|
Dietary fat intake and
the risk of incident dementia in the Rotterdam
Study.
Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A,
Breteler MM Department of Epidemiology and Biostatistics,
Erasmus University Medical School, Rotterdam, The
Netherlands.
Ann Neurol 1997 Nov;42(5):776-82
A high intake of saturated fat and cholesterol and a low
intake of polyunsaturated fatty acids have been related to
an increased risk of cardiovascular disease. Cardiovascular
disease has been associated with dementia. We investigated
the association between fat intake and incident dementia
among participants, age 55 years or older, from the
population-based prospective Rotterdam Study. Food intake
of 5,386 nondemented participants was assessed at baseline
with a semiquantitative food-frequency questionnaire. At
baseline and after an average of 2.1 years of follow-up, we
screened for dementia with a three-step protocol that
included a clinical examination. The risk of dementia at
follow-up (RR [95% CI]) was assessed with logistic
regression. After adjustment for age, sex, education, and
energy intake, high intakes of the following nutrients were
associated with an increased risk of dementia: total fat
(RR = 2.4 [1.1-5.2]), saturated fat (RR = 1.9 [0.9-4.0]),
and cholesterol (RR = 1.7 [0.9-3.2]). Dementia with a
vascular component was most strongly related to total fat
and saturated fat. Fish consumption, an important source of
n-3 polyunsaturated fatty acids, was inversely related to
incident dementia (RR = 0.4 [0.2-0.91), and in particular
to Alzheimer's disease (RR = 0.3 [0.1-0.9]). This study
suggests that a high saturated fat and cholesterol intake
increases the risk of dementia, whereas fish consumption
may decrease this risk.
Cerebrospinal fluid
biopterin is decreased in Alzheimer's disease.
Kay AD, Milstien S, Kaufman S, Creasey H, Haxby JV,
Cutler NR, Rapoport SI.
Arch Neurol 1986 Oct;43(10):996-9
Tetrahydrobiopterin is the cofactor in the hydroxylation
of phenylalanine, tyrosine, and tryptophan leading to the
eventual synthesis of the monoaminergic neurotransmitters,
dopamine, norepinephrine, and serotonin, respectively.
Total biopterin (90% of which is in the tetrahydro form)
was measured in cerebrospinal fluid (CSF) and plasma of 30
patients with Alzheimer's disease and of 19 healthy
controls. Plasma and CSF biopterin concentrations were not
significantly correlated, but the mean CSF biopterin
concentration in patients with Alzheimer's disease was
significantly less than in age-matched controls, 13.5
pmol/mL as compared with 18.9 pmol/mL. The CSF biopterin
concentration was not correlated with ventricular volume,
as estimated by quantitative computed tomography, nor with
the severity of dementia, as measured by various cognitive
tests. The results suggest that a central biopterin
deficiency exists in Alzheimer's disease.
A review of nutrients and
botanicals in the integrative management of cognitive
dysfunction.
Kidd PM
Altern Med Rev 1999 Jun;4(3):144-61
Dementias and other severe cognitive dysfunction states
pose a daunting challenge to existing medical management
strategies. An integrative, early intervention approach
seems warranted. Whereas, allopathic treatment options are
highly limited, nutritional and botanical therapies are
available which have proven degrees of efficacy and
generally favorable benefit-to-risk profiles. This review
covers five such therapies: phosphatidylserine (PS),
acetyl-l-carnitine (ALC), vinpocetine, Ginkgo biloba
extract (GbE), and Bacopa monniera (Bacopa). PS is a
phospholipid enriched in the brain, validated through
double-blind trials for improving memory, learning,
concentration, word recall, and mood in middle-aged and
elderly subjects with dementia or age-related cognitive
decline. PS has an excellent benefit-to-risk profile. ALC
is an energizer and metabolic cofactor which also benefits
various cognitive functions in the middle-aged and elderly,
but with a slightly less favorable benefit-to-risk profile.
Vinpocetine, found in the lesser periwinkle Vinca minor, is
an excellent vasodilator and cerebral metabolic enhancer
with proven benefits for vascular-based cognitive
dysfunction. Two meta-analyses of GbE demonstrate the best
preparations offer limited benefits for vascular
insufficiencies and even more limited benefits for
Alzheimer's, while "commodity" GbE products offer little
benefit, if any at all. GbE (and probably also vinpocetine)
is incompatible with blood-thinning drugs. Bacopa is an
Ayurvedic botanical with apparent anti-anxiety,
anti-fatigue, and memory-strengthening effects. These five
substances offer interesting contributions to a
personalized approach for restoring cognitive function,
perhaps eventually in conjunction with the judicious
application of growth factors.
Decreased brain
histamine-releasing factor protein in patients with Down
syndrome and Alzheimer's disease.
Kim SH, Cairns N, Fountoulakisc M, Lubec G. Department
of Pediatrics, University of Vienna, Waehringer Guertel 18,
A-1090, Vienna, Austria.
Neurosci Lett 2001 Mar 2;300(1):41-4
Histamine-releasing factor (HRF) stimulates secretion of
histamine that is widely distributed in brain and released
as neurotransmitter. Several studies suggested that
histaminergic deficits could contribute to the cognitive
decline in Alzheimer's disease (AD). Based upon deranged
histamine metabolism in brain of patients with AD and Down
Syndrome (DS), we aimed to study HRF in brain of AD and DS.
We used two-dimensional gel electrophoresis,
matrix-assisted laser desorption ionization mass
spectroscopy and specific software to quantify HRF. HRF was
significantly reduced in temporal cortex, thalamus and
caudate nucleus of DS and in temporal cortex of AD as
compared to controls. This is the first report to show
decreased HRF brain levels in DS and AD suggesting the
explanation for the decreased cognitive function in
neurodegenerative/dementing disorders.
Do raised brain aluminium
levels in Alzheimer's dementia contribute to cholinergic
neuronal deficits?
King RG.
Med Hypotheses 1984 Jul;14(3):301-6
Raised aluminium levels have been found in brains of
patients with Alzheimer's dementia (1,2), a disease in
which reductions have been reported in various parameters
of presynaptic cholinergic nerve function, including
choline uptake, acetylcholine synthesis and choline
acetyltransferase activity (3). Aluminium has been found to
inhibit choline transport by isolated rat brain nerve
endings (4) and human erythrocytes (5), and also to cause
an encephalopathy in rabbits with neurofibrillary tangles
and reduced neuronal choline acetyltransferase activity
(6). It is therefore hypothesised that raised brain
aluminium levels in Alzheimer's dementia may contribute to
the cholinergic neuronal deficits in this disease. If this
is the case, then aluminium chelating agents may be of
value in its treatment.
Influence of vitamin E
and C supplementation on lipoprotein oxidation in patients
with Alzheimer's disease.
Kontush A, Mann U, Arlt S, Ujeyl A, Luhrs C,
Muller-Thomsen T, Beisiegel U. Clinic of Internal Medicine,
University Hospital Eppendorf, Martinistrasse 52, 20246
Hamburg, Germany.
Free Radic Biol Med 2001 Aug 1;31(3):345-54
Because increased oxidation is an important feature of
Alzheimer's disease (AD) and low concentrations of
antioxidant vitamins C and E have been observed in
cerebrospinal fluid (CSF) of AD patients, supplementation
with these antioxidants might delay the development of AD.
Major targets for oxidation in brain are lipids and
lipoproteins. We studied whether supplementation with
antioxidative vitamins E and C can increase their
concentrations not only in plasma but also in CSF, and as a
consequence decrease the susceptibility of lipoproteins to
in vitro oxidation. Two groups, each consisting of 10
patients with AD, were for 1 month supplemented daily with
either a combination of 400 IU vitamin E and 1000 mg
vitamin C, or 400 IU vitamin E alone. We found that
supplementation with vitamin E and C significantly
increased the concentrations of both vitamins in plasma and
CSF. Importantly, the abnormally low concentrations of
vitamin C were returned to normal level following
treatment. As a consequence, susceptibility of CSF and
plasma lipoproteins to in vitro oxidation was significantly
decreased. In contrast, the supplementation with vitamin E
alone significantly increased its CSF and plasma
concentrations, but was unable to decrease the lipoprotein
oxidizability. These findings document a superiority of a
combined vitamin E + C supplementation over a vitamin E
supplementation alone in AD and provide a biochemical basis
for its use.
Amantadine and memantine
are NMDA receptor antagonists with neuroprotective
properties.
Kornhuber J, Weller M, Schoppmeyer K, Riederer P.
Department of Psychiatry, University of Wurzburg, Federal
Republic of Germany.
J Neural Transm Suppl 1994;43:91-104
The pharmacological inhibition of excitatory amino acid
neurotransmission has evolved to be a major topic in
neuropharmacology since enhanced synaptic action of
glutamate and possibly other related neurotransmitters has
been suggested to play a role both in acute neurological
conditions such as ischemia and epilepsy and in chronic
degenerative neurological diseases including Parkinson's
disease, Huntington's disease and Alzheimer's disease.
While antagonists at N-methyl-D-aspartate (NMDA) type
glutamate receptors include psychotomimetic and neurotoxic
agents such as phencyclidine and MK-801, the
aminoadamantanes represent a class of drugs which may be
largely free of such actions and which have already been
used clinically as antiviral and antiparkinsonian agents.
Multiple in vitro studies have recently delineated the
neuroprotective properties of amantadine, and of its more
potent congener, memantine, which appear to mediate
neuroprotection via inhibition of NMDA receptor-dependent
glutamate activity. Thus, neuroprotection targeting
glutamate receptors does apparently not have to be
associated with prominent psychotogenicity, and the
development and evaluation of new neuroprotective drugs
will have to performed in consideration both of the
relative safety and of the good clinical effect of the
already known and established aminoadamantanes.
Music therapy increases
serum melatonin levels in patients with Alzheimer's
disease.
Kumar AM, Tims F, Cruess DG, Mintzer MJ, Ironson G,
Loewenstein D, Cattan R, Fernandez JB, Eisdorfer C, Kumar
M. Department of Psychiatry and Behavioral Sciences,
University of Miami School of Medicine, FL 33101, USA.
akumar@med.miami.edu
Altern Ther Health Med 1999 Nov;5(6):49-57
CONTEXT: Music therapy is known to have healing and
relaxing effects. Although these effects appear to be
mediated by release of neurotransmitters and neurohormones,
the specific neurohormonal systems involved have not been
fully investigated.
OBJECTIVE: To assess the effects of a music therapy
intervention on concentrations of melatonin,
norepinephrine, epinephrine, serotonin, and prolactin in
the blood of a group of patients with Alzheimer's
disease.
DESIGN: Blood samples were obtained before initiating
the therapy, immediately at the end of 4 weeks of music
therapy sessions, and at 6 weeks follow-up after cessation
of the sessions.
SETTING: Miami Veterans Administration Medical Center,
Miami, Fla.
PATIENTS: 20 male inpatients with Alzheimer's
disease.
INTERVENTION: 30- to 40-minute morning sessions of music
therapy 5 times per week for 4 weeks.
MAIN OUTCOME MEASURES: Changes in melatonin,
norepinephrine, epinephrine, serotonin, and prolactin
following music therapy.
RESULTS: Melatonin concentration in serum increased
significantly after music therapy and was found to increase
further at 6 weeks follow-up. A significant increase was
found between baseline values and data recorded after the
music therapy sessions as well as at 6 weeks follow-up.
Norepinephrine and epinephrine levels increased
significantly after 4 weeks of music therapy, but returned
to pretherapy levels at 6 weeks follow-up. Serum
concentration of prolactin and platelet serotonin levels
remained unchanged after 4 weeks of music therapy and at 6
weeks follow-up.
CONCLUSION: Increased levels of melatonin following
music therapy may have contributed to patients' relaxed and
calm mood.
Low serum docosahexaenoic
acid is a significant risk factor for Alzheimer's
dementia.
Kyle DJ, Schaefer E, Patton G, Beiser A. Tufts
University School of Medicine, Boston, Massachusetts 02118,
USA.
Lipids 1999;34 Suppl:S245
No Abstract Available
Melatonin affects the
metabolism of the beta-amyloid precursor protein in
different cell types.
Lahiri DK Department of Psychiatry and Medical and
Molecular Genetics, Indiana University School of Medicine,
Indianapolis 46202, USA. dlahiri@iupui.edu
J Pineal Res 1999 Apr;26(3):137-46
Melatonin is released in mammals during the dark phase
of the circadian cycle, and its production declines with
age in animals and humans. Since supplemental
administration of melatonin may be beneficial in delaying
age-related degenerative conditions, it is necessary to
study its effect on neuronal differentiation and the
processing of key neuronal proteins, such as beta-amyloid
precursor protein (beta APP) and synaptophysin. One of the
important pathological hallmarks of Alzheimer's disease
(AD) is the cerebrovascular deposition of amyloid plaques.
The amyloid in senile plaques is mainly composed of the
amyloid beta-peptide (A beta) of 39-43 amino acids derived
from a larger beta APP. The proteolytic cleavage by
'alpha-secretase' generate soluble derivatives of beta APP
(sAPP), lacking the cytoplasmic tail, transmembrane domain,
and a small portion of the extracellular domain. Here
levels of sAPP and beta APP were analyzed in cell lines of
different origins by Western immunoblot of samples from
conditioned media and cell lysates, respectively. Normal
levels of secretion of sAPP into conditioned media were
severely inhibited by treating different cell lines with a
high dose of melatonin. In PC12 cells, levels of the fully
matured beta APP forms of the post-Golgi compartment were
more drastically decreased than the unglycosylated beta APP
of the endoplasmic-reticulum (ER) forms. In other cell
types, the unglycosylated ER-bound beta APP derivatives are
predominant forms that were marginally affected by
melatonin treatment. When the treatment of cells with
melatonin was withdrawn, the normal level of secretion of
sAPP was restored. Melatonin reduces the secretion of
soluble A beta. Melatonin also inhibits the secretion of
synaptophysin in PC12 cells. Taken together, these data
suggest that melatonin probably affects the secretion of
sAPP in the conditioned medium by interfering with its full
maturation, and melatonin also affects the presysnaptic
terminal marker.
Interactions between
melatonin, reactive oxygen species, and nitric
oxide.
Lahiri DK, Ghosh C. Department of Psychiatry, Indiana
University School of Medicine, Indianapolis 46202-4887,
USA. DLAHIRI@IUPUI.EDU
Ann N Y Acad Sci 1999;893:325-30
Accumulation of reactive oxygen species is critical for
the neuropathology of Alzheimer's disease. Melatonin
hormone, an antioxidant, could play a key role in aging and
senescence. Nitric oxide, a biologically active unstable
radical, is synthesized by nitric oxide synthase when
converting L-arginine to L-citrulline. We have investigated
whether the treatment of cultured cells with melatonin
could possibly reduce the release of free radicals and
other ROS. We assayed NO indirectly by measuring the level
of its stable end products, nitrite/nitrate (NOx), using
the Griess reagent. When the neuroblastoma cells such as
N1E-115 were treated with a NO donor such as sodium
nitroprusside (SNP), a significant level of NOx was
detected in a time- and dose-dependent manner in the
conditioned medium compared to the untreated cells or
SNP-containing media. In neuroblastoma cells, the release
of NOx as mediated by SNP was significantly inhibited by
treatment with (i) carboxy-PTIO, a NO scavenger; (ii)
SOD-1, superoxide dismutase; and (iii) melatonin. In these
cells SNP-mediated NOx release was mediated by superoxide
ions and/or free radicals that can be inhibited by
melatonin. The ROS-scavenging function of melatonin along
with its neuroprotective and neurodifferentiating role can
be utilized for the prevention of neurodegenerative
disorders such as AD.
A placebo-controlled,
double-blind, randomized trial of an extract of Ginkgo
biloba for dementia. North American EGb Study
Group.
Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM,
Schatzberg AF. New York Institute for Medical Research,
Tarrytown 10591, USA. NYI@HZI.com
JAMA 1997 Oct 22-29;278(16):1327-32
CONTEXT: EGb 761 is a particular extract of Ginkgo
biloba used in Europe to alleviate symptoms associated with
numerous cognitive disorders. Its use in dementias is based
on positive results from only a few controlled clinical
trials, most of which did not include standard assessments
of cognition and behavior.
OBJECTIVE: To assess the efficacy and safety of EGb in
Alzheimer disease and multi-infarct dementia.
DESIGN: A 52-week, randomized double-blind,
placebo-controlled, parallel-group, multicenter study.
PATIENTS: Mildly to severely demented outpatients with
Alzheimer disease or multi-infarct dementia, without other
significant medical conditions.
INTERVENTION: Patients assigned randomly to treatment
with EGb (120 mg/d) or placebo. Safety, compliance, and
drug dispensation were monitored every 3 months with
complete outcome evaluation at 12, 26, and 52 weeks.
PRIMARY OUTCOME MEASURES: Alzheimer's Disease Assessment
Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation
by Relative's Rating Instrument (GERRI), and Clinical
Global Impression of Change (CGIC).
RESULTS: From 309 patients included in an
intent-to-treat analysis, 202 provided evaluable data for
the 52-week end point analysis. In the intent-to-treat
analysis, the EGbgroup had an ADAS-Cog score 1.4 points
better than the placebo group (P=.04) and a GERRI score
0.14 points better than the placebo group (P=.004). The
same patterns were observed with the evaluable data set in
which 27% of patients treated with EGb achieved at least a
4-point improvement on the ADAS-Cog, compared with 14%
taking placebo (P=.005); on the GERRI, 37% were considered
improved with EGb, compared with 23% taking placebo
(P=.003). No difference was seen in the CGIC. Regarding the
safety profile of EGb, no significant differences compared
with placebo were observed in the number of patients
reporting adverse events or in the incidence and severity
of these events.
CONCLUSIONS: EGb was safe and appears capable of
stabilizing and, in a substantial number of cases,
improving the cognitive performance and the social
functioning of demented patients for 6 months to 1 year.
Although modest, the changes induced by EGb were
objectively measured by the ADAS-Cog and were of sufficient
magnitude to be recognized by the caregivers in the
GERRI.
A 26-week analysis of a
double-blind, placebo-controlled trial of the ginkgo biloba
extract EGb 761 in dementia.
Le Bars PL, Kieser M, Itil KZ Memory Centers of America
Inc., New York, NY, USA. info@mcai.com
Dement Geriatr Cogn Disord 2000 Jul-Aug;11(4):230-7
This intent-to-treat (ITT) analysis was performed to
provide a realistic image of the efficacy that could be
expected after 26 weeks treatment with a 120-mg dose (40 mg
t.i.d.) of EGb 761 (EGb). The data were collected during a
52-week, double-blind, placebo-controlled, fixed dose,
parallel-group, multicenter study. Patients were mildly to
severely impaired and diagnosed with uncomplicated
Alzheimer's disease or multi-infarct dementia according to
ICD-10 and DSM-III-R criteria. The primary outcome measures
included the Alzheimer's Disease Assessment Scale-Cognitive
Subscale (ADAS-Cog), Geriatric Evaluation by Relative's
Rating Instrument (GERRI) and Clinical Global Impression of
Change. From 309 patients included in the ITT analysis, 244
patients (76% for placebo and 73% for EGb) actually reached
the 26th week visit. In comparison to the baseline values,
the placebo group showed a statistically significant
worsening in all domains of assessment, while the group
receiving EGb was considered slightly improved on the
cognitive assessment and the daily living and social
behavior. Mean treatment differences favored EGb with 1.3
and 0.12 points, respectively, on the ADAS-Cog (p = 0.04)
and the GERRI (p = 0.007). In the group receiving EGb, 26%
of the patients achieved at least a 4-point improvement on
the ADAS-Cog, compared to 17% with placebo (p = 0.04). On
the GERRI, 30% of the EGb group improved and 17% worsened,
while the placebo group showed an opposite trend with 37%
of patients worsening for 25% improved (p = 0.006).
Regarding safety, no differences between EGb and placebo
were observed.
Hyperhomocysteinemia in
dementia.
Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Widner
B, Reibnegger G, Fuchs D. Department of Gerontology,
Landesnervenklinik Wagner Jauregg, Linz, Austria.
J Neural Transm 2000;107(12):1469-74
Hyperhomocysteinemia is a strong risk factor for
atherosclerotic vascular disease, and elevated serum
homocysteine is correlated with vitamin B deficiency. In
this pilot study, significantly elevated homocysteine
levels were found in patients with Alzheimer's disease as
well as in patients with vascular dementia, probably
indicating similar pathophysiological pathways. We found
significant correlations between low folic acid
concentrations as well as high homocysteine concentrations
and cognitive decline. Supplementation with folic acid may
be an inexpensive way to reduce elevated homocysteine
levels in demented patients.
Identification of
cognitive impairment in the elderly: homocysteine is an
early marker.
Lehmann M, Gottfries CG, Regland B. Goteborg University,
Institute of Clinical Neuroscience, Department of
Psychiatry and Neurochemistry, Molndal, Sweden.
Dement Geriatr Cogn Disord 1999 Jan-Feb;10(1):12-20
In 336 consecutive patients attending a
university-affiliated memory unit, clinical and
psychological findings, neuroimaging and laboratory tests
were analyzed. The patients were diagnosed with early
Alzheimer's disease 3%, senile dementia (SDAT) 16%,
vascular dementia (VAD) 20%, other dementias 9%, minor
cognitive impairment (dysmentia) 32% and subjective
symptoms only 21%. Increases in vascular risk factors,
serum homocysteine, ApoE4 load and neuroimaging pathology
were found in dementia but also in dysmentia and in
patients with subjective symptoms only. The homocysteine
levels correlated inversely with cognitive performance. The
increases in serum homocysteine, which were pathological in
VAD, Dysmentia and SDAT, may be indicative of a disturbed
cerebral one-carbon metabolism and signal-accelerated
development of cognitive disease.
Ibuprofen suppresses
plaque pathology and inflammation in a mouse model for
Alzheimer's disease.
Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T,
Ubeda O, Ashe KH, Frautschy SA, Cole GM. University of
California Los Angeles, Departments of Medicine and
Neurology, 90095, USA.
J Neurosci 2000 Aug 1;20(15):5709-14
The brain in Alzheimer's disease (AD) shows a chronic
inflammatory response characterized by activated glial
cells and increased expression of cytokines and complement
factors surrounding amyloid deposits. Several
epidemiological studies have demonstrated a reduced risk
for AD in patients using nonsteroidal anti-inflammatory
drugs (NSAIDs), prompting further inquiries about how
NSAIDs might influence the development of AD pathology and
inflammation in the CNS. We tested the impact of chronic
orally administered ibuprofen, the most commonly used
NSAID, in a transgenic model of AD displaying widespread
microglial activation, age-related amyloid deposits, and
dystrophic neurites. These mice were created by
overexpressing a variant of the amyloid precursor protein
found in familial AD. Transgene-positive (Tg+) and negative
(Tg-) mice began receiving chow containing 375 ppm
ibuprofen at 10 months of age, when amyloid plaques first
appear, and were fed continuously for 6 months. This
treatment produced significant reductions in final
interleukin-1beta and glial fibrillary acidic protein
levels, as well as a significant diminution in the ultimate
number and total area of beta-amyloid deposits. Reductions
in amyloid deposition were supported by ELISA measurements
showing significantly decreased SDS-insoluble Abeta.
Ibuprofen also decreased the numbers of ubiquitin-labeled
dystrophic neurites and the percentage area per plaque of
anti-phosphotyrosine-labeled microglia. Thus, the
anti-inflammatory drug ibuprofen, which has been associated
with reduced AD risk in human epidemiological studies, can
significantly delay some forms of AD pathology, including
amyloid deposition, when administered early in the disease
course of a transgenic mouse model of AD.
Risk factors for
Alzheimer's disease: a prospective analysis from the
Canadian Study of Health and Aging.
Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B,
Hill GB, McDowell I. Department of Epidemiology and
Community Medicine, Faculty of Medicine, University of
Ottawa, Ottawa, ON, Canada. Joan_Lindsay@hc-sc.gc.ca
Am J Epidemiol 2002 Sep 1;156(5):445-53
A prospective analysis of risk factors for Alzheimer's
disease was a major objective of the Canadian Study of
Health and Aging, a nationwide, population-based study. Of
6,434 eligible subjects aged 65 years or older in 1991,
4,615 were alive in 1996 and participated in the follow-up
study. All participants were cognitively normal in 1991
when they completed a risk factor questionnaire. Their
cognitive status was reassessed 5 years later by using a
similar two-phase procedure, including a screening
interview, followed by a clinical examination when
indicated. The analysis included 194 Alzheimer's disease
cases and 3,894 cognitively normal controls. Increasing
age, fewer years of education, and the apolipoprotein E
epsilon4 allele were significantly associated with
increased risk of Alzheimer's disease. Use of nonsteroidal
anti-inflammatory drugs, wine consumption, coffee
consumption, and regular physical activity were associated
with a reduced risk of Alzheimer's disease. No
statistically significant association was found for family
history of dementia, sex, history of depression, estrogen
replacement therapy, head trauma, antiperspirant or antacid
use, smoking, high blood pressure, heart disease, or
stroke. The protective associations warrant further study.
In particular, regular physical activity could be an
important component of a preventive strategy against
Alzheimer's disease and many other conditions.
A double-blind, placebo
controlled trial of high-dose lecithin in Alzheimer's
disease.
Little A, Levy R, Chuaqui-Kidd P, Hand D.
J Neurol Neurosurg Psychiatry 1985 Aug;48(8):736-42
The first long-term double-blind placebo controlled
trial of high dose lecithin in senile dementia of the
Alzheimer type is reported. Fifty one subjects were given
20-25 g/day of purified soya lecithin (containing 90%
phosphatidyl plus lysophosphatidyl choline) for six months
and followed up for at least a further six months. Plasma
choline levels were monitored throughout the treatment
period. There were no differences between the placebo group
and the lecithin group but there was an improvement in a
subgroup of relatively poor compliers. These were older and
had intermediate levels of plasma choline. It is suggested
that the effects of lecithin are complex but that there may
be a "therapeutic window" for the effects of lecithin in
the condition and that this may be more evident in older
patients.
Decreased melatonin
levels in postmortem cerebrospinal fluid in relation to
aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4
genotype.
Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF.
Netherlands Institute for Brain Research, Amsterdam.
J Clin Endocrinol Metab 1999 Jan;84(1):323-7
Sleep disruption, nightly restlessness, sundowning, and
other circadian disturbances are frequently seen in
Alzheimer's disease (AD) patients. Changes in the
suprachiasmatic nucleus and pineal gland are thought to be
the biological basis for these behavioral disturbances.
Melatonin is the main endocrine message for circadian
rhythmicity from the pineal. To determine whether melatonin
production was affected in AD, melatonin levels were
determined in the cerebrospinal fluid (CSF) of 85 patients
with AD (mean age, 75 +/- 1.1 yr) and in 82 age-matched
controls (mean age, 76 +/- 1.4 yr). Ventricular postmortem
CSF was collected from clinically and neuropathologically
well defined AD patients and from control subjects without
primary neurological or psychiatric disease. In old control
subjects (>80 yr of age), CSF melatonin levels were half
of those in control subjects of 41-80 yr of age [176 +/- 58
(n = 29) and 330 +/- 66 (n = 53) pg/mL, respectively; P =
0.016]. We did not find a diurnal rhythm in CSF melatonin
levels in control subjects. In AD patients the CSF
melatonin levels were only one fifth (55 +/- 7 pg/mL) of
those in control subjects (273 +/- 47 pg/mL; P = 0.0001).
There was no difference in the CSF melatonin levels between
the presenile (42 +/- 11 pg/mL; n = 21) and the senile (59
+/- 8 pg/mL; n = 64; P = 0.35) AD patients. The melatonin
level in AD patients expressing apolipoprotein E-epsilon3/4
(71 +/- 11 pg/mL) was significantly higher than that in
patients expressing apolipoprotein E-epsilon4/4 (32 +/- 8
pg/ml; P = 0.02). In the AD patients no significant
correlation was observed between age of onset or duration
of AD and CSF melatonin levels. In the present study, a
dramatic decrease in the CSF melatonin levels was found in
old control subjects and even more so in AD patients.
Whether supplementation of melatonin may indeed improve
behavioral disturbances in AD patients should be
investigated.
Efficacy and safety of
nicotine on Alzheimer's disease patients.
Lopez-Arrieta JM, Rodriguez JL, Sanz F. Hospital de
Cantoblanco, Consejeria de Sanidad, Carretera de Colmenar
km 14.500, Madrid, Madrid, Spain, 28049.
med013440@nacom.es
Cochrane Database Syst Rev 2001;(2):CD001749
BACKGROUND: Nicotine is a cholinergic agonist that also
has a presynaptic effect in releasing acetylcholine. In
animal model has been shown to reverse spatial memory
deficits produced by lesions in the medial septal nucleus
of rats, and in aged monkeys nicotine administration
improves memory and alertness to visual stimuli.
Observational studies have claimed a protective effect of
smoking against Alzheimer's disease (AD), but recent
studies have called this into question. Smoking is a risk
factor for stroke and so, possibly, for vascular dementia.
Because nicotine has adverse effects, it is important to
conduct a systematic review to assess the clinical efficacy
and safety of nicotine for patients with AD
OBJECTIVES: To evaluate the efficacy and safety of
nicotine, administered in any way or form, for people with
Alzheimer's disease.
SEARCH STRATEGY: The trials were identified from a
search of the Specialized Register of the Cochrane Dementia
and Cognitive Improvement Group on 24 January 2001 using
the term nicotine.
SELECTION CRITERIA: All unconfounded, double-blind,
randomized trials in which treatment with nicotine patches
or administration of nicotine intravenously or in any other
way or form was administered for more than a day and
compared with placebo for people with Alzheimer's
disease.
DATA COLLECTION AND ANALYSIS: The one included trial did
not present results suitable for inclusion in the
review.
MAIN RESULTS: The poor quality of trials did not allow
any synthesis of data across studies.
REVIEWER'S CONCLUSIONS: This review is not able to
provide any evidence that nicotine is a useful treatment
for Alzheimer's disease.
Nonsteroidal
anti-inflammatory drug use and Alzheimer-type pathology in
aging.
Mackenzie IR, Munoz DG. Department of Pathology and
Laboratory Medicine, Vancouver General Hospital, British
Columbia, Canada.
Neurology 1998 Apr;50(4):986-90
Anti-inflammatory drugs have been suggested as a
possible treatment for Alzheimer's disease (AD). The
association of immune proteins and immune-competent
microglial cells with senile plaques (SP) in both AD and
normal aging suggests that these drugs may be able to
modify the course of AD, either by interfering with SP
formation or by suppressing the inflammation associated
with SP. We compared postmortem brain tissue from elderly,
nondemented, arthritic patients with a history of chronic
nonsteroidal anti-inflammatory drug (NSAID) use (n = 32,
aged 77 +/- 7 years) and nondemented control subjects with
no history of arthritis or other condition that might
promote the regular use of NSAIDs (n = 34, aged 77 +/- 6
years). In both the NSAID-treated group and control
subjects, 59% of patients had some SP. There was no
difference between the two groups in the mean number of
plaques or in the number of specific SP subtypes (diffuse
or neuritic). The degree of neurofibrillary pathology was
also similar. Activated microglia were identified using
CR3/43, an anti-MHC class II antibody. Both patient age and
the presence of SP correlated positively with the number of
CR3/43+ microglia (p < 0.02), whereas NSAID use was
associated with less microglial activation (p < 0.01).
Control patients with SP had almost three times the number
of activated microglia as NSAID-treated patients with SP
(11 versus 4 cells/mm2, p < 0.02). These results suggest
that if NSAID use is effective in treating AD, the
mechanism is more likely to be through the suppression of
microglial activity than by inhibiting the formation of SP
or neurofibrillary tangles.
Association between
changes in adrenal secretion and cerebral morphometric
correlates in normal aging and senile
dementia.
Magri F, Terenzi F, Ricciardi T, Fioravanti M, Solerte
SB, Stabile M, Balza G, Gandini C, Villa M, Ferrari E
Department of Internal Medicine and Medical Therapy, Chair
of Geriatrics, University of Pavia, Italy.
ferrari@ipv36.unipv.it
Dement Geriatr Cogn Disord 2000 Mar-Apr;11(2):90-9
The circadian organization of adrenal secretion was
studied in 23 healthy elderly subjects, 23 elderly demented
patients and 10 healthy young subjects, in order to
investigate the relationships between the
hypothalamic-pituitary-adrenal axis and some cerebral
morphometric parameters. The cerebral morphometric analysis
was performed in some subjects of the three groups by MRI.
A significant increase in cortisol levels during evening
and nighttime was found in both groups of the aged
subjects. In elderly subjects, particularly if demented,
the mean serum dehydroepiandrosterone sulfate (DHEAs)
levels throughout the 24-hour cycle were significantly
lower than in young controls. A significant reduction of
the hippocampal and temporal volume and an enlargement of
the lateral ventricles were found in aged subjects, these
changes being significantly related to subjects' age.
Moreover, the hippocampal volume was positively correlated
with the circadian mesor of DHEAs (i.e., the circadian
rhythm adjusted mean) and with the cortisol nocturnal
increase. Our data may suggest the existence of a link
between the selective impairment of cortisol secretion and
DHEAs levels, and the progression of hippocampal
degeneration.
Molecular basis of the
neurodegenerative disorders.
Martin JB. Harvard Medical School, Boston, MA 02115,
USA. josephvmartin@hms.harvard.edu
N Engl J Med 1999 Jun 24;340(25):1970-80
No Abstract Available
The therapeutic
potential for tryptophan and melatonin: possible roles in
depression, sleep, Alzheimer's disease and abnormal
aging.
Maurizi CP.
Med Hypotheses 1990 Mar;31(3):233-42
Evidence suggests that stress and/or a dietary lack of
tryptophan may make deficiencies of serotonin and melatonin
common. In addition, older animals and human beings have a
reduced ability to synthesize melatonin. Disorders of
melatonin levels and rhythms are suggested to be a cause of
affective disease, abnormal sleep, Alzheimer's disease, and
some age related disorders. If these ideas prove to be
true, then preventive measures are possible.
Analogues, ageing and
aberrant assimilation of vitamin B12 in Alzheimer's
disease.
McCaddon A, Hudson P, Abrahamsson L, Olofsson H, Regland
B. Gardden Road Surgery, Rhosllanerchrugog, Wrexham, North
Wales, UK. Andrew@mccaddon.demon.co.uk
Dement Geriatr Cogn Disord 2001 Mar-Apr;12(2):133-7
Vitamin B12 assimilation might be disrupted in patients
with Alzheimer's disease. We therefore measured B12 carrier
protein saturation and inactive B12 'analogues' in patients
compared with healthy elderly individuals in a prospective
case-controlled survey. Twenty-three patients, aged 60 or
over, with features compatible with DSM-IV criteria for
primary degenerative dementia of the Alzheimer type were
recruited together with 18 cognitively intact age-matched
control subjects. Total vitamin B12 (active corrinoids),
holo- and apo-haptocorrin and transcobalamin were measured
in serum. B12 analogues (inactive corrinoids) were
estimated from the difference between R-binder-determined
corrinoids and an intrinsic factor based B12 assay.
Alzheimer patients had significantly lower active corrinoid
than control subjects and the analogue/corrinoid ratio was
significantly higher in the Alzheimer group. The
inter-relationship between age, analogues and
transcobalamin polarised patients into two distinct groups.
Two disparate mechanisms might exist for the development of
cerebral B12 deficiency in Alzheimer's disease, although
both imply a disruption of selective B12 assimilation and
analogue elimination in such patients. Copyright 2001 S.
Karger AG, Basel
Total serum
homocysteine in senile dementia of Alzheimer
type.
McCaddon A, Davies G, Hudson P, Tandy S, Cattell H
Wrexham Maelor Hospital, North Wales, UK.
andrew@mccaddon.demon.co.uk
Int J Geriatr Psychiatry 1998 Apr;13(4):235-9
OBJECTIVE: The main hypothesis was that subtle vitamin
B12 deficiencies occur more commonly in senile dementia of
Alzheimer type (SDAT) that in healthy elderly individuals,
and may be revealed by elevated total serum homocysteine
(tHcy). A subsidiary hypothesis was that such deficiencies
would be nutritionally independent as determined by retinol
binding protein (RBP).
DESIGN: A prospective case-controlled survey.
SETTING: A Welsh urban psychogeriatric assessment centre
and local general practice.
PATIENTS: Thirty patients, aged 65 or over, seen
consecutively in 1994 with features compatible with
DSM-III-R criteria for primary degenerative dementia of
Alzheimer type and 30 cognitively intact age-matched
control subjects.
MEASURES: Diagnosis was assessed using the CAMDEX.
Cognitive scores were evaluated with the CAMCOG scale for
patients and MMSE scores for control subjects. THcy was
measured using high performance liquid chromatography
(HPLC), and RBP assayed by a radial immunodiffusion
method.
RESULTS: Patients had a highly significant elevation of
tHcy compared with control (p < 0.0001). Multiple
regression highlighted the interrelated effects of tHcy and
total serum cobalamin on cognitive scores. RBP did not
differ between groups. Macrocytosis was absent, and
neutrophil hypersegmentation uncommon, in
hyperhomocysteinaemic patients.
CONCLUSIONS: SDAT patients have significantly elevated
tHcy. This is independent of RBP determined nutritional
status. 'Classical' haematological changes of cobalamin or
folate deficiency are poor predictors of tHcy in these
patients. Aberrant cobalamin tissue delivery appears to
contribute to SDAT cognitive decline. Relative
contributions of other tHcy determinants require further
investigation.
Homocysteine and
cognitive decline in healthy elderly.
McCaddon A, Hudson P, Davies G, Hughes A, Williams JH,
Wilkinson C. University of Wales College of Medicine,
Wrexham, LL14 2EN, Wales, UK.
andrew@mccaddon.demon.co.uk
Dement Geriatr Cogn Disord 2001 Sep-Oct;12(5):309-13
Serum homocysteine is increased, and correlates
inversely with cognitive scores, in Alzheimer's disease
(AD), vascular dementia and "age-associated memory
impairment". Elevated levels might signal accelerated
cognitive decline, although this remains to be established.
We therefore repeated Mini-Mental State Examinations,
together with additional ADAS-Cog assessments, in 32
healthy elderly individuals to determine whether prior
homocysteine levels predicted cognitive changes over a
5-year period. Homocysteine predicted follow-up cognitive
scores and rate of decline in cognitive performance
independently of age, sex, education, renal function,
vitamin B status, smoking and hypertension (p < 0.001).
Homocysteine predicted word recall (p = 0.01), orientation
(p = 0.02) and constructional praxis scores (p <
0.0001). One subject, with the second highest initial
homocysteine, had developed probable AD at follow-up.
Fasting total serum homocysteine appears to be an
independent predictor of cognitive decline in healthy
elderly and exerts a maximal effect on spatial copying
skills. Copyright 2001 S. Karger AG, Basel
Vascular nitric oxide,
sex hormone replacement, and fish oil may help to prevent
Alzheimer's disease by suppressing synthesis of acute-phase
cytokines.
McCarty MF Nutrition 21/AMBI, San Diego, CA, USA.
Med Hypotheses 1999 Nov;53(5):369-74
The neurodegenerative plaques of Alzheimer's disease
(AD) are characterized by a self-sustaining acute-phase
reaction in which both interleukin-1 (IL-1) and
interleukin-6 (IL-6) are up-regulated. The fact that IL-6
is detectable in early stage diffuse plaques encourages the
speculation that the acute-phase process is crucial to the
pathogenesis of AD. The epidemiological association of AD
with estrogen deficiency, as well as with various disorders
characterized by vascular endotheliopathy, suggest a
protective role for vascular nitric oxide (NO). NO has an
autocrine anti-inflammatory impact on endothelium, owing in
part to antagonism of NF-kappaB activity; since induction
of IL-6 is dependent on NF-kappaB, this may explain recent
evidence that NO inhibits macrophage IL-6 production. It is
reasonable to postulate that, analogously, cerebrovascular
NO decreases IL-6 production in the brain. Vascular NO may
also have direct europrotective activity. Estrogen, in
addition to promoting vascular NO synthesis, can block IL-6
production by a more direct mechanism in cells expressing
estrogen receptors; since such receptors have been reported
in brain glia and astrocytes, estrogen has the potential to
limit brain IL-1 activity. Testosterone likewise can
inhibit IL-6 induction in androgen-responsive cells, which
may include brain glia and astrocytes. Since fish oil and
gamma linolenic acid (GLA) suppress IL-1 production by
stimulated monocytes, they conceivably could exert this
effect in the brain as well; the comparatively low
prevalence of AD in elderly Japanese is intriguing in this
regard. These considerations suggest that a healthy
cerebrovascular endothelium, sex hormone activity, and
dietary fish oil/GLA may slow or prevent AD onset by
dampening acute-phase mechanisms in the brain.
Brain aluminum in aging
and Alzheimer disease.
McDermott JR, Smith AI, Iqbal K, Wisniewski HM.
Neurology 1979 Jun;29(6):809-14
Aluminum was assayed by atomic absorption spectroscopy
in 274 brain samples, and assayed in neurons isolated in
bulk from the frontal cortex of patients with Alzheimer
dementia and from age-matched patients with no neurologic
disease. Brain aluminum concentration increased with age,
from late middle age to old age. There were no
statistically significant differences in brain aluminum
concentration between the 10 patients with Alzheimer
disease (mean, 2.7 microgram per gram dry weight of tissue;
mean age, 81 years), and the 9 nonneurologic controls
(mean, 2.5 microgram per gram; mean age, 73 years). In both
groups, the hippocampus had the highest concentration of
aluminum (5.6 microgram per gram), and the corpus callosum
the lowest (1.5 microgram per gram).
Brain inflammation in
Alzheimer disease and the therapeutic
implications
McGeer E.G.; McGeer P.L. E.G. McGeer, Kinsmen Lab. of
Neurol. Research, University of British Columbia, 2255
Wesbrook Mall, Vancouver, BC V6T IZ3 Canada
mcgeerpl@interchange.ubc.ca
Current Pharmaceutical Design ( CURR. PHARM. DES. )
(Netherlands) 1999, 5/10 (821-836)
Immunohistochemical studies suggested the existence of a
chronic inflammatory condition in affected regions of the
brain in Alzheimer disease (AD). Since inflammation can be
damaging to host tissue, it was hypothesized that
antiinflammatory drugs might inhibit both the onset and the
progression of AD. This hypothesis is supported by a number
of epidemiological studies suggesting that the prevalence
of AD in persons is reduced by 40 - 50% in persons using
antiinflammatory drugs. In one small pilot trial in early
AD, the nonsteroidal antiinflammatory drug indomethacin
appeared to halt the progressive memory loss.
Immunohistochemical and molecular biological studies on
immune system components in AD brain are revealing the
complexities of the innate immune reaction. This very
complexity may offer points of therapeutic intervention for
new types of antiinflammatory agents. The complement
system, microglia and cytokines are key components. This
review summarizes the present state of knowledge on the
immune system elements found in AD brain.
Risk for
neuropathologically confirmed Alzheimer's disease and
residual aluminum in municipal drinking water employing
weighted residential histories.
McLachlan DR, Bergeron C, Smith JE, Boomer D, Rifat SL.
Department of Physiology and Medicine, University of
Toronto, ON, Canada.
Neurology 1996 Feb;46(2):401-5
We investigated a possible relation between aluminum
concentration ([Al]) in public drinking water and
Alzheimer's disease (AD), with AD cases and controls
defined on the basis of strict neuropathologic criteria.
Using the case/control odds ratio as an estimate of
relative risk and [Al] > or = 100 microgram/L as the
cutoff point, elevated risks for histopathologically
verified AD were associated with higher [Al]. Comparing all
AD cases with all non-AD controls, and using the [Al] of
public drinking water at last residence before death as the
measure of exposure, the estimated relative risk associated
with [Al] > or = 100 microgram/L was 1.7 (95% CI:
1.2-2.5). Estimating aluminum exposure from a 10-year
weighted residential history resulted in estimates of
relative risk of 2.5 or greater. The public health
implications of the observed relationship between [Al] in
drinking water and AD prevalence in the population depend
in large measure on population exposure characteristics. In
Ontario, it is estimated that 19% of the population was
exposed to residual [Al] greater than or equal to 100
microgram/L. Based on the estimated relative risk and the
assumption of causality, this translates to an etiologic
fraction of 0.23. Although the potential contributions of
confounding and mitigating factors are not defined in this
report, the merit of limiting residual aluminum in drinking
water supplies deserves serious attention.
Subnormal serum vitamin
B12 and behavioural and psychological symptoms in
Alzheimer's disease.
Meins W, Muller-Thomsen T, Meier-Baumgartner HP
Memory-Clinic, Department of Geriatric Medicine, Albertinen
Hospital, Hamburg, Germany.
Int J Geriatr Psychiatry 2000 May;15(5):415-8
The objective of this study was to examine whether
patients with Alzheimer's disease (AD) with subnormal
vitamin B12 levels show more frequent behavioural and
psychological symptoms of dementia (BPSD) than AD patients
with normal vitamin B12 levels. The design was a
prospective case-control study. The study took place at a
memory-clinic of a department of geriatric medicine in a
teaching hospital. There were seventy-three consecutive
outpatients with probable AD, including 61 patients with
normal and 12 patients with subnormal (<200 pg/ml)
vitamin B12. BPSD were measured using the subscales
disturbed behaviour and mood of the Nurses' Observation
Scale for Geriatric Patients (NOSGER), the Cornell Scale
for Depression and the four criteria for personality change
in dementia from the International Classification of
Diseases (ICD-10). Controlling for dementia duration and
degree of severity of the cognitive deficits, there were
significant inverse associations between vitamin B12 status
and ICD-10 irritability (p=0.045) and NOSGER subscale
disturbed behaviour (p=0.015). Low vitamin B12 serum levels
are associated with BPSD in AD. Vitamin B12 could play a
role in the pathogenesis of behavioural changes in AD.
Homocysteine and
Alzheimer's disease.
Miller JW. University of California-Davis Medical
Center, Department of Medical Pathology, Sacramento 95817,
USA.
Nutr Rev 1999 Apr;57(4):126-9
In a recent case-control study of 164 patients with
clinically diagnosed Alzheimer's disease (AD), including 76
patients with the AD diagnosis confirmed postmortem, mean
total serum homocysteine concentration was found to be
significantly higher than that of a control group of
elderly individuals with no evidence of cognitive
impairment. Because homocysteine is considered an
independent risk factor for vascular disease, this finding
is consistent with the emerging hypothesis that vascular
disease is a contributing factor in the pathogenesis of
AD.
Cholinergic deficits
contribute to behavioral disturbance in patients with
dementia.
Minger SL, Esiri MM, McDonald B, Keene J, Carter J, Hope
T, Francis PT. Dementia Research Laboratory, Centre for
Neuroscience Research, GKT School of Biomedical Sciences,
King's College London, UK.
Neurology 2000 Nov 28;55(10):1460-7
BACKGROUND: Noncognitive behavioral changes such as
depression, aggressive behavior, psychosis, and
overactivity occur frequently in patients with dementia, in
addition to cognitive impairment, and often determine the
need for institutionalization. The biochemical basis of
such changes is poorly understood. Clinical trial data
indicate that cholinomimetics improve noncognitive
behaviors. This study investigated the relationship between
markers of the cholinergic and dopaminergic
neurotransmitter systems and noncognitive behavioral
symptoms assessed during the course of dementing
illness.
METHOD: Brains from 46 patients with dementia (36 with
AD and 10 with mixed or other dementias using Consortium to
Establish a Registry for AD criteria) were examined
together with 32 normal controls. The patients with
dementia had been evaluated every 4 months, often over
several years, for cognitive performance (Mini-Mental State
Examination) and behavior (Present Behavioral Examination).
Concentrations of dopamine (DA) and major metabolites,
choline acetyltransferase activity (ChAT), and density
(Bmax) of DA D1 receptors in frontal and temporal cortex
were studied by radioligand binding protocols. None of the
patients was receiving cholinomimetic drugs.
RESULTS: ChAT activity, but no other neurochemical
markers, was reduced in AD compared with controls. Loss of
ChAT activity correlated with cognitive impairment. Lowered
ChAT activity also correlated with increasing overactivity
in patients with dementia in both frontal and temporal
cortex whereas ChAT:DA and ChAT:D1 ratios in temporal
cortex correlated negatively with aggressive behavior.
CONCLUSIONS: Disturbance of the cholinergic system may
underlie both cognitive and some noncognitive behavioral
changes in dementia, providing a basis for rational
therapy.
Vitamin E and vitamin C
supplement use and risk of incident Alzheimer
disease.
Morris MC, Beckett LA, Scherr PA, Hebert LE, Bennett DA,
Field TS, Evans DA. Rush Institute for Healthy Aging and
Rush Alzheimer's Disease Center, Rush University, Chicago,
Illinois, USA.
Alzheimer Dis Assoc Disord 1998 Sep;12(3):121-6
Oxidative stress may play a role in neurologic disease.
The present study examined the relation between use of
vitamin E and vitamin C and incident Alzheimer disease in a
prospective study of 633 persons 65 years and older. A
stratified random sample was selected from a disease-free
population. At baseline, all vitamin supplements taken in
the previous 2 weeks were identified by direct inspection.
After an average follow-up period of 4.3 years, 91 of the
sample participants with vitamin information met accepted
criteria for the clinical diagnosis of Alzheimer disease.
None of the 27 vitamin E supplement users had Alzheimer
disease compared with 3.9 predicted based on the crude
observed incidence among nonusers (p = 0.04) and 2.5
predicted based on age, sex, years of education, and length
of follow-up interval (p = 0.23). None of the 23 vitamin C
supplement users had Alzheimer disease compared with 3.3
predicted based on the crude observed incidence among
nonusers (p = 0.10) and 3.2 predicted adjusted for age,
sex, education, and follow-up interval (p = 0.04). There
was no relation between Alzheimer disease and use of
multivitamins. These data suggest that use of the
higher-dose vitamin E and vitamin C supplements may lower
the risk of Alzheimer disease.
Piracetam: novelty in a
unique mode of action.
Muller WE, Eckert GP, Eckert A Department of
Pharmacology, Biocenter University of Frankfurt,
Germany.
Pharmacopsychiatry 1999 Mar;32 Suppl 1:2-9
Extensive research of the recent years has demonstrated
that piracetam is effective in the treatment of cognitive
decline in aging and dementia. It is usually much more
active in situations of impaired brain function.
Accordingly, its mechanism of action has been associated
with neurochemical deficits of the aged brain relevant to
cognitive dysfunctions. Since many of these neurochemical
deficits depend on changes of membrane properties,
including fluidity, it is of special importance that
piracetam not only modifies membrane properties by
interacting with the polar head moieties of the
phospholipid bilayer, but also that this effect is more
pronounced in membranes of aged as opposed to young animal
and human brains, and that this mechanism also has specific
relevance for brain membranes of Alzheimer's disease
patients. Altering membrane properties might also be
involved in vascular effects of piracetam such as improved
erythrocyte deformability and normalization of hyperactive
platelet aggregation. This novel mechanism of piracetam
thus combines a rather non-specific physico-chemical mode
of action with the pharmacological and clinical experience
with this unique drug - effects are always much more
pronounced when function is impaired.
Influence of advanced
glycation end-products and AGE-inhibitors on
nucleation-dependent polymerization of beta-amyloid
peptide.
Munch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P,
Muller R, Neumann A, Schinzel R, Cunningham AM.
Theodor-Boveri-Institute (Biocenter), Wurzburg, Germany.
muench@biozentrum.uni-wuerzburg.de
Biochim Biophys Acta 1997 Feb 27;1360(1):17-29
Nucleation-dependent polymerization of beta-amyloid
peptide, the major component of plaques in patients with
Alzheimer's disease, is significantly accelerated by
crosslinking through Advanced Glycation End-products (AGEs)
in vitro. During the polymerization process, both nucleus
formation and aggregate growth are accelerated by
AGE-mediated crosslinking. Formation of the AGE-crosslinked
amyloid peptide aggregates could be attenuated by the
AGE-inhibitors Tenilsetam, aminoguanidine and carnosine.
These experimental data, and clinical studies, reporting a
marked improvement in cognition and memory in Alzheimer's
disease patients after Tenilsetam treatment, suggest that
AGEs might play an important role in the etiology or
progression of the disease. Thus AGE-inhibitors may
generally become a promising drug class for the treatment
of Alzheimer's disease.
Hippocampal perfusion
and pituitary-adrenal axis in Alzheimer's
disease.
Murialdo G, Nobili F, Rollero A, Gianelli MV, Copello F,
Rodriguez G, Polleri A Department of Endocrinological and
Metabolic Sciences, Epidemiology Service, University of
Genova, Italy. disem@unige.it
Neuropsychobiology 2000;42(2):51-7
The hippocampus is involved in Alzheimer's disease (AD)
and regulates the hypothalamus-pituitary-adrenal axis
(HPAA). Enhanced cortisol secretion has been reported in
AD. Increased cortisol levels affect hippocampal neuron
survival and potentiate beta-amyloid toxicity. Conversely,
dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are
believed to antagonize noxious glucocorticoid effects and
exert a neuroprotective activity. The present study was
aimed at investigating possible correlations between
hippocampus perfusion - evaluated by SPECT - and HPAA
function in AD. Fourteen patients with AD and 12 healthy
age-matched controls were studied by (99m)Tc-HMPAO
high-resolution brain SPECT. Plasma adrenocorticotropin,
cortisol, and DHEAS levels were determined at 2.00, 8.00,
14.00, 20.00 h in all subjects and their mean values were
computed. Cortisol/DHEAS ratios (C/Dr) were also
calculated. Bilateral impairment of SPECT hippocampal
perfusion was observed in AD patients as compared to
controls. Mean cortisol levels were significantly increased
and DHEAS titers were lowered in patients with AD, as
compared with controls. C/Dr was also significantly higher
in patients. Using a stepwise procedure for dependent SPECT
variables, the variance of hippocampal perfusional data was
accounted for by mean basal DHEAS levels. Moreover,
hippocampal SPECT data correlated directly with mean DHEAS
levels, and inversely with C/Dr. These data show a
relationship between hippocampal perfusion and HPAA
function in AD. Decreased DHEAS, rather than enhanced
cortisol levels, appears to be correlated with changes of
hippocampal perfusion in dementia.
Effects of
co-dergocrine mesylate (Hydergine) in multi-infarct
dementia as evaluated by positron emission
tomography.
Nagasawa H, Kogure K, Kawashima K, Ido T, Itoh M,
Hatazawa J Department of Neurology, Tohoku University
School of Medicine, Sendai, Japan.
Tohoku J Exp Med 1990 Nov;162(3):225-33
Three female patients aged from 74 to 79 with
multi-infarct dementia were studied using positron emission
tomography (PET) to assess the effect of co-dergocrine
mesylate (Hydergine) on cerebral glucose metabolism. The
cerebral glucose utilization (CMRGlc) of each patient was
evaluated by PET scan using
2-deoxy-[18F]-2-fluoro-D-glucose (FDG). Following the first
PET study, 0.04 mg/kg of co-dergocrine mesylate was
injected intravenously with 250 ml saline solution, and
then the second PET study was performed. The CMRGlc was
determined from the images of the PET scan and the
radioactivity of 18F in the plasma. After the
administration of co-dergocrine mesylate, the value of
CMRGlc increased significantly in the cerebral cortex (p
less than 0.01 and p less than 0.05) and basal ganglia (p
less than 0.05) compared with values before the
administration, but no significant increase was found in
the centrum semiovale. These results suggest that
co-dergocrine mesylate stimulates glucose metabolism of
neurons in the human brain.
|