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PubMed1999

Evidence for cortical dysfunction in clinically non-demented patients with Parkinson's disease: a proton MR spectroscopy study.

OBJECTIVES: To investigate whether proton magnetic resonance spectroscopy (1H MRS) can detect cortical dysfunction in non-demented patients with Parkinson's disease, and to correlate changes with cognitive function on formal neuropsychological testing. METHODS: Multivoxel 1H MRS was performed in 17 patients with levodopa treated idiopathic Parkinson's disease with out clinical dementia, and 10 age match ed control subjects. Measurements of N-acetylaspartate (NAA)/choline (Cho), NAA/creatine+phosphocreatine (Cr), and Cho/Cr were obtained from right and left temporoparietal cortex and occipital cortex. Fourteen patients with Parkinson's disease underwent a full battery of neuropsychological testing including performance and verbal subtests of the WAIS-R, Boston naming test, FAS test, and California verbal learning test. RESULTS: There were significant temporoparietal cortex reductions in NAA/Cr ratios in right and left averaged spectra of the patients with Parkinson's disease (p=0.012 after Bonferroni correction) and in spectra contralateral to the worst clinically affected limbs of the patients with Parkinson's disease compared with controls (p = 0.003 after Bonferroni correction). There was a significant correlation between reduction in NAA/Cr ratios and measures of global cognitive decline, occurring independently of motor impairment (p=0.019). CONCLUSIONS: This study suggests that 1H MRS can detect temporoparietal cortical dysfunction in non-demented patients with Parkinson's disease. Further longitudinal studies are needed to investigate whether these 1H MRS changes are predictive of future cognitive impairment in the subset of patients with Parkinson's disease who go on to develop dementia, or occur as part of the normal Parkinson's disease process.

Aged↗
PubMed1999

Brain correlates of memory dysfunction in alcoholic Korsakoff's syndrome.

OBJECTIVES: To investigate the relation between anterograde amnesia and atrophy of brain structures involved in memory processing in alcoholic Korsakoff's syndrome. METHODS: The volume of brain structures involved in memory processing was measured with MRI from 13 subjects with Korsakoff's syndrome, 13 subjects with chronic alcoholism without Korsakoff's syndrome, and 13 control subjects. The brain structures analysed were the hippocampus, the parahippocampal gyrus, the mamillary bodies, the third ventricle, and the thalamus. Brain volumes were correlated with the delayed recall of a verbal learning test. RESULTS: Compared with subjects with chronic alcoholism and control subjects, subjects with Korsakoff's syndrome had a reduced volume of the hippocampus, the mamillary bodies, and the thalamus, and enlargement of the third ventricle. The impairment of delayed recall correlated with the volume of the third ventricle (r=-0.55, p=0.05) in the Korsakoff group. CONCLUSIONS: Anterograde amnesia in alcoholic Korsakoff's syndrome is associated with atrophy of the nuclei in the midline of the thalamus, but not with atrophy of the mamillary bodies, the hippocampus, or the parahippocampal gyrus.

Alcoholism↗
PubMed2002

Medial temporal lobe atrophy predicts Alzheimer's disease in patients with minor cognitive impairment.

OBJECTIVES: To investigate whether medial temporal lobe atrophy predicted outcome in patients with minor cognitive impairment and whether assessment of the medial temporal lobe could increase the predictive accuracy of age and delayed recall for outcome. Quantitative and qualitative methods of assessing the medial temporal lobe were also compared. METHODS: Patients with minor cognitive impairment older than 50 years (n=31) were selected from a memory clinic and were followed up for on average 1.9 years. The medial temporal lobe was assessed in three different ways: volumetry of the hippocampus, volumetry of the parahippocampal gyrus, and qualitative rating of medial temporal lobe atrophy (MTA). Outcome measures were Alzheimer type dementia or cognitive decline at follow up. Delayed recall was tested with a verbal learning test. RESULTS: Ten patients had experienced cognitive decline at follow up, of whom seven had probable Alzheimer type dementia. All medial temporal lobe measurements were associated with cognitive decline at follow up (p trend analysis between 0.001 (hippocampus) and 0.05 (parahippocampal gyrus)). Only the hippocampal volume and MTA score were associated with Alzheimer type dementia at follow up (p trend analysis respectively 0.003 and 0.01). All medial temporal lobe measurements increased the predictive accuracy of age and the delayed recall score for cognitive decline (p increase in predictive accuracy varied between <0.001 (hippocampus) and 0.02 (parahippocampal gyrus and MTA score)) and the hippocampal volume and the MTA score increased the predictive accuracy of age and the delayed recall score for Alzheimer type dementia (p= 0.02). CONCLUSIONS: The ability to detect patients at high risk for Alzheimer type dementia among those with minor cognitive impairment increases when data on age and memory function are combined with measures of medial temporal lobe atrophy. Volumetry of the hippocampus is preferred, but qualitative rating of medial temporal lobe atrophy is a good alternative.

Aged↗
PubMed2006

Dose-effect relationships between manganese exposure and neurological, neuropsychological and pulmonary function in confined space bridge welders.

BACKGROUND: Although adverse neuropsychological and neurological health effects are well known among workers with high manganese (Mn) exposures in mining, ore-processing and ferroalloy production, the risks among welders with lower exposures are less well understood. METHODS: Confined space welding in construction of a new span of the San Francisco-Oakland Bay Bridge without adequate protection was studied using a multidisciplinary method to identify the dose-effect relationship between adverse health effects and Mn in air or whole blood. Bridge welders (n = 43) with little or no personal protection equipment and exposed to a welding fume containing Mn, were administered neurological, neuropsychological, neurophysiological and pulmonary tests. Outcome variables were analysed in relation to whole blood Mn (MnB) and a Cumulative Exposure Index (CEI) based on Mn-air, duration and type of welding. Welders performed a mean of 16.5 months of welding on the bridge, were on average 43.8 years of age and had on average 12.6 years of education. RESULTS: The mean time weighted average of Mn-air ranged from 0.11-0.46 mg/m(3) (55% >0.20 mg/m(3)). MnB >10 microg/l was found in 43% of the workers, but the concentrations of Mn in urine, lead in blood and copper and iron in plasma were normal. Forced expiratory volume at 1s: forced vital capacity ratios (FEV(1)/FVC) were found to be abnormal in 33.3% of the welders after about 1.5 years of welding at the bridge. Mean scores of bradykinesia and Unified Parkinson Disease Rating Scale exceeded 4 and 6, respectively. Computer assisted tremor analysis system hand tremor and body sway tests, and University of Pennsylvania Smell Identification Test showed impairment in 38.5/61.5, 51.4 and 88% of the welders, respectively. Significant inverse dose-effect relationships with CEI and/or MnB were found for IQ (p<or=0.05), executive function (p<or=0.03), sustaining concentration and sequencing (p<or=0.04), verbal learning (p<or=0.01), working (p<or=0.04) and immediate memory (p<or=0.02), even when adjusted for demographics and years of welding before Bay Bridge. Symptoms reported by the welders while working were: tremors (41.9%); numbness (60.5%); excessive fatigue (65.1%); sleep disturbance (79.1%); sexual dysfunction (58.1%); toxic hallucinations (18.6%); depression (53.5%); and anxiety (39.5%). Dose-effect associations between CEI and sexual function (p<0.05), fatigue (p<0.05), depression (p<0.01) and headache (p<0.05) were statistically significant. CONCLUSIONS: Confined space welding was shown to be associated with neurological, neuropsychological and pulmonary adverse health effects. A careful enquiry of occupational histories is recommended for all welders presenting with neurological or pulmonary complaints, and a more stringent prevention strategy should be considered for Mn exposure due to inhalation of welding fume.

Adult↗
PubMed2005

Posterior cortical atrophy: clinical presentation and cognitive deficits compared to Alzheimer's disease.

BACKGROUND: Posterior cortical atrophy (PCA) is an uncommon dementia syndrome with initial manifestations of visual dysfunction and preservation of memory and language until late in the disease. Since prognosis and management differ from typical Alzheimer's disease (tAD), clinical tests to distinguish PCA from tAD are needed. METHODS: Fifteen PCA cases and 15 tAD cases, defined by clinical and MRI criteria, were compared by present symptoms and scores on four cognitive tests. RESULTS: Symptoms of visual disturbance and dyslexia were more commonly reported in PCA cases (p = 0.0001 and p = 0.006, respectively), and memory loss was more commonly reported in tAD (p = 0.006). Patients with PCA were less accurate on the Cortical Vision Screening Test (t = 6.0; p < 0.001) and in copying the Rey-Osterreith Complex Figure (t = 6.0; p < 0.001), in comparison to the tAD group. Memory, evaluated by the Rey Auditory Verbal Learning Test, was impaired in both groups; however, delayed recall was more impaired in the tAD group (t = 2.5; p = 0.03). CONCLUSION: Compared to patients with tAD, patients with PCA are more likely to present to their providers with symptoms of visual dysfunction. Performance on simple tests of visual perception and copying can be used to distinguish the two disorders even a few years after initial symptoms.

Age of Onset↗
PubMed2004

[18F]FDG-PET in patients with Alzheimer's disease: marker of disease spread.

BACKGROUND: It is not known yet whether temporoparietal glucose hypometabolism in patients with probable Alzheimer's disease (AD) reflects disease severity or different subtypes of patients. METHODS: Twenty-five subjects with mild probable AD [NINCDS-ADRDA criteria; age 65.8 +/- 9.3 years (mean +/- SD); Mini-Mental State Examination (MMSE) 26.0 +/- 3.3] were investigated. [(18)F]FDG-PET data were analyzed visually with raters blinded to the diagnosis and with a quantitative analysis in the region of interest on individual anatomically normalized PET scans. RESULTS: Thirteen of 25 patients showed temporoparietal hypometabolism on visual inspection (PET+; age 65.7 +/- 10.7), 12 patients had normal FDG-PET results (PET-; age 65.9 +/- 8.0; n.s.). The MMSE and immediate reproduction of the Wechsler Memory Scale (WMS-R-I) were 27.7 +/- 1.9 and 31.1 +/- 6.1 in the PET- vs. 24.5 +/- 3.6 (p = 0.012) and 22.0 +/- 7.4 (p = 0.006) in the PET+ group. Immediate and delayed recall in the California Verbal Learning Test and delayed reproduction in the Wechsler Memory Scale were alike. Regression analysis revealed a significant correlation of temporoparietal glucose metabolism with the block span (r = 0.60; p < 0.01) and the WMS-R-I (r = 0.68; p < 0.01) but not with measures of hippocampal function. CONCLUSIONS: Temporoparietal glucose metabolism in patients with very mild AD is a sign of disease spread beyond the temporal lobe. This may aid in establishing objective parameters for future therapeutic studies.

Aged↗
PubMed2006

Differential CSF biomarker levels in APOE-epsilon4-positive and -negative patients with memory impairment.

OBJECTIVES: To investigate the relationships between episodic memory, APOE genotype, CSF markers (total tau, T-tau; phospho-tau, P-tau; beta-amyloid, Abeta42) and longitudinal cognitive decline. METHODS: 124 memory clinic patients were retrospectively divided into 6 groups based on (i) episodic memory function (Rey Auditory Verbal Learning Test, RAVLT): severe, moderate or no impairment (SIM, MIM or NIM), and (ii) APOE genotype (epsilon4+ or epsilon4-). CSF marker levels and cognitive decline were compared across groups. RESULTS: Episodic memory function, according to RAVLT scores, was significantly correlated with CSF marker levels only among epsilon4+ subjects and not among epsilon4- subjects. When comparing the 6 subgroups, SIM epsilon4+ and MIM epsilon4+ groups showed significantly lower Abeta42 levels than the other groups. T-tau and P-tau levels were significantly increased in SIM epsilon4+ when compared to all the other groups, including the SIM epsilon4- group. However, both SIM epsilon4+ and SIM epsilon4- declined cognitively during the follow-up. CONCLUSION: It remains to be determined whether APOE genotype affects the expression of biomarkers in CSF, or whether the different biomarker patterns reflect different types of disease processes in patients with progressive cognitive dysfunction.

Amyloid beta-Protein Precursor↗
PubMedDate not supplied

Amygdala-hippocampal atrophy and memory performance in dementia of Alzheimer type.

The aim of the present study was to examine the involvement of brain structures, especially the amygdala-hippocampal complex, in dementia of Alzheimer type (DAT), and to assess the relation of amygdala-hippocampal atrophy with memory dysfunction. 14 patients with DAT and 10 healthy age-matched controls were examined with different neuropsychologic tests including the UCLA-Auditory Verbal Learning Test. MRI was performed with a conventional 1.5-tesla scanner. Atrophy was found in many brain structures of demented subjects in comparison with healthy age-matched controls. The volumes of amygdala-hippocampal complexes and of the temporal lobes of demented subjects were more reduced than the total brain volume and other structures. Memory dysfunction was highly correlated with atrophy of the amygdala-hippocampal complexes and of the temporal lobes. Consequently, DAT seems to affect the amygdala-hippocampal complex and their related function (i.e. memory) more than other cerebral structures, but cerebral degeneration in DAT is not restricted to these structures.

Aged↗
PubMedDate not supplied

Absence of nimodipine premedication effect on memory after electroconvulsive therapy.

While highly efficacious for affective disorders, electroconvulsive therapy (ECT) is sometimes accompanied by troublesome although temporary cognitive dysfunction. We speculated that the efficacy of ECT can be separated from its cognitive dysfunction by administration of nimodipine, a calcium channel blocker that crosses the blood-brain barrier and has prevented electroshock-induced amnesia in animal studies. However, in our single-blind repeated-measures trial on 8 patients, nimodipine 30-60 mg orally 2 h prior to ECT was indistinguishable from placebo in effects on verbal learning and retrograde and anterograde memory during the 2 h after ECT.

Adult↗
PubMed1999

Neuropsychological change and S-100 protein release in 130 unselected patients undergoing cardiac surgery.

BACKGROUND AND PURPOSE: S-100 protein promises to be a valuable surrogate end point for cerebral injury. This is of particular interest within the context of cardiac surgery. We sought to explore the relationship between change in neurospychological performance attributable to cardiopulmonary bypass and the release of brain-specific S-100 protein. METHODS: In an observational comparative study in a University Hospital Cardiac Surgical Unit, S-100 protein release during and 5 hours after the onset of cardiopulmonary bypass was compared with change (from preoperative to 6 to 8 weeks postoperative) in neuropsychological tests in 130 patients undergoing the full range of cardiac surgical procedures. RESULTS: Neuropsychological performance usually improved, being significantly so in 10 of 25 parameters. S-100 area under the curve (AUC) protein release correlated with age (r=0.24, P<0.008) and bypass time (r=0.17, P<0.02). S-100 Cmax correlated with bypass times (r=0.29, P<0.0001). Bypass times correlated with memory performance (Rey R5; r=-0.21, P<0.03). Less S-100 protein release was associated with better neuropsychological performance, as indexed by significant correlations with the Rey Auditory Verbal Learning memory test, descending Critical Flicker Fusion thresholds, and the Hospital Anxiety and Depression rating scales, typically around r=0.2. Multiple regression models showed that neuropsychological tests accounted for 23% of the variance associated with S-100 AUC release, after partialing out the effects of age and bypass time. CONCLUSIONS: The correlation between S-100 protein release and neuropsychological function supports the belief that it is a measure of brain injury, which may be useful in future studies of mechanisms and prevention.

Affect↗
PubMed2000

Stroke and apolipoprotein E epsilon4 are independent risk factors for cognitive decline: A population-based study.

BACKGROUND AND PURPOSE: Stroke and apolipoprotein E epsilon4 (ApoE epsilon4) are individually important risk factors for cognitive decline, including Alzheimer disease. It has been suggested that ApoE epsilon4 multiplies the risk for cognitive decline following stroke. In a population-based sample, using well-defined sensitive cognitive measures, this study investigates whether cognitive decline following stroke is worse for patients who carry the ApoE epsilon4 allele. METHODS: Subjects were participants in the Longitudinal Aging Study Amsterdam (LASA). The sample consisted of 1224 subjects, aged 62 to 85 years, who participated in the 3-year follow-up examination and for whom ApoE and stroke data were complete. We assessed cognitive decline using the Mini-Mental State Examination, the Auditory Verbal Learning Test (memory: immediate and delayed recall), and the Coding Task (information processing speed). The effects of stroke and ApoE epsilon4 on cognitive decline were evaluated with ANOVA and multiple logistic regression analysis, adjusted for age, sex, education, and baseline cognition. RESULTS: A synergistic effect modification for stroke and ApoE epsilon4 on cognitive decline was not observed. Unexpectedly, instead, stroke patients carrying the epsilon4 allele demonstrated a nonsignificantly lowered risk for Mini-Mental State Examination decline (OR=0.3; 95% CI 0.1 to 1.1). ApoE epsilon4 was associated with declines in information processing speed (OR=1.5; 95% CI 1.1 to 2.1) and small declines for immediate and delayed recall. CONCLUSIONS: Stroke and ApoE epsilon4 may impair cognition through distinct nonsynergistic mechanisms. The slowing of information processing speed for ApoE epsilon4 carriers was more evident than impairment in memory.

Aged↗
PubMed1988

Association of low serum anticholinergic levels and cognitive impairment in elderly presurgical patients.

Low-dose scopolamine, given as presurgery medication, resulted in low levels of serum anticholinergic activity and caused measurable cognitive impairment in 18 psychiatrically healthy elderly patients. The degree of impairment was directly related to serum anticholinergic activity levels and, in the small subgroup of patients scheduled for spinal anesthesia, to CSF anticholinergic activity. Two of the mental status tests used, the Rey Auditory-Verbal Learning Test and the Saskatoon Delirium Checklist, were sensitive enough to detect these mild drug-induced changes, while two other tests, the Mini-Mental State and the Symbol Digit Modalities Test, were not.

Aged↗
PubMed2004

Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism.

OBJECTIVE: A family history of alcoholism is a risk factor for the development of ethanol dependence. Ethanol is an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor, and alterations in NMDA receptor function are thought to be involved in ethanol abuse and dependence. The purpose of this study was to determine in healthy individuals with no ethanol dependence whether response to the NMDA receptor antagonist ketamine would differentiate those with a family history of ethanol dependence from those without such a family history. METHOD: Healthy subjects between the ages of 21 and 30 received 40-minute intravenous infusions of saline, low-dose ketamine (0.1 mg/kg), and high-dose ketamine (0.5 mg/kg) on three separate test days in a randomized order under double-blind conditions. The healthy individuals with at least one first-degree relative and another first- or second-degree relative with ethanol dependence (N=16) were compared with those who had no family history of ethanol dependence in any first- or second-degree relative (N=29). Outcome measures included the Brief Psychiatric Rating Scale, Clinician-Administered Dissociative States Scale, verbal fluency, Hopkins Verbal Learning Test, a biphasic alcohol effects scale, visual analog scales of mood states, and ketamine levels. RESULTS: During ketamine infusion, individuals with a family history of ethanol dependence showed an attenuated response in terms of perceptual alterations and dysphoric mood relative to those without such a family history. CONCLUSIONS: These data suggest that alterations in NMDA receptor function may contribute to subjective response to ethanol and therefore also to the risk of developing alcoholism.

Adult↗
PubMed2006

Volumetric analysis and three-dimensional glucose metabolic mapping of the striatum and thalamus in patients with autism spectrum disorders.

OBJECTIVE: In patients with autism, behavioral deficits as well as neuroimaging studies of the anterior cingulate cortex suggest ventral rather than dorsal striatal and thalamic abnormalities in structure and function. The authors used imaging studies to map volumetric and metabolic differences within the entire dorsoventral extent of the striatum and thalamus. METHOD: Magnetic resonance imaging (MRI) and positron emission tomography (PET) were used to measure volumes and metabolic activity in the thalamus, caudate, and putamen in 17 patients with autism or Asperger's disorder and 17 age- and sex-matched comparison subjects. Subjects performed a serial verbal learning test during the [(18)F]-fluorodeoxyglucose uptake period. The regions of interest were outlined on contiguous axial MRI slices. After PET/MRI coregistration, region-of-interest coordinates were applied to the PET scan for each individual. Between-group differences in metabolism were assessed by three-dimensional statistical probability mapping. RESULTS: The patients with autism spectrum disorders had greater volumes of the right caudate nucleus than comparison subjects as well as a reversal of the expected left-greater-than-right hemispheric asymmetry. Patients also had lower relative glucose metabolic rates bilaterally in the ventral caudate, putamen, and thalamus. Patients with autism had lower metabolic activity in the ventral thalamus than those with Asperger's disorder, but they did not differ from comparison subjects in metabolic activity in the caudate nucleus. CONCLUSIONS: These results are consistent with a deficit in the anterior cingulate-ventral striatum-anterior thalamic pathway in patients with autism spectrum disorders. The results also suggest an important role for the caudate in helping support working-memory demands.

Adolescent↗
PubMedDate not supplied

Cognitive effects of exogenous melatonin administration in elderly persons: a pilot study.

OBJECTIVE: Given that circadian rhythm disruption is associated with impairments in cognitive performance similar to those found in age-related cognitive decline, the authors investigated whether exogenous melatonin administration would improve cognitive functioning in healthy elderly subjects. METHODS: This double-blind, placebo-controlled pilot study assigned 26 healthy elderly subjects to receive either melatonin 1 mg or placebo nightly for 4 weeks. Participants completed a sleep questionnaire and a battery of cognitive tests at baseline and at 4 weeks. RESULTS: Melatonin administration improved reported morning "restedness" and sleep latency after nocturnal awakening, and also improved scores on the California Verbal Learning Test-interference subtest. CONCLUSIONS: Melatonin administration at a dose of 1 mg nightly may be effective in improving certain aspects of cognitive functioning and subjective reports of sleep quality in elderly subjects. It may prove to be a useful therapeutic agent in the treatment of age-related cognitive decline.

Aged↗
PubMedDate not supplied

Altered PET functional brain responses in cognitively intact elderly persons at risk for Alzheimer disease (carriers of the epsilon4 allele).

OBJECTIVE: Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects. METHODS: Using H215O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-epsilon4 carriers and 6 epsilon4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD-SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the epsilon4 allele) as the independent variable. RESULTS: Compared with non-carriers, epsilon4 carriers exhibited significantly decreased TD-SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because epsilon4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition. CONCLUSION: Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the epsilon4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.

Aged↗
PubMed2005

Effects of anxiety versus depression on cognition in later life.

OBJECTIVE: The authors investigated the relationship between anxiety and cognition in older persons, taking account of comorbid depression. METHODS: Data were used from the Longitudinal Aging Study Amsterdam (LASA), a large epidemiological study of 3,107 elderly citizens in The Netherlands. Anxiety and depression were measured with the Hospital Anxiety and Depression Scale-Anxiety subscale and the Center for Epidemiologic Studies-Depression Scale. In measuring cognitive performance, general cognitive functioning was measured by means of Mini-Mental State Exam, episodic memory was measured with the Auditory Verbal Learning Test (AVLT), fluid intelligence by using the RAVEN, and information-processing speed by the coding task. Analysis of variance examined the association between anxiety symptoms and cognition in persons with and without depression. RESULTS: Main effects of anxiety symptoms were found for learning and delayed recall of the AVLT. Depression symptoms showed significant main effects on almost all cognitive performance tests. Mild anxiety symptoms were associated with better cognitive performance, whereas severe anxiety symptoms were negatively associated with cognitive functioning. In contrast, depressive symptoms showed a linear association with cognition; more depression was associated with worse cognition. CONCLUSION: This study suggests that anxiety has a curvilinear relationship with cognition. Depressive symptoms, however, were always negatively associated with cognitive performance.

Aged↗