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Abstracts

LE Magazine March 2004
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Memory Assessment

Early detection of isolated memory deficits in the elderly: the need for more sensitive neuropsychological tests.
BACKGROUND: Early detection of cognitive decline in the elderly is important because this may precede progression to Alzheimer’s disease. The aim of this study was to see whether sensitive neuropsychological tests could identify pre-clinical cognitive deficits and to characterize the cognitive profile of a subgroup with poor memory. METHODS: A neuropsychological test battery was administered to a community-dwelling sample of 155 elderly volunteers who were screened with CAMCOG at enrolment (mean age 74.7 years). The battery included tests of episodic memory. semantic and working memory, language and processing speed. RESULTS: Episodic memory test scores below 1 S.D. from the cohort mean identified 25 subjects with non-robust memory performance. This group was compared to the remaining ‘robust memory’ group with a General Linear Model controlling for age, IQ, education, and gender. Test performance was significantly different in all tests for episodic and semantic memory, but not in tests for working memory, processing speed, and language. CANTAB paired associates learning and spatial recognition tests identified the highest percentages of those in the ‘non-robust memory group. Processing speed partialled out the age effect on memory performance for the whole cohort, but the ‘non-robust memory’ group’s performance was not associated with age or processing speed. CONCLUSIONS: Sensitive neuropsychological tests can detect performance below the norm in elderly people whose performance on MMSE and CAMCOG tests is well within the normal range. Age-related decline in memory performance in a cohort of the elderly may be largely due to inclusion within the cohort of individuals with undetected pre-clinical Alzheimer’s disease or isolated memory impairment.

Psychol Med. 2002 Apr;32(3):483-91

Decline in learning ability best predicts future dementia type: the freedom house study.
The authors studied longitudinal change in learning efficiency as a predictor of future dementia type among healthy, well-educated, noninstitutionalized elderly retirees. Serial assessments of memory were obtained using the California Verbal Learning Test (CVLT). Latent growth (LG) models were developed from the slopes of the subjects’ performance over the first five CVLT learning trials at each of three serial administrations (e.g., cohort inception [i.e., baseline] [CVLT1], 18 months [CVLT2] and 36 months [CVLT3]). The resulting growth curves were incorporated into a higher order LG model representing the dynamic change in learning efficiency over time (DeltaCVLT). DeltaCVLT was used to predict each subject’s “dementia type” (i.e., clinical state) at 36 months (e.g., no dementia, Type 1 [Alzheimer type] dementia or Type 2 [non-Alzheimer type] dementia), after adjusting for CVLT1, baseline age, and baseline dementia type. Nonlinear (logarithmic) LG models of CVLT1-CVLT3 and DeltaCVLT best fit the data. There was significant variability about both CVLT1 and DeltaCVLT, suggesting subgroups in the sample with significantly different baseline memory function, and different rates of deterioration in learning efficiency. Age, baseline dementia type, and DeltaCVLT made significant independent contributions to final dementia type. CVLT1 did not predict final dementia type independently of the other covariates. These data suggest that baseline memory performance in noninstitutionalized elderly retirees does not predict future dementia type independently of the dynamic rate of change in memory measures. Serial administrations of memory tests may help identify nondemented persons at greater or lesser risk for conversion to frank dementia in the near-term.

Exp Aging Res. 2003 Oct-Dec;29(4):385-406

P300 (latency) event-related potential: an accurate predictor of memory impairment.
To determine if P300 latency changes precede and correlate with memory and mental status, patients (N=1506 aged 20-100 years) who received medical and psychiatric diagnoses (from 1997 to 2002), were assessed for P300 (N=1496), WMS-III (N=694), and MMSE (N=456). Patient and control groups included, a) normal WMS-III on all 4 subscales (N=36), b) normal WMS-III and MMSE (N=189) with subjective memory/mental status complaints, and c) medical patients with normal WMS-III and no memory complaints (N=205), and d) P300 control group without medical, psychiatric or memory problems for ROC. Patients with impaired/borderline memory had a prolonged P300 latency (P<0.02) compared to age matched non-impaired controls; in patients with normal WMS-III/MMSE, with subjective mild memory/mental status impairment, P300 latency was prolonged compared to controls (P=0.0004). The P300 latency increased by 0.72ms per year (P=7.9x10(-65)) and voltage decreased by 0.03dV per year (P=6.7x10(-10)), and both parameters were linearly correlated with the age of the subjects. Male subjects had an average voltage of 6.1dV and female 6.8dV (P=0.00009). Statistically, prolonged latency began at age range 41-50 (P=0.0002); reduced P300 voltage began at age range 51-60 (P=0.003). WMS-III memory decline for all measures began in females at age range 61-70 (P value at least=0.02) and for males at age range 61-80 (P=0.02). Prolonged P300 latency (P<0.0001) and memory impairment (at least <0.02) were greater for females than males. MMSE memory decline, male and female, began at age range 81-90 (P value of at least 0.00007). In our logistic regression model P300 latency was more predictive of WMS-III impairment than MMSE > 24. In patients whose WMS-III score is impaired < or = 69, or borderline < or = 79 (P at least=0.004), a P300 latency more prolonged than the norm (> or = 300 + 30 + Age) identifies these patients, whereas a MMSE > 24 failed. With the ROC curve, we confirmed that P300 latency could accurately identify borderline/impaired memory.

Clin Electroencephalogr. 2003 Jul;34(3):124-39

P300 latency and age: a quadratic regression explains their relationship from age 5 to 85.
The use of P300 latency to demonstrate cognitive dysfunction is important. P300 latency decreases with age in children and then increases with age in adults. It has been debated whether the relationship between age and P300 latency is linear or quadratic. If the relationship is linear, then at least two regression equations in opposite directions are required for children and for adults, and perhaps a third for the elderly. This is a report of data from an age-stratified sample of 97 normal individuals ages 5 through 85. The best regression equation is quadratic, using log transformed age, with accurate projection of 95% confidence limits for P300 latency by age. This quadratic regression simplifies the application of P300 latency across the lifespan in the management of disorders affecting cognition, such as Traumatic Brain Injury, Attention Deficit-Hyperactivity Disorder, and Obstructive Sleep Apnea.

Clin Electroencephalogr. 1998 Jan;29(1):1-6

A critical discussion of the role of neuroimaging in mild cognitive impairment.
OBJECTIVE: In this paper, the current neuroimaging literature is reviewed with regard to characteristic findings in mild cognitive impairment (MCI). Particular attention is drawn to the possible value of neuroimaging modalities in the prediction and early diagnosis of Alzheimer’s disease (AD). METHODS: First, the potential contribution of neuroimaging to an early, preclinical diagnosis of degenerative disorders is discussed at the background of our knowledge about the pathogenesis of AD. Second, relevant neuroimaging studies focusing on MCI are explored and summarized. Neuroimaging studies were found through Medline search and by systematically checking through the bibliographies of relevant articles. RESULTS: Structural volumetric magnetic resonance imaging (MRI) and positron emission tomography (PET)/single photon emission tomography (SPECT) are currently the most commonly used neuroimaging modalities in studies focusing on MCI. There were considerable variations in demographical and clinical characteristics across studies. However, significant hippocampal and entorhinal cortex volume reductions were consistently found in subjects with MCI as compared with cognitively unimpaired controls. While hippocampal and entorhinal cortex atrophy in subjects with MCI are also well-established risk factors for the development of AD, these measures cannot be regarded as being of high predictive value in an individual case. Evidence for other typical neuroimaging changes in MCI is still scarce. In PET and SPECT studies, reduced blood flow and/or glucose metabolism in temporoparietal association areas, posterior cingulate and hippocampus were associated with a higher risk of progressive cognitive decline in MCI. In quantitative electroencephalogram (QEEG), low beta, high theta, low alpha and slowed mean frequency were associated with development of dementia. CONCLUSIONS: Existing studies suggest that neuroimaging measures have the potential to become valuable tools in the early diagnosis of AD. To establish their value in routine use, larger studies, preferably with long prospective follow-up are needed.

Acta Neurol Scand Suppl. 2003;179:52-76

Effects of alcoholism, anxiety and depression on P300 in women: a pilot study.
OBJECTIVE: The present investigation was designed for the purpose of revealing functional brain impairments associated with alcoholism, anxiety and depression. METHOD: The subjects were 56 women, with an average (SD) age of 34.8 (7.3) years. None reported a history of neurological or major medical disorders, or drug abuse. Twenty-nine of the women met DSM-IV lifetime criteria for a diagnosis of alcohol abuse or dependence. Twenty-five women reported mild or higher levels of anxiety, as indexed by a Beck Anxiety Inventory (BAI) score greater than 7. Electroencephalographic activity was recorded while subjects performed a visual (“oddball”) selective attention task comprised of rare target, rare nontarget and frequent nontarget stimuli. P300 event-related potentials elicited by the rare target and rare nontarget stimuli were analyzed. RESULTS: The initial analysis was structured as a 2 (alcoholism) by 2 (anxiety) factorial. Analyses revealed no significant effects of alcoholism on P300. However, women reporting a BAI score greater than 7 exhibited significantly smaller P300 amplitudes than their nonanxious counterparts. The P300 decrement remained significant when depression level (Beck Depression Inventory [BDI-II]) and age were entered as covariates. A separate analysis was conducted in which the 56 subjects were classified by alcoholism and depression level (BDI-II score < or =13 vs >13). The analysis revealed no significant P300 differences associated with these factors. CONCLUSIONS: It is hypothesized that anxiety might play a role in mediating or amplifying the P300 decrements that have been attributed to alcoholism and depression in women. Additional and more comprehensive studies are needed to discern the validity of this hypothesis.

J Stud Alcohol. 2001 Sep;62(5):571-9

The P300 brain potential is reduced in smokers.
RATIONALE: Tobacco smoking is the most prevalent type of substance abuse, yet its biobehavioral etiology is little understood. Identification of differences between smokers and non-smokers on basic characteristics of neurocognitive functioning may help to elucidate the mechanisms of tobacco dependence. OBJECTIVES: This study assessed the relationship between smoking status and the P300 component of event-related potential (ERP) while controlling for potential confounders such as alcoholism, drug abuse, and psychopathology. METHODS: The ERP responses elicited by a visual oddball task were measured at the mid-parietal site in 905 current smokers, 463 ex-smokers, and 979 never smokers. RESULTS: P300 amplitude was significantly lower in current cigarette smokers compared to never-smokers. Ex-smokers did not differ significantly from never-smokers. P300 reduction was also associated with alcoholism, drug dependence, and family density of alcoholism. However, after controlling for smoking, only family density of alcoholism remained a significant predictor of P300 amplitude. CONCLUSIONS: The results indicate a significant effect of smoking status on P300 amplitude, which is additive to family history of alcoholism and suggest that either (1) long-term tobacco smoking may produce a reversible change in brain function, or (2) reduced P300 may be a marker of risk for nicotine dependence.

Psychopharmacology (Berl). 2000 May;149(4):409-13

Pectin

Endogenous galactoside-binding lectins: a new class of functional tumor cell surface molecules related to metastasis.
The formation of secondary tumors by circulating cancer cells (blood-borne metastasis) correlates with an increased tendency of the cells to form emboli by aggregation with other tumor cells or with host cells. Although it is evident that cell-cell recognition and adhesion are mediated by cell surface components, the identity of these molecules is only now being unraveled. Over the last decade an increasing number of studies have demonstrated the presence of endogenous carbohydrate-binding proteins on the surface of various normal cells, and it has been proposed that such lectin-like molecules might be involved in intercellular adhesion. We have shown that various tumor cell lines contain endogenous galactose-specific lectins. Lectin activity was detected at the cell surface by the binding of asialofetuin. This glycoprotein also enhanced the aggregation of the tumor cells. After purification by affinity chromatography on immobilized asialofetuin the lectin activity was associated with two proteins of Mr 14,500 and 34,000. By using polyclonal and monoclonal antilectin antibodies in conjunction with various immunologic techniques we have demonstrated that the endogenous lectins are present on the surface of different tumor cells. Quantitation of cell surface lectins by flow cytometric analyses of antilectin antibody binding revealed that among related tumor cells those exhibiting a higher metastatic potential expressed more lectin on their surface. The binding of monoclonal antilectin antibodies to metastatic cells decreased asialofetuin-induced homotypic aggregation in vitro and suppressed the ability of the cells to form lung metastases after intravenous injection in the tail vein of syngeneic mice. These results strongly implicate the tumor cell surface lectins in cell adhesion and metastasis. We propose that such lectins can increase the ability of tumor cells that enter the blood stream to form aggregates with other tumor cells, or to adhere to host cells or the extracellular matrix and thereby increase their metastatic potential. Other contributing components to tumor cell-host cell interactions are cell surface carbohydrate-binding proteins that have been detected on lymphocytes, platelets, macrophages, hepatocytes, and endothelial cells. These lectin-like molecules might recognize and bind carbohydrates expressed on the surface of tumor cells and enhance emboli formation and organ colonization.

Cancer Metastasis Rev. 1987;6(3):433-52

Expression of the endogenous galactose-binding protein galectin-3 correlates with the malignant potential of tumors in the central nervous system.

BACKGROUND: The 31-kilodalton beta-galactoside-binding protein galectin-3 has been associated with cellular transformation and metastasis. Because neural tissues contain large amounts of glycoconjugates, and endogenous carbohydrate-binding proteins have been described in the human brain, the authors examined the expression of galectin-3 in human brain tumors and metastases to the central nervous system. METHODS: Brain tumors were categorized by the World Health Organization system and galectin-3 expression by immunoperoxidase staining using a quantitative staining score. RESULTS: Glioblastomas (Grade 4 astrocytomas) all stained strongly for galectin-3, whereas low grade astrocytomas (Grade 2) did not express the endogenous lectin. Anaplastic astrocytomas (Grade 3) exhibited intermediate expression. The staining score was significantly associated with tumor grade (P < 0.001). Normal brain tissue and benign tumors did not express galectin-3, whereas metastases to the brain were all positive for galectin-3 expression. Metastases expressed significantly more galectin-3 than the primary tumors from which they were derived (P = 0.003). CONCLUSIONS: Galectin-3 expression correlates with the malignant potential of tumors in the central nervous system.

Cancer. 1997 Aug 15;80(4):776-87

Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin.
BACKGROUND: Prostate cancer is the most common cancer diagnosed in U.S. men and remains incurable once it has metastasized. Many stages of the metastatic cascade involve cellular interactions mediated by cell surface components, such as carbohydrate-binding proteins, including galactoside-binding lectins (galectins). Modified citrus pectin (pH-modified), a soluble component of plant fiber derived from citrus fruit, has been shown to interfere with cell-cell interactions mediated by cell surface carbohydrate-binding galectin-3 molecules. PURPOSE: The aim of this study was to determine whether modified citrus pectin, a complex polysaccharide rich in galactosyl residues, could inhibit spontaneous metastasis of prostate adenocarcinoma cells in the rat. METHODS: The ability of modified citrus pectin to inhibit the adhesion of Dunning rat prostate cancer MAT-LyLu cells to rat endothelial cells was measured by 51Cr-labeling. Modified citrus pectin inhibition of MAT-LyLu cell anchorage-independent growth was measured by colony formation in agarose. The presence of galectin-3 in rat MAT-LyLu cells and human prostate carcinoma was demonstrated by immunoblotting and immunohistochemistry. One million MAT-LyLu cells were injected subcutaneously into the hind limb of male Copenhagen rats on day 0. Rats were given 0.0%, 0.01%, 0.1%, or 1.0% (wt/vol) modified citrus pectin continuously in their drinking water (from day 4 until necropsy on day 30). The number of MAT-LyLu tumor colonies in the lungs were counted. RESULTS: Compared with 15 or 16 control rats that had lung metastases on day 30, seven of 14 rats in the 0.1% and nine of 16 rats in the 1.0% modified citrus-pectin group had statistically significant (two-sided; P < .03 and P < .001, respectively) reductions in lung metastases. The lungs of the 1.0% modified citrus pectin-treated rats had significantly (two-sided; P < .05) fewer metastatic colonies than control groups (9 colonies +/- 4 [mean +/- SE] in the control group compared with 1 colony +/- 1 in the treated group). Modified citrus pectin had no effect on the growth of the primary tumors. In vitro, modified citrus pectin inhibited MAT-LyLu cell adhesion to rat endothelial cells in a time- and dose-dependent manner as well as their colony formation in semisolid medium. CONCLUSIONS: We present a novel therapy in which oral intake of modified citrus pectin acts as a potent inhibitor of spontaneous prostate carcinoma metastasis in the Copenhagen rat. IMPLICATIONS: Further investigations are warranted to determine the following: 1) the role of galectin-3 in normal and cancerous prostate tissues and 2) the ability of modified citrus pectin to inhibit human prostate metastasis in nude mice.

J Natl Cancer Inst. 1995 Mar 1;87(5):348-53

Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study.
This trial investigated the tolerability and effect of modified citrus pectin (Pecta-Sol®) in 13 men with prostate cancer and biochemical prostate-specific antigen (PSA) failure after localized treatment, that is, radical prostatectomy, radiation, or cryosurgery. A total of 13 men were evaluated for tolerability and 10 for efficacy. Changes in the prostate-specific antigen doubling time (PSADT) of the 10 men were the primary end point in the study. We found that the PSADT increased (P-value<0.05) in seven (70%) of 10 men after taking MCP for 12 months compared to before taking MCP. This study suggests that MCP may lengthen the PSADT in men with recurrent prostate cancer.

Prostate Cancer Prostatic Dis. 2003;6(4):301-4