineer 10 yr H/O gradual ST memory impairment Frequently mislaid objects / forgot people’s names Father † senile dementia aged 74

Poor 6CIT (12/28). Elevated tHcy (15.6 µmol/L) but normal B12 (368 ng/L),

folate (9.3µg/L) and RCF (492 µg/L)

Diagnosis? Probable SDAT

Commenced oral CN-B12 (1mg) folate (5mg) and NAC (600mg)

Wife reported a “.. definite and immediate improvement” within 2 weeks

tHcy fell to 9.6 µmol/L. 1/12 later scored 28/30 on MMSE

Summary Homocysteine is a modifiable risk factor for cognitive impairment and cognitive decline

Homocysteine is likely also a marker of neuro-inflammatory oxidative stress in these patients

NAC can be used together with B-vitamins to address oxidative stress and lower blood Hcy

Can we delay the onset of dementia?