The Treviso Dementia (TREDEM) Study: A Biomedical, Neuroradiological, Neuropsychological and Social Investigation of Dementia in North-Eastern Italy.

BACKGROUND: The incidence of dementia increases exponentially with age but knowledge of real disease-modifying interventions is still limited. OBJECTIVES: To describe the study design and methods of a large prospective cohort study aimed at exploring the complex underlying relationships existing among cognition, frailty, and health-related events in older persons with cognitive impairment. DESIGN: Prospective cohort study of a representative population of outpatients attending the Treviso Cognitive Impairment Center between 2000 and 2010. SETTING: The TREVISO DEMENTIA (TREDEM) Study conducted in Treviso, Italy. PARTICIPANTS: 490 men and 874 women, mean age 79.1 ± 7.8 years (range 40.2-100 years). MEASUREMENTS: Physiological data, biochemical parameters, clinical conditions, neuroradiological parameters (e.g., brain atrophy and cerebral vascular lesions identified by computerized tomography scans), neuropsychological assessment, and physical function markers were measured at baseline. Patients were followed-up to 10 years. RESULTS: The final sample included in the study was predominantly composed of women and characterized by an initial physical function impairment and increased vascular risk profile. Cognitive function of the sample population showed moderate cognitive impairment (Mini Mental State Examination 20.2 ± 6.3; Clinical Dementia Rating 1.2 ± 0.7), and a prevalence of vascular dementia of 26.9%. Cortical, subcortical and hippocampus atrophy were all significantly correlated with age and cognitive function. CONCLUSION: Results obtained from the preliminary analyses conducted in the TREDEM study suggest that the database will support the accomplishment of important goals in understanding the nature of cognitive frailty and neurodegenerative diseases.

Factors related to disability: evidence from the "Treviso Longeva (TRELONG) study".

Prolongation of life is an important public health goal as long as there is an emphasis on the quality of life (QoL) and independent living. Diminishing abilities to ambulate and participate in activities of daily living point to a serious decline in functional health, increasing the risk of institutionalization and death. In our work we found a pattern of factors associated with disability, especially cognitive impairment, as well as stroke, physical activity and performance, reading, and the nutritional biomarkers, blood albumin and high-density lipoprotein cholesterol (HDL-C). The attention to this cluster of markers, suggesting multidimensional prevention, may have unexpected good effects against disability.

Semantic memory activation in individuals at risk for developing Alzheimer disease.

OBJECTIVE: To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE epsilon4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names. METHODS: Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n = 23 each) based on AD risk: 1) no family history, no epsilon4 allele (control [CON]); 2) family history, no epsilon4 allele (FH); and 3) family history and epsilon4 allele (FH+epsilon4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only). RESULTS: Cognitively intact older adults with AD risk factors (FH and FH+epsilon4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FH+epsilon4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression. CONCLUSIONS: Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults.

Semantic memory activation in amnestic mild cognitive impairment.

Cognitively intact older individuals at risk for developing Alzheimer's disease frequently show increased functional magnetic resonance imaging (fMRI) brain activation presumably associated with compensatory recruitment, whereas mild cognitive impairment (MCI) patients tend not to show increased activation presumably due to reduced neural reserve. Previous studies, however, have typically used episodic memory activation tasks, placing MCI participants at a performance disadvantage relative to healthy elders. In this event-related fMRI study, we employed a low effort, high accuracy semantic memory task to determine if increased activation of memory circuits is preserved in amnestic MCI when task performance is controlled. Fifty-seven participants, aged 65-85 years, comprised three groups (n = 19 each): amnestic MCI patients; cognitively intact older participants at risk for developing Alzheimer's disease based on having at least one ApoE epsilon4 allele and a positive family history of Alzheimer's disease (At Risk); and cognitively intact participants without Alzheimer's disease risk factors (Control). fMRI was conducted on a 3T MR scanner while participants performed a famous name discrimination task. Participants also underwent neuropsychological testing outside the scanner; whole brain and hippocampal atrophy were assessed from anatomical MRI scans. The three groups did not differ on demographic variables or on fame discrimination performance (>87% correct for all groups). As expected, the amnestic MCI participants demonstrated reduced episodic memory performance. Spatial extent of activation (Fame--Unfamiliar subtraction) differentiated the three groups (Control = 0 ml, At Risk = 9.7 ml, MCI = 34.7 ml). The MCI and At Risk groups showed significantly greater per cent signal change than Control participants in 8 of 14 functionally defined regions, including the medial temporal lobe, temporoparietal junction, and posterior cingulate/precuneus. MCI participants also showed greater activation than Controls in two frontal regions. At Risk, but not MCI, participants showed increased activity in the left hippocampal complex; MCI participants, however, evidenced increased activity in this region when hippocampal atrophy was controlled. When performance is equated, MCI patients demonstrate functional compensation in brain regions subserving semantic memory systems that generally equals or exceeds that observed in cognitively intact individuals at risk for Alzheimer's disease. This hyperactivation profile in MCI is even observed in the left hippocampal complex, but only when the extent of hippocampal atrophy is taken into consideration.

Physical activity, socialization and reading in the elderly over the age of seventy: what is the relation with cognitive decline? Evidence from "The Treviso Longeva (TRELONG) study".

Evidence in the literature suggests that physical activity, social contacts and cognitively stimulating activity, such as reading, often considered individually, may improve cognitive performance. Our work examines their interactions and confirms their positive effects on cognitive functions. The correlations between physical activity, socialization, reading and improved cognitive performance remained significant after adjusting for confounding factors, such as comorbidity and hearing function. Our work suggests that these factors are important for the prevention of cognitive decline in the elderly.

Auto-Contractive Maps: an artificial adaptive system for data mining. An application to Alzheimer disease.

This article presents a new paradigm of Artificial Neural Networks (ANNs): the Auto-Contractive Maps (Auto-CM). The Auto-CM differ from the traditional ANNs under many viewpoints: the Auto-CM start their learning task without a random initialization of their weights, they meet their convergence criterion when all their output nodes become null, their weights matrix develops a data driven warping of the original Euclidean space, they show suitable topological properties, etc. Further two new algorithms, theoretically linked to Auto-CM are presented: the first one is useful to evaluate the complexity and the topological information of any kind of connected graph: the H Function is the index to measure the global hubness of the graph generated by the Auto-CM weights matrix. The second one is named Maximally Regular Graph (MRG) and it is an development of the traditionally Minimum Spanning Tree (MST). Finally, Auto-CM and MRG, with the support of the H Function, are applied to a real complex dataset about Alzheimer disease: this data come from the very known Nuns Study, where variables measuring the abilities of normal and Alzheimer subject during their lifespan and variables measuring the number of the plaques and of the tangles in their brain after their death. The example of the Alzheimer data base is extremely useful to figure out how this new approach can help to re design bottom-up the overall structure of factors related to a complex disease like this.

Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease.

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.

Perfusion fMRI detects deficits in regional CBF during memory-encoding tasks in MCI subjects.

OBJECTIVE: To determine how memory-encoding tasks elicit functional perfusion change in subjects with amnestic mild cognitive impairment (aMCI). METHODS: Twelve subjects with aMCI and 14 age-matched cognitively normal (CN) subjects were recruited for this study. Arterial spin-labeling perfusion MRI (ASL-MRI) was employed to measure regional cerebral blood flow (CBF) during both control and encoding task conditions. RESULTS: Experimental results demonstrated that hypoperfusion occurred in the right precuneus and cuneus in the aMCI group, and not the CN group, during the control state. During the memory-task performance, the difference in these regional hypoperfusion areas extended to the posterior cingulate. These regional perfusion rates correlated with the Mini-Mental State Examination and the Rey Auditory Verbal Learning Test scores. In addition, a CBF percentage increase (22.7%) occurred in the right parahippocampus region during the memory-encoding task performance in the CN group, with approximately no change in the aMCI group. CONCLUSION: Subjects with amnestic mild cognitive impairment had significant regional cerebral hypoperfusion and lacked the dynamic capability to modulate their regional cerebral blood flow responses to the challenge of the functional tasks.

Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients.

Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.

Alzheimer disease risk associated with APOE4 is modified by STH gene polymorphism.

The association of the STH gene polymorphism with Alzheimer disease (AD) is debated. In the analysis of two genetically and diagnostically distinct groups of Alzheimer patients from the USA and Italy, the authors did not find an association with the STH polymorphism. However, the APOE-4-associated risk of AD greatly increased if the STH-G allele was also present. The STH-G allele appears to be a risk modifier for AD.

Decreased glutamate + glutamine in Alzheimer's disease detected in vivo with (1)H-MRS at 0.5 T.

OBJECTIVE: To determine whether glutamate + glutamine (GLX) levels in the brain as measured in vivo with proton MRS at 0.5 tesla (T) distinguish between probable Alzheimer's disease and normal aging. BACKGROUND: Glutamatergic markers had been measured previously in postmortem brain tissue. Conventional proton MRS at 1.5 T cannot reliably detect the GLX resonance in vivo. The authors developed a technique at 0.5 T that is sensitive to the GLX resonance. METHODS: Metabolite ratios using creatine and phosphocreatine resonance as an internal standard were acquired from the cingulate region of 18 patients with AD and 12 healthy controls. The major resonances in the spectrum were examined: N-acetylaspartate (NAA), choline-containing compounds, myo-inositol, and GLX. The Mini-Mental State Examination (MMSE) was used to assess cognitive status. The Instrumental Activities of Daily Living Scale (Instrumental ADL) was used to assess functional status. RESULTS: Reduced ratios of GLX (-10%, p = 0.001) and NAA (-12%, p = 0.000) were found in patients with AD. Increased ratios of myo-inositol in patients with AD approached significance (+14%). GLX ratios of patients with AD were correlated with MMSE (r = 0.61, p = 0.007) and Instrumental ADL (r = 0.59, p = 0.01) scores. The combined sensitivity of NAA and myo-inositol in correctly diagnosing AD was 78%. The addition of GLX to NAA and myo-inositol increased the sensitivity to 89%. Overall diagnostic accuracy improved from 80 to 83% with the addition of GLX. CONCLUSIONS: Glutamate + glutamine reduction may be a biologic marker for AD and may be a potential aid in the early clinical diagnosis of AD.

The burden of dementia. A medical and research perspective.

Alzheimer's disease remains the most common form of dementia. Dementia symptoms vary depending on individual personality, life experience, and social and cultural influences. As dementia progresses, involvement of multi-disciplinary health care professionals is needed to manage the disease. Alzheimer research is progressing rapidly. While 5% of all Alzheimer's disease may be genetically determined, the majority is not. Susceptibility genes can reveal the risk of contracting Alzheimer's disease. Early life risk factors such as education, nutrition, and vascular disease may increase the likelihood of dementia in later life. In the United States, two acetylcholinesterase inhibitors have been approved as cognitive enhancers. Possible prevention and symptomatic treatment interventions have focused on estrogen replacement therapy, antioxidants, and anti-inflammatory medications. Research advances have improved the clinical management of dementia. Ethical implications to the patient, family, and society are multiple and remain challenging.

Diagnostic criteria for dementia in clinical trials. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines.

Some of the issues associated with standardizing the diagnosis of dementia in clinical trials are outlined. Deliberations of the Working Group on Diagnostic Criteria and their recommendations for future actions needed to develop a consensus are described.

Cytochrome oxidase in Alzheimer's disease: biochemical, histochemical, and immunohistochemical analyses of the visual and other systems.

Defects in oxidative metabolism have been implicated in Alzheimer's disease (AD). The present study evaluated the level of cytochrome oxidase (C.O.), an indicator of neuronal oxidative capacity, in various brain regions of post-mortem AD and control patients. We found a statistically significant reduction in C.O. levels in all cortical areas examined, including the primary and secondary visual cortices. In addition, all layers of the dorsal lateral geniculate nucleus and sublaminae of the primary visual cortex in AD cases examined suffered a reduction in their relative C.O. activity and protein amount. Our results suggest a generalized suppression of oxidative metabolism throughout the cortex, as well as in a major subcortical visual center in AD. Such hypometabolism may form the basis for not only deficits in higher cortical functions, but also a variety of visual dysfunctions known to occur in AD.

A treatment and withdrawal trial of besipirdine in Alzheimer disease.

Besipirdine hydrochloride (HP 749) is an indole-substituted analog of 4-aminopyridine. Besipirdine enhances both cholinergic and adrenergic neurotransmission in the central nervous system. The present study examined the efficacy and tolerability of two doses of besipirdine (5 and 20 mg b.i.d.) in 275 patients with Alzheimer disease during 3 months of treatment and for 3 months after withdrawal of treatment. Assessment after withdrawal of treatment was used in an effort to distinguish persistent efficacy attributable to a neuroprotective mechanism from reversible symptomatic efficacy. Besipirdine was generally well tolerated. The level of performance on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog) was sustained during 3 months of treatment with besipirdine, whereas some deterioration in the performance of patients treated with placebo was observed over the same period. The small difference between active and placebo treatment groups approached, but did not reach statistical significance in the primary intent-to-treat analysis (p = 0.067); analysis of patients who completed all assessments was supportive (p = 0.031). Global ratings using the Clinician Interview-Based Impression of Change did not detect a besipirdine treatment benefit, possibly because of an adverse effect on mood and behavior in some patients. A high ratio of adrenergic to cholinergic potency may have resulted in the adverse effects of besipirdine and hence its failure to support the hypothesis that multiple neurotransmitter treatment may be more efficacious than monotherapy. The efficacy apparent on the ADAS-Cog after 3 months of treatment did not persist 3 months after withdrawal of treatment, suggesting that the benefit was symptomatic. This study provides a practical example of the use of treatment withdrawal assessment to distinguish neuroprotective from symptomatic efficacy.

Effectiveness and safety of velnacrine for the treatment of Alzheimer's disease. A double-blind, placebo-controlled study. Mentane Study Group.

BACKGROUND: Alzheimer's disease is characterized by cognitive and behavioral disturbances that are mediated in part by cholinergic brain deficits. OBJECTIVE: To evaluate the long-term effectiveness and safety of an investigational cholinesterase inhibitor, that is, velnacrine maleate, in treating patients with clinically probable Alzheimer's disease (according to the criteria of the National Institute of Neurological Disorders and Stroke [Washington, DC]-Alzheimer Disease and Related Disorders Association [Chicago, Ill]). METHODS: This was a double-blind, placebo-controlled study. After a single-blind washout period, patients were randomized to receive placebo (n = 152), velnacrine maleate, 150 mg/d (n = 149), or velnacrine maleate, 225 mg/d (n = 148) for 24 weeks. Primary end points were cognitive behavior and memory components of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale. Secondary end points were caregiver-rated scales. RESULTS: The scores for the cognitive behavior and memory components of the Alzheimer's Disease Assessment Scale deteriorated in the placebo-treated group (P < .05) but not in the velnacrine-treated groups. Between-group comparisons favored velnacrine maleate, 225 mg over 150 mg (P < .05). Findings were similar for the Clinical Global Impression of Change scale and three of the four caregiver-rated scales. Treatment-related adverse clinical events occurred in 36%, 28%, and 30% of patients in the groups that received placebo, velnacrine maleate (150 mg), and velnacrine maleate (225 mg), respectively. The most common adverse clinical event was diarrhea, which rarely interrupted therapy. Treatment was stopped because of reversible abnormal liver function test results (five or more times the upper limits of normal) in 3%, 30%, and 24% of the patients who received placebo, velnacrine maleate (150 mg), and velnacrine maleate (225 mg), respectively. CONCLUSIONS: Velnacrine produces modest but significant benefits in patients with Alzheimer's disease. Velnacrine maleate (225 mg) is more effective than 150 mg of velnacrine. Both dosages have acceptable safety profiles.

Leukocyte hexokinase activity in aging and Alzheimer disease.

We determined the effects of clinical variables on hexokinase (HK) activity in leukocytes from Alzheimer's disease (AD) patients and controls. Age accounted for 51% of the variance in HK activity in the young and 23% in the old. Duration of illness in both familial and sporadic AD accounted for HK levels by 32 and 38%, respectively. Hexokinase activity increases with age and does not discriminate between familial and sporadic AD.

Correlation of neuronal cell body size in motor cortex and hippocampus with body height, body weight, and axonal length.

This study examined the comparative effects of body height and body weight on the neuronal cell size in humans and investigated their possible mechanisms. A total of 21 cases between the ages of 20 and 40 years were studied. Data on body height, body weight, and neuropathology were obtained from autopsy records. Mean cross sectional areas of cell bodies for 30 normal neurons were determined for the motor cortex projecting to lumbar spinal cord segments (L) 1-4 (Betz cells) as well as various regions of the hippocampus. Approximate axonal length of the motor neuron studied was measured from motor cortex to L2. We found that only motor cortex neuronal cell body size was significantly proportional to body height and the respective axonal length (p < .05). The findings indicate that: 1) body height has a greater effect than body weight on the motor neuron cell size, probably because of its association with axonal length; 2) the effect is regional (motor cortex) rather than general.

Potential clinical use of an adrenergic/cholinergic agent (HP 128) in the treatment of Alzheimer's disease.

A novel compound designated HP 128, which manifests adrenergic and cholinergic properties, was administered for 10 days to patients with Alzheimer's disease in a double-blind, placebo-controlled trial. All patients who entered the trial had previously failed to respond to a structurally related cholinesterase inhibitor without adrenergic properties (HP 029). The primary purpose of the study was to assess the safety and tolerance of HP 128. Efficacy measures were obtained to generate hypotheses for possible future studies. In the dosage range examined, HP 128 was safe and well tolerated. Effects on clinical measures of dementia severity were equivocal.