Mitigating cellular aging and enhancing cognitive functionality: visual arts-mediated Cognitive Activation Therapy in neurocognitive disorders.

The growing phenomenon of population aging is redefining demographic dynamics, intensifying age-related conditions, especially dementia, projected to triple by 2050 with an enormous global economic burden. This study investigates visual arts-mediated Cognitive Activation Therapy (CAT) as a non-pharmacological CAT intervention targets both biological aging [leukocyte telomere length (LTL), DNA methylation age (DNAmAge)] and cognitive functionality. Aligning with a broader trend of integrating non-pharmacological approaches into dementia care. The longitudinal study involved 20 patients with mild to moderate neurocognitive disorders. Cognitive and functional assessments, and biological aging markers -i.e., LTL and DNAmAge- were analyzed before and after CAT intervention. Change in LTL was positively correlated with days of treatment (p =0.0518). LTL significantly elongated after intervention (p =0.0269), especially in men (p =0.0142), correlating with younger age (p =0.0357), and higher education (p =0.0008). DNAmAge remained instead stable post-treatment. Cognitive and functional improvements were observed for Copy of complex geometric figure, Progressive Silhouettes, Position Discrimination, Communication Activities of Daily Living-Second edition, Direct Functional Status (p < 0.0001) and Object decision (p =0.0594), but no correlations were found between LTL and cognitive gains. Visual arts-mediated CAT effectively mitigates cellular aging, especially in men, by elongating LTL. These findings underscore the potential of non-pharmacological interventions in enhancing cognitive and functional status and general well-being in dementia care. Further research with larger and longer-term studies is essential for validation.

Reference intervals for cardiometabolic risk factors in China: a national multicenter cross-sectional study on an adult population sample.

Background: The reference intervals (RIs) of adult blood lipid parameters currently used in China are not derived from the results of research in local populations and have not been adjusted for age and sex. In this study, we aimed to determine accurate RIs for blood lipid parameters and blood glucose (GluG) for Chinese adults using a national multicenter study. Methods: A total of 11,333 adults between 18 and 90 years of age were recruited in seven representative regions in China between June 2020 and December 2020. Hospitals participating in the study were regrouped into two geographical regions, southern China (Changsha, Chengdu, Hangzhou, and Nanning) and northern China (Beijing, Shenyang, and Ningxia), according to their geographical and administrative location. All samples were freshly collected and measured collectively in one laboratory on the Mindray full Automatic biochemical analyzer chemistry BS2000 analytical systems. Outliers were removed using the Tukey test. Three-level nested analysis of variance and scatter plot were used to explore the variations in sex, age, and region. Percentile curves of each indicator were plotted using the least mean square (LMS) method. The lower limit (2.5th percentile) and the upper limit (97.5th percentile) of the RI were determined by using nonparametric statistical methods. We also calculated the 90% confidence interval (CI) for the lower and upper limits. Results: A total of 8,283 participants were enrolled in the final analysis, with 3,593 (43.4%) men and 4,690 (56.6%) women. Regionality was observed in three analytes [small dense low density lipoprotein cholesterol (sd-LDLC), GluG, and apolipoprotein A1 (ApoA1)]. In northern China, the sd-LDLC and GluG levels in Shenyang were significantly higher than those in Ningxia and Beijing (P<0.05). In southern China, the sd-LDLC and GluG levels in Nanning were significantly higher than those in the three other cities (P<0.05), whereas the sd-LDLC and GluG levels in Chengdu were significantly lower than those in the three other cities (P<0.05). The level of ApoA1 in Chengdu was significantly higher than that in the three other cities. The homocysteine (HCY) level in male participants was clearly higher than that in female participants [ratio of standard deviation (SDR)sex =0.56], whereas the levels of high density lipoprotein cholesterol (HDLC) (SDRsex =0.40) and ApoA1 (SDRsex =0.27) in males were lower. The GluG and HCY level increased gradually with age. In females aged 45-55 years, there was an interesting change in scatter charts, where triglyceride (TG) and total cholesterol (TC) increased rapidly. We also found that for the age group of >55 years, the levels of TG and TC in females gradually surpassed those in males. Conclusions: The findings of this study may help establish age- and sex-specific reference values for the blood lipids of Chinese adults and serve as a valuable guide for the screening, diagnosis, treatment, prevention, and monitoring of cardiovascular disease (CVD).

Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study.

Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81-0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.

Hyperhomocysteinemia and Dementia Associated With Severe Cortical Atrophy, but No Amyloid Burden.

We report a case of a 77 years old patient who was admitted to our memory clinic because of progressive gait impairment and amnestic cognitive decline associated with extrapyramidal symptoms and behavioral changes. The clinical picture was consistent with a possible diagnosis of Alzheimer's Disease associated with parkinsonian symptoms or with a Parkinson Plus syndrome. After a complete investigation, she was found to have a high plasma level of homocysteine due to homozygous methylene-tetrahydrofolate reductase (MTHFR) gene C665 T polymorphism, cognitive and motor impairment were associated with a severe cortical atrophy and mild subcortical vascular disease. PET neuroimaging excluded a significant amyloid load. Clinically, she showed improvement of the movement disorder and functional status after folate integration plus levodopa and memantine administration. We concluded for a primary degenerative dementia with movement impairment associated with persistent hyperhomocysteinemia. We hypothesized that neurodegeneration is driven by mechanisms linked to homocysteine metabolism possibly associated with tauopathy.

From beta amyloid to altered proteostasis in Alzheimer's disease.

Alzheimer's disease (AD) is an age related neurodegenerative disorder causing severe disability and important socio-economic burden, but with no cure available to date. To disentangle this puzzling disease genetic studies represented an important way for the comprehension of pathogenic mechanisms. Abnormal processing and accumulation of amyloid-ß peptide (Aß) has been considered the main cause and trigger factor of the disease. The amyloid cascade theory has fallen into crisis because the failure of several anti-amyloid drugs trials and because of the simple equation AD = abnormal Aß deposition is not always the case. We now know that multiple neurodegenerative diseases share common pathogenic mechanisms leading to accumulation of misfolded protein species. Genome Wide Association studies (GWAS) led to the identification of large numbers of DNA common variants (SNPs) distributed on different chromosomes and modulating the Alzheimer's risk. GWAS genes fall into several common pathways such as immune system and neuroinflammation, lipid metabolism, synaptic dysfunction and endocytosis, all of them addressing to novel routes for different pathogenic mechanisms. Other hints could be derived from epidemiological and experimental studies showing some lifestyles may have a major role in the pathogenesis of many age-associated diseases by modifying cell metabolism, proteostasis and microglia mediated neuroinflammation.

Correspondence Between Cognitive and Audiological Evaluations Among the Elderly: A Preliminary Report of an Audiological Screening Model of Subjects at Risk of Cognitive Decline With Slight to Moderate Hearing Loss.

Epidemiological studies show increasing prevalence rates of cognitive decline and hearing loss with age, particularly after the age of 65 years. These conditions are reported to be associated, although conclusive evidence of causality and implications is lacking. Nevertheless, audiological and cognitive assessment among elderly people is a key target for comprehensive and multidisciplinary evaluation of the subject's frailty status. To evaluate the use of tools for identifying older adults at risk of hearing loss and cognitive decline and to compare skills and abilities in terms of hearing and cognitive performances between older adults and young subjects, we performed a prospective cross-sectional study using supraliminal auditory tests. The relationship between cognitive assessment results and audiometric results was investigated, and reference ranges for different ages or stages of disease were determined. Patients older than 65 years with different degrees of hearing function were enrolled. Each subject underwent an extensive audiological assessment, including tonal and speech audiometry, Italian Matrix Sentence Test, and speech audiometry with logatomes in quiet. Cognitive function was screened and then verified by experienced clinicians using the Montreal Cognitive Assessment Score, the Geriatric Depression Scale, and further investigations in some. One hundred twenty-three subjects were finally enrolled during 2016-2019: 103 were >65 years of age and 20 were younger participants (as controls). Cognitive functions showed a correlation with the audiological results in post-lingual hearing-impaired patients, in particular in those affected by slight to moderate hearing loss and aged more than 70 years. Audiological testing can thus be useful in clinical assessment and identification of patients at risk of cognitive impairment. The study was limited by its sample size (CI 95%; CL 10%), strict dependence on language, and hearing threshold. Further investigations should be conducted to confirm the reported results and to verify similar screening models.

Aging, Cognitive Decline and Hearing Loss: Effects of Auditory Rehabilitation and Training with Hearing Aids and Cochlear Implants on Cognitive Function and Depression among Older Adults.

A growing interest in cognitive effects associated with speech and hearing processes is spreading throughout the scientific community essentially guided by evidence that central and peripheral hearing loss is associated with cognitive decline. For the present research, 125 participants older than 65 years of age (105 with hearing impairment and 20 with normal hearing) were enrolled, divided into 6 groups according to their degree of hearing loss and assessed to determine the effects of the treatment applied. Patients in our research program routinely undergo an extensive audiological and cognitive evaluation protocol providing results from the Digit Span test, Stroop color-word test, Montreal Cognitive Assessment and Geriatric Depression Scale, before and after rehabilitation. Data analysis was performed for a cross-sectional and longitudinal study of the outcomes for the different treatment groups. Each group demonstrated improvement after auditory rehabilitation or training on short- and long-term memory tasks, level of depression and cognitive status scores. Auditory rehabilitation by cochlear implants or hearing aids is effective also among older adults (median age of 74 years) with different degrees of hearing loss, and enables positive improvements in terms of social isolation, depression and cognitive performance.

Decreased VLDL-Apo B 100 Fractional Synthesis Rate Despite Hypertriglyceridemia in Subjects With Type 2 Diabetes and Nephropathy.

CONTEXT: Subjects with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) often exhibit hypertriglyceridemia. The mechanism(s) of such an increase are poorly known. OBJECTIVE: We investigated very low-density lipoprotein (VLDL)-Apo B 100 kinetics in T2DM subjects with and without DN, and in healthy controls. DESIGN: Stable isotope (13)C-leucine infusion and modeling analysis of tracer-to-tracee ratio dynamics in the protein product pool in the 6-8-h period following tracer infusion were employed. SETTING: Male subjects affected by T2DM, either with (n = 9) or without (n = 5) DN, and healthy male controls (n = 6), were studied under spontaneous glycemic levels in the post-absorptive state. RESULTS: In the T2DM patients with DN, plasma triglyceride (TG) (mean ± SD; 2.2 ± 0.8 mmol/L) and VLDL-Apo B 100 (17.4 ± 10.4 mg/dL) concentrations, and VLDL-Apo B 100 pool (0.56 ± 0.29 g), were ∼60-80% greater (P < .05 or less) than those of the T2DM subjects without DN (TG, 1.4 ± 0.5 mmol/L; VLDL-Apo B 100, 9.9 ± 2.5 mg/dL; VLDL-Apo B 100 pool, 0.36 ± 0.09 g), and ∼80-110% greater (P < .04 or less) than those of nondiabetic controls (TG, 1.2 ± 0.4 mmol/L; VLDL-Apo B 100, 8.2 ± 1.7 mg/dL; VLDL-Apo B 100, 0.32 ± 0.09 g). In sharp contrast however, in the subjects with T2DM and DN, VLDL-Apo B 100 fractional synthesis rate was ≥50% lower (4.8 ± 2.2 pools/d) than that of either the T2DM subjects without DN (9.9 ± 4.3 pools/d; P < .025) or the control subjects (12.5 ± 9.1 pools/d; P < .04). CONCLUSIONS: The hypertriglyceridemia of T2DM patients with DN is not due to hepatic VLDL-Apo B 100 overproduction, which is decreased, but it should be attributed to decreased apolipoprotein removal.

Effectiveness of switching to the rivastigmine transdermal patch from oral cholinesterase inhibitors: a naturalistic prospective study in Alzheimer's disease.

Oral donepezil and rivastigmine are two commonly used cholinesterase inhibitors (ChEIs) used in Alzheimer's disease (AD). The rivastigmine transdermal patch formulation has high tolerability profile, allowing patients to achieve optimal therapeutic doses and providing potential advantages over oral ChEIs. This is a 6-month, multicentre, observational efficacy and tolerability study of switching from oral ChEIs to rivastigmine patch in AD patients who failed to show benefit from previous treatment. The reasons of the switch were: (1) lack/loss of benefit from previous oral ChEI treatment; (2) tolerability problems. The primary outcome was cognitive changes measured with the mini-mental state examination (MMSE) test. Secondary outcomes were modifications of functional independence and behavioral disturbances and occurrence of adverse events (AEs) after switching. 174 patients, over 180 patients screened, entered the study (lack/loss of efficacy: 57 %, tolerability problems: 33 %, both reasons: 10 %). 6 months after switching 56 % of patients stabilized or increased the MMSE score respect to baseline. The only predictor of this outcome was the response at 3 months. In the group with lack/loss of response to oral ChEI, the decline of the MMSE score changed from -3.4 ± 2.5 points in the 6 months before switching to -0.5 ± 3.2 in the 6 months after the switch (p < 0.001). There were no significant changes in the IADL or NPI scores. Drug discontinuation rate was 20 %, due to AEs (18 %) and lack of compliance (2 %). Switching from an unsuccessful oral ChEI therapy to rivastigmine patch is effective and safe in more than half of the switched patients after a 6-month period.

Aging, cognitive load, dementia and hearing loss.

Sensorineural systems play a crucial role in the diagnosis, treatment and management of several neurological disorders. The function of the eye and ear represents a unique window for testing various conditions in cognitive decline or dementia. Touch and smell have also been found to be strongly involved in neurodegenerative conditions, and their decline has been significantly associated with the progression of the disease; hence, the idea that restoring sensory function in cognitively impaired adults might enable a significant improvement in their cognitive status, reducing the worldwide incidence and prevalence of dementia. Not all sensorineural 'windows' can benefit equally from the same procedures; however, hearing and vision can certainly gain the most from dependable therapeutic and other diagnostic options. The ear, including the vestibular system, deserves an honored place among the sensory organs in this context due mainly to the sophisticated electrical devices available that have amply demonstrated their effectiveness in treating hearing loss. Restoring an individual's hearing can reduce the cognitive 'load', i.e. the neural activity needed to understand/recognize the spoken word - an activity that becomes more demanding if the brain is obliged to recruit different neural populations to achieve the same performance, as happens in older adults with sensory impairments. The sensory interfaces may also facilitate the early diagnosis of conditions characterized by a lengthy preclinical phase, as well as enabling noninvasive, follow-up procedures to assess the outcome of rehabilitation measures and distinguish physiological brain aging from neurodegenerative disorders. The present study is a brief literature review on the issues and prospects relating to the unique relationship between hearing and cognitive decline, with a general introduction to the main topics before focusing on rehabilitation training with hearing aids and cochlear implants to combat cognitive decline.

Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia.

Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth through its binding to monomeric G-actin, have been recently identified in familial amyotrophic lateral sclerosis (ALS). Functional studies performed on ALS-associated PFN1 mutants demonstrated aggregation propensity, alterations in growth cone, and cytoskeletal dynamics. Previous screening of PFN1 gene in sporadic ALS (SALS) cases led to the identification of the p.E117G mutation, which is likely to represent a less pathogenic variant according to both frequency data in control subjects and cases, and functional experiments. To determine the effective contribution of PFN1 mutations in SALS, we analyzed a large cohort of 1168 Italian SALS patients and also included 203 frontotemporal dementia (FTD) cases because of the great overlap between these 2 neurodegenerative diseases. We detected the p.E117G variant in 1 SALS patient and the novel synonymous change p.G15G in another patient, but none in a panel of 1512 control subjects. Our results suggest that PFN1 mutations in sporadic ALS and in FTD are rare, at least in the Italian population.

Ubiquilin 2 mutations in Italian patients with amyotrophic lateral sclerosis and frontotemporal dementia.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving cortical and spinal motor neurones. Molecular studies have recently identified different mutations in the  ubiquilin-2 (UBQLN2) gene as causative of a familial form of X-linked ALS, 90% penetrant in women. The aim of our study was to analyse the UBQLN2 gene in a large cohort of patients with familial (FALS) and sporadic (SALS) amyotrophic lateral sclerosis, with or without frontotemporal dementia (FTD), and in patients with FTD. METHODS: We analysed the UBQLN2 gene in 819 SALS cases, 226 FALS cases, 53 ALS-FTD patients, and 63 patients with a clinical record of FTD. Molecular analysis of the entire coding sequence was carried out in all FALS and ALS-FTD patients, while SALS and FTD patients were analysed specifically for the genomic region coding for the PXX repeat tract. Healthy controls were 845 anonymous blood donors and were screened for the PXX repeat region only. RESULTS: We found five different variants in the UBQLN2 gene in five unrelated ALS patients. Three variants, including two novel ones, involved a proline residue in the PXX repeat region and were found in three FALS cases. The other two were novel variants, identified in one FALS and one SALS patient. None of these variants was present in controls, while one control carried a new heterozygous variant. CONCLUSIONS: Our data support the role of the UBQLN2 gene in the pathogenesis of FALS, being conversely a rare genetic cause in SALS even when complicated by FTD.

An APOE haplotype associated with decreased ε4 expression increases the risk of late onset Alzheimer's disease.

This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the ε4, one of the established genetic risk factor for Alzheimer's disease (AD), and its expression levels as determined by APOE promoter polymorphisms. Five polymorphisms (-491 rs449647, -427 rs769446, -219 rs405509, and ε rs429358-rs7412) were studied in 1308 AD patients and 1082 control individuals from the Central-Northern Italy. Major findings of the present study are the following: 1) the variants -219T and ε4 increase the risk for late onset AD (LOAD) when they are both present in cis on the same chromosome (in phase); 2) the correlation between the haplotype (-219T/ε4) and AD risk persists when the data are stratified by age; 3) this haplotype likely anticipates the age of onset of the disease. These data, while confirming the association between -219T and AD, highlight the importance of the phase of the alleles for the observed effects on AD risk, suggesting that this information has to be taken into account when assessing the AD genetic risk. Moreover, the data help to clarify the apparent discrepancy that emerges from the genetic analysis where an SNP characterizing the haplotype responsible for an increased risk for LOAD is coherently associated with a reduced expression of ApoE levels. Our data are compatible with the hypothesis of a complex role of ApoE in the AD pathogenesis, with positive and negative effects occurring concomitantly according to its expression levels and its protein-protein interactions largely unclarified.

Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease.

BACKGROUND: Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD. METHODOLOGY/PRINCIPAL FINDINGS: We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR=1.85, 95% CI:1.04-3.23) in particular for females (OR=2.19, 95% CI:1.06-4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p=0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p=0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls. CONCLUSIONS: Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD.

Effects of donepezil, galantamine and rivastigmine in 938 Italian patients with Alzheimer's disease: a prospective, observational study.

Acetylcholinesterase inhibitors (AChEIs) have been used to improve cognitive status and disability in patients with mild to moderate Alzheimer's disease (AD). However, while the efficacy of AChEIs (i.e. how they act in randomized controlled trials) in this setting is widely accepted, their effectiveness (i.e. how they behave in the real world) remains controversial. To compare the effects of three AChEIs, donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon), in an Italian national, prospective, observational study representative of the 'real world' clinical practice of AChEI treatment for AD. 938 patients with mild to moderate AD collected within the framework of the Italian National Cronos Project (CP), involving several UVAs (AD Evaluation Units) spread over the entire national territory, who were receiving donepezil, galantamine or rivastigmine were followed for 36 weeks by measuring: (i) function, as determined by the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales; (ii) cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [primary outcome measures]; and (iii) behaviour, as measured on the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) scale. Moreover, all patients were genotyped for apolipoprotein E (apoE) genetic variants. No statistically significant improvement in the primary outcome measures (MMSE and ADAS-Cog) was observed with drug therapy at 36 weeks, at which point all groups had lost, on average, 1 point on the MMSE and gained 2-3 points on the ADAS-Cog scale compared with baseline. On the secondary outcome measures at week 36, all treatment groups showed a significant worsening on the ADL and IADL scales compared with baseline, while on the NPI scale there were no significant differences from baseline except for the galantamine-treated group which worsened significantly. Moreover, patients receiving galantamine worsened significantly compared with the donepezil-treated group on the IADL scale. ApoE epsilon4 allele did not influence the effect of drug therapy. Over a 36-week follow-up period, no significant difference in the effects of donepezil, galantamine and rivastigmine on a variety of functional and cognitive parameters was observed in a large number of apoE-genotyped patients with mild to moderate AD recruited within the framework of a national project representative of the scenario usually encountered in actual clinical practice in Italy. The limitations (possibility of administration of lower drug doses than are used in clinical trials, relatively short follow-up period and the lack of randomization) and strengths (large number of patients, concomitant observation of the three drugs and the number of parameters assessed, including apoE genotype) of the present study are acknowledged. Our type of naturalistic study should complement clinical trials because 'real world' practice operates in the face of the numerous variables (e.g. health status and co-morbidities) associated with a complex disease such as AD in elderly people.

The added value of neuropsychologic tests and structural imaging for the etiologic diagnosis of dementia in italian expert centers.

Aim of the study was to assess the added diagnostic value of neuropsychologic tests and structural neuroimaging (computed tomography or magnetic resonance) in the routine clinical assessment of demented patients in Italian expert centers. Nine centers were involved, located across the whole country (3 in Northern, 3 in Central, and 3 in Southern Italy). Diagnostic pathways were tracked for 474 patients with an expert diagnosis of neurodegenerative or vascular dementia (age 76+/-8; 62% females; Mini-Mental State Examination 17.70+/-5.7). The contribution of neuropsychology and structural neuroimaging to diagnosis was estimated as "number needed to test" (NNT), denoting the number of patients who need to undergo such procedures to improve expert diagnosis of 1 unit. Expert physicians reached their diagnosis without resorting to structural imaging examinations and neuropsychologic tests in 93% of Alzheimer disease (AD) and 76% of non-AD dementias. The completion of the extended assessment led to improvement of diagnostic accuracy in both cases: the NNT was 15.3 (95% confidence interval: 10.4-29.1) and 4.1 (3.0 to 6.5) for AD and non-AD diagnoses. The added value of structural imaging and neuropsychologic testing in the routine clinical assessment of demented patients is substantial in both AD and non-AD cases.

Mutations in MTP gene in abeta- and hypobeta-lipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are inherited disorders of apolipoprotein B (apo B)-containing lipoproteins that result from mutations in apo B and microsomal triglyceride transfer protein (MTP) genes, respectively. Here we report three patients with severe deficiency of plasma low-density lipoprotein (LDL) and apo B. Two of them (probands F.A. and P.E.) had clinical and biochemical phenotype consistent with ABL. Proband F.A. was homozygous for a minute deletion/insertion (c.1228delCCCinsT) in exon 9 of MTP gene predicted to cause a truncated MTP protein of 412 amino acids. Proband P. E. was heterozygous for a mutation in intron 9 (IVS9-1G>A), previously reported in an ABL patient. We failed to find the second pathogenic mutation in MTP gene of this patient. No mutations were found in apo B gene. The third proband (D.F.) had a less severe lipoprotein phenotype which was similar to that of heterozygous FHBL and appeared to be inherited as a co-dominant trait. However, he had no mutations in apo B gene. He was found to be a compound heterozygote for two missense mutations (D384A and G661A), involving highly conserved regions of MTP. Since this proband was also homozygous for varepsilon2 allele of apolipoprotein E (apo E), it is likely that his hypobetalipoproteinemia derives from a combined effect of a mild MTP deficiency and homozygosity for apo E2 isoform.

Glycerol metabolism and the determination of triglycerides--clinical, biochemical and molecular findings in six subjects.

Recent recommendations in the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATPIII) are expected to increase the number of triglyceride (TG) determinations and consequently the risk of misinterpretation of "non-blanked" results with co-determination of free glycerol. Glycerol-kinase deficiency (GKD) is one cause of falsely elevated TG results. The natural history of isolated GKD with symptom-free cases and cases with e.g. severe episodes of hypoglycemia and/or ketoacidosis challenges the laboratories to identify cases of GKD and family members at risk. "Blanked" methods reporting both glycerol and TG concentration are therefore desirable. Molecular studies of the glycerol kinase (GK) and DAX1 genes were performed on four cases of "persistent hypertriglyceridemia" found in an Italian population and on two pediatric cases with high serum glycerol concentration. Two new missense mutations were found (C358Y, T961). Molecular modeling on GK from E. coli, indicate that these mutations are located in parts of the enzyme important for enzyme formation or activity. One splice-site mutation, (IVS9A-1G>A), was found in two brothers. Splice-junction analysis indicates that it destroys the splice site and results in a mixture of mRNA. Deletion of the GK and DAX1 genes was found in one child with symptoms of adrenal failure. A female with glycerolemia and glyceroluria had normal GK activity but possibly slightly decreased ability to oxidize glycerol.