Normal Middle-aged Individuals Research Articles

The mitochondrial hypothesis: Dysfunction, bioenergetic defects, and the metabolic link to Alzheimer's disease.

Alzheimer's disease (AD) features mitochondrial dysfunction and altered metabolism. Other pathologies could drive these changes, or alternatively these changes could drive other pathologies. In considering this question, it is worth noting that perturbed AD patient mitochondrial and metabolism dysfunction extend beyond the brain and to some extent define a systemic phenotype. It is difficult to attribute this systemic phenotype to brain beta-amyloid or tau proteins. Conversely, mitochondria increasingly appear to play a critical role in cell proteostasis, which suggests that mitochondrial dysfunction may promote protein aggregation. Mitochondrial and metabolism-related characteristics also define AD endophenotypes in cognitively normal middle-aged individuals, which suggests that mitochondrial and metabolism-related AD characteristics precede clinical decline. Genetic analyses increasingly implicate mitochondria and metabolism-relevant genes in AD risk. Collectively these factors suggest that mitochondria are more relevant to the causes of AD than its consequences, and support the view that a mitochondrial cascade features prominently in AD. This chapter reviews the case for mitochondrial and metabolism dysfunction in AD and the challenges of proving that a primary mitochondrial cascade is pertinent to the disease.

REGION-SPECIFIC ATROPHY AS MEASURED BY CORTICAL GRAY MATTER VOLUME IS ASSOCIATED WITH BOTH REGIONAL AND TOTAL CORTICAL AMYLOID-BETA BURDEN IN COGNITIVELY NORMAL INDIVIDUALS AT RISK FOR ALZHEIMER'S DISEASE

Introduction Models of preclinical Alzheimer's disease (AD) have proposed that cerebral amyloidosis and subsequent neurodegeneration may occur years, if not decades prior to observable cognitive decline. We previously demonstrated that total cortical amyloid-beta burden was inversely associated with cortical gray matter volume but not episodic memory in a sample of cognitively normal, middle-aged participants, with a first-degree family history and varying genetic risks of AD (Mecca et al., 2018). The current study utilizes an exploratory approach to determine the regional contribution of cortical amyloid deposition to gray matter volume and neuropsychological test performance in pre-symptomatic individuals at varying genetic risk for AD. Methods As described previously (Mecca et al., 2018), cognitively normal participants aged 50-66 with a first-degree family history for AD were genetically screened to select three groups: APOE genotype e4e4 (n=15), e3e4 (n=15), and e3e3 (n=15), matched for age and sex. Participants were then studied with [11C]PiB PET, MRI, and neuropsychological testing. PET and MR images were co-registered for application of a ROI template (AAL for SPM2) to generate regional time-activity curves with cerebellum as the reference region. MRI images were segmented into gray matter, white matter, and CSF. Mask images of these segments were smoothed to the system resolution (∼6mm), and gray matter values of BPND were partial volume corrected (PVC). PVC-BPND was then computed using SRTM2 for frontal, posterior cingulate, precuneus, lateral parietal, lateral temporal, medial temporal, occipital, and basal ganglia ROIs. A cortical BPND (cortical amyloid) was also calculated by taking a weighted average of only the frontal, posterior cingulate, precuneus, lateral parietal, and lateral temporal regions. To quantify GM within each ROI, we applied inverse transformations of the AAL from MNI to subject space and calculated GM fraction as the number of voxels segmenting a GM divided by the total number of voxels in a region. Results The study sample consisted of 24 females and 21 males with an average age of 59.12 (SD 4.72) and 16.33 (SD 1.86) years of education. Participants demonstrated an average MMSE score of 29.66 (SD 0.91), GDS score of 0.71 (SD 1.25), WAIS-III FSIQ score of 115.04 (SD 13.32), and WRAT-3 Reading score of 109.47 (SD 9.64). As previously reported, mean cortical BPND was 0.145 ± 0.131 for APOE-e3e3, 0.297 ± 0.299 for APOE-e3e4, and 0.389 ± 0.222 for APOE-e4e4 participants. An exploratory analysis was performed to examine the regional contributions to the association between cortical amyloid burden and gray matter volume. There were significant inverse associations between gray matter fraction and cortical amyloid in the frontal (spearman r=-0.459, p=0.002), lateral temporal (spearman r=-0.546, p Conclusions Based on our regional exploratory analyses, the inverse association between cortical amyloid burden and gray matter volume is strongest in the frontal, lateral, and medial temporal lobes. This is consistent with models of preclinical AD in which neurodegeneration occurs early in the disease process and before manifest cognitive decline. Interestingly, although the occipital lobeis traditionally thought to be a region of low amyloid deposition, we find the regional gray matter volume is significantly correlated with both regional and cortical amyloid. This perhaps implicates the occipital lobe as part of the cortical signature of AD, at least in cognitively normal middle-aged individuals with an increased risk of developing AD. It is also noted that medial temporal lobe atrophy isn't associated with regional amyloid, but instead significantly correlated with total cortical amyloid deposition. This is expected given the medial temporal lobe's reputation as a known area of early atrophy but not amyloid deposition in AD. This research was funded by This research was supported by the Alzheimer's Association IIRG-07-60026 (CHvD) and National Institute on Aging (P50-AG047270). APM was supported in part by the NIH/NIA K23-AG057794. RSO was supported in part by the NIMH R25 IMPORT grant (#R25MH071584).

Gender Differences in Normal Swallow

requires precise coordination between 34 pairs of muscles in just over one second. The rapid sequential and overlapping motions characterizing adult human swallowing behavior were better appreciated with the introduction of radiography, and especially video radiography. There are data suggesting that women swallow liquids at a lower flow rate and ingest smaller volumes in each swallow than men. Aim of the work: To assess the physiological difference between males and females in oropharyngeal and esophageal phases of swallowing in normal middle-aged individuals. Patients and Methods: Cross sectional study, included 30 healthy volunteers (15 males & 15 females) with normal swallowing, whose age ranged from 18-45 yrs. This study was conducted in SohagUniversityHospital, Phoniatric Unit. All volunteers were subjected to Video-Fluroscopic Swallowing Study (VFSS) in sitting position. Oral transit time (OTT), Pharyngeal transient time (PTT), Oropharyngeal transient time, Esophageal transit time (ETT), Total swallow time (TST) were measured. Also, hyoid peak was calculated. Results: There were nosignificant difference between males and females swallowing in both fluid and solid boluses. Conclusion: This study provided insights into normal swallowing physiology and defines measurement alternatives for evaluation of the dysphagic patients

Redox Modulating Factors Affect Longevity Regulation in Rotifers

Rotifers are microinvertebrate models to study the phylogenetically based mechanisms of aging. Our study aimed to develop a physiological system with electron deprivation via a chemical electron carrier/acceptor pair together with extreme caloric restriction (ECR). Middle-aged Philodina acuticornis rotifers were treated with combinations of phenazine methosulfate (PMS, electron carrier) and 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt (XTT, electron acceptor) for a period of 72 hours under total food deprivation (preselection). The ability of XTT to be reduced was confirmed both in vitro (with NADH) and in vivo (with live rotifers). Subsequently, the respective electron acceptor alone at a lower dose was administered in combination with ECR for several months on preselected survivors. We found that the longevity of rotifers markedly increased (4×) after PMS/XTT/total food deprivation preselection followed by XTT/ECR treatment. Ascorbic acid in equivalent concentrations caused similar but less pronounced tendencies. The synergistic effect of chemical electron deprivation and ECR caused delayed aging and the development of an outstanding phenotype that we refer to as "super rotifers," characterized by increased longevity and retained reproductive ability compared with normal middle-aged individuals. The presented model provides new insights into the connection between redox modulation and age-related features in vivo.

Regional vulnerability to lipoxidative damage and inflammation in normal human brain aging.

Oxidative damage and inflammation coexist in healthy human brain aging. The present study analyzes levels of protein adduction by lipid peroxidation (LP) end-products neuroketal (NKT) and malondialdehyde (MDA), as markers of protein oxidative damage, cycloxygenase-2 (COX-2) levels, as a marker of inflammation, and cytochrome P450 2J2 (CYP2J2), responsible of generation of neuroprotective products, in twelve brain regions in normal middle-aged individuals (MA) and old-aged (OA) individuals. In addition, levels of these markers were evaluated as a function of age as a continuous variable and correction for multiple comparisons. Selection of regions was based on their different vulnerability to prevalent neurodegenerative diseases in aging. Our findings show region-dependent LP end-products, COX-2 and CYP2J2 changes in the aging human brain. However, no clear relationship can be established between NKT, MDA, COX-2 and CYP2J2 levels, and regional vulnerability to neurodegeneration in old age.

Cortical β-amyloid burden, gray matter, and memory in adults at varying APOE ε4 risk for Alzheimer's disease

Models of preclinical Alzheimer's disease (AD) propose that cerebral amyloidosis leads to neurodegeneration and subsequent cognitive decline. This study investigated whether APOE genotype is related to β-amyloid (Aβ) burden in brain regions preferentially affected by AD and whether Aβ burden is associated with gray-matter (GM) fraction (as a marker of neurodegeneration) and episodic memory performance in cognitively normal middle-aged individuals at varying genetic risk for AD. Three groups of cognitively normal participants aged 50–65 years with a first-degree family history of AD (APOE genotype ε4ε4 [n = 15], ε3ε4 [n = 15], and ε3ε3 [n = 15]) underwent [11C]PiB positron emission tomography scans to quantify cortical Aβ, brain magnetic resonance imaging, and neuropsychological testing. APOE ε4ε4 participants demonstrated significantly higher cortical Aβ burden than APOE ε3ε3 (p < 0.001). Furthermore, cortical Aβ burden was inversely associated with cortical GM fraction (p = 0.017) but not episodic memory performance. In cognitively normal, middle-aged individuals, Aβ burden is significantly associated with GM fraction but not episodic memory performance. These findings are consistent with models of preclinical AD in which neurodegeneration occurs before manifest cognitive decline.

Putative Tests of Frontal Lobe Function: A PET-Study of Brain Activation During Stroop's Test and Verbal Fluency

Stroop's test and the Verbal Fluency test are commonly argued to be measures of the integrity of the prefrontal cortex. This assumption has only to some degree been confirmed by lesion studies. In the present study, Positron Emission Tomography (PET) with H 2 15 O was used to further validate Stroop's test and the Verbal Fluency as measures of frontal lobe function; both tests were implemented as activation paradigms during scanning of normal middleaged individuals. Stroop interference was found to activate the left anterior cingulate cortex, the supplementary motor cortex, thalamus, and the cerebellum. Although the prominent anterior cingulate activation is in the frontal lobe, it is not prefrontal. Verbal Fluency activated the left inferior frontal cortex and the left dorsolateral prefrontal cortex, the supplementary motor cortex, the anterior cingulate cortex and the cerebellum. These results bring this latter test closer to being a specific test of prefrontal function.

Studies on the Spatial Ventricular Gradient in Essential Hypertension

Spatial ventricular gradients in essential hyper-tension were investigated by means of three com-ponent leads of the Frank system, with the purpose of clarifying changes characteristic of the left ventricular overloading. Three component leads (X, Y and Z leads) of the Frank system were recorded simultaneously with a paper speed of 100mm per second for 100 cases of essential hypertension. Based on these records, spatial ventricular gradients and their analytical values were calculated by means of a digital computer, OKITAC 5090-H type. Kyushu University Computation Center. The methods of measurement of the spatial ventricular gradients and the items of analysis were the same as the previous reports. Hypertensive subjects were classified into four groups by mean blood pressures (Table I): Group A (110 mmHg, 31 cases), Group B (110-119 mmHg, 29 cases), Group C (120-139 mmHg, 21 cases), and Group D (140 mmHg, 19 cases). Spatial ventricular gradients (SA^^^VG) and their analytical values are shown in Tables IIIV. Spatial ventricular gradients and their analytical values in the above-mentioned four groups are given in Table V. Statistical comparisons of the observed and analytical values of the ventricular gradients among the young and middle-aged indi-viduals with normo-and hypertension are given in Table VI. Changes in the spatial ventricular gradients characteristic of the left ventricular overloading were decrease in the spatial magnitude and increase in azimuth and elevation, which tended to appear in the above order with an advance of the left ventricular overloading. These changes of SA^^^VG were resulted from decreases in magnitude of X as well as Y components in the same degrees without accompanying any significant change of Z component. The characteristic changes of the spatial ventricular gradients projected on the three perpendicular planes were decrease in right sagittal angle. Spatial QRS area vectors (SA^^^QRS) and spatial T area vectors (SA^^^T) which constitute the spatial ventricular gradients were also investigated concerning the spatial magnitude, azimuth, elevation, magnitudes and directions projected on the three perpendicular planes, and X, Y and Z components of these vectors. The spatial magnitude and elevation of SA^^^QRS increased, and azimuth angle decreased in the left ventricular overloading. As for the X, Y, and Z components of SA^^^QRS, increase in magnitude of X component and decrease in magnitude of Z-component were as certained, but there was no significant change in Y component. As for SA^^^T, the spatial magnitude decreased, and azimuth and elevation increased in the state of left ventricular overload-ing. X and Y components of SA^^^T decreased, but the anterior elements of Z components increased. SA^^^QRS-SA^^^T angles (dA), SA^^^QRS-SA^^^VG angles (dB), and SA^^^VG-SA^^^T angles (dC) enlarged with an advance of the left ventricular overloading. The ratio of dA, dB, and dC were 1 : 0.52 : 0.48 in hypertensive subjects, indicating relatively narrow dB and wide dC as compared to the ratio (1 : 0.7 : 0.3) in normal middle-aged individuals. The enlargement of dC angle was observed even in hypertension of slight degree (Group A). Accordingly, enlargement of this angle may be taken into account as an early sign of the left ventricular overloading. The progress of the left ventricular overloading resulted in increase in magnitude of dB angle, because the displacement of SA^^^VG-H were developed forward to the opposite direction against the displacement of SA^^^QRS-H, which were usually moved backward for the hypertension. However, dC angle has not significantly changed, because the displacement of SA^^^VG-V and SA^^^T-V developed in the same directions. SA^^^VG-Mag/SA^^^QRS-Mag ratio and SA^^^T-Mag/ SA^^^QRS-Mag ratio decreased in the left ventricular overloading because of the diminutions in SA^^^VG-Mag and SA^^^T-Mag and the increases in SA^^^QRS-Mag. [the rest omitted]