Cognitive Memory Decline Research Articles

White Matter Microstructure Analysis in Subjective Memory Complaints and Cognitive Impairment: Insights from Diffusion Kurtosis Imaging and Free-Water DTI.

Dementia is characterized by a cognitive decline in memory and other domains that lead to functional impairments. As people age, subjective memory complaints (SMC) become common, where individuals perceive cognitive decline without objective deficits on assessments. SMC can be an early sign and may precede amnestic mild cognitive impairment (MCI), which frequently advances to Alzheimer's disease (AD). This study aims to investigate white matter microstructure in individuals with SMC, in cognitively impaired (CI) cohorts, and in cognitively normal individuals using diffusion kurtosis imaging (DKI) and free water imaging (FWI). The study also explores voxel-based correlations between DKI/FWI metrics and cognitive scores to understand the relationship between brain microstructure and cognitive function. Twelve healthy controls (HCs), ten individuals with SMC, and eleven CI individuals (MCI or AD) were enrolled in this study. All participants underwent MRI 3T scan and the BNI Screen (BNIS) for Higher Cerebral Functions. The mean kurtosis tensor and anisotropy of the kurtosis tensor showed significant differences across the three groups, indicating altered white matter microstructure in CI and SMC individuals. The free water volume fraction (f) also revealed group differences, suggesting changes in extracellular water content. Notably, these metrics effectively discriminated between the CI and HC/SMC groups. Additionally, correlations between imaging metrics and BNIS scores were found for CI and SMC groups. These imaging metrics hold promise in discriminating between individuals with CI and SMC. The observed differences indicate their potential as sensitive and specific biomarkers for early detection and differentiation of cognitive decline.

A REVIEW OF THE LITERATURE ON HIV AND NEUROPSYCHOLOGICAL FUNCTIONING IN OLDER ADULTS: IS MORE RESEARCH NEEDED?

The increase in the number of ageing people living with HIV and the documented neurocognitive impairments have highlighted the need to illuminate the existing findings and evaluate the impact that HIV has on older individuals. A review of the evidence for neuropsychological declines in memory, executive functions, attention and language in people aged 60 years or more was conducted. The databases MEDLINE, PsychINFO and Pubmed were searched for eligible studies based on keywords. Eight studies of low to high quality that looked at HIV+ older adults (≥ 60) were identified. The majority of older HIV+ adults experienced severe declines in all the cognitive domains under study. There were mixed results regarding the association among advancing age, functioning decline and HIV. Comparisons between HIV-infected and HIV-uninfected older adults showed that HIV+ subjects demonstrate higher scores of cognitive decline in memory, attention, language and executive functions. Further, comparisons among HIV+ adults, demographically matched individuals with mild cognitive impairment of the Alzheimer's type and healthy controls demonstrated that both disease groups perform worse, but the Alzheimer’s type group reports a greater decline in memory and language. Neuropsychological functioning in HIV+ adults presents great decline but studies on this population are limited. As individuals with HIV are increasingly living longer, studies should pay attention to these individuals and examine predictors of neuropsychological decline in the face of well-controlled interventions and treatments. Keywords: HIV, memory, neuropsychological function, executive functions, older adults

The effect of basal forebrain atrophy on the rate of cognitive decline in older adults without dementia

AbstractBackgroundIn early Alzheimer’s disease, degeneration of the cholinergic basal forebrain (BF) system correlates with amyloid‐β (Aβ) burden and contributes to cognitive decline, particularly in the domains of memory and attention processing. However, the nature of these interrelationships remains unclear. This study investigated the effects of Aβ and BF atrophy on cognitive decline of memory and attention in older individuals without dementia.MethodThe BF volumes were quantified from MRIs of 577 participants (73.3 ± 6.3 years old, 55.1% female) from the Australian Imaging, Biomarker and Lifestyle (AIBL) study, including 495 cognitive unimpaired (CU) individuals and 82 with mild cognitive impairment. Aβ‐PET assessment was completed at baseline, and Aβ+ was determined using Centiloid > 20. The cognitive decline in memory and attention was assessed using the relevant AIBL composite scores, over 6.0 ± 3.1 years (up to 13 years). BF z‐scores were calculated using the mean and standard deviation of BF volumes in the CU Aβ‐ group, and z‐scores < ‐1 was classified as BF atrophy (BF+). Participants were then grouped according to the Aβ status and presence of BF atrophy (Table 1). Linear mixed‐effects models assessed differences in rates of cognitive decline in memory and attention across different classification groups. Magnitudes of differences in slopes of decline were expressed using Cohen’s d. ResultIn Aβ‐ individuals, BF atrophy was associated with faster rates of cognitive decline in both memory and attention, with medium effect sizes (Table 2 and Figure 1). In re‐analyses restricted to Aβ+ subjects, BF atrophy remained related to memory decline (p = 0.035, d = 0.33) but not to decline in attention. Compared to Aβ‐ subjects without BF atrophy, both Aβ+ groups had faster decline in both domains, with large effect sizes (all d > 0.8).ConclusionThese findings indicate that the effects of Aβ and BF atrophy are additive in terms of their influence on the rate of decline in memory. However, BF atrophy influences the rate of decline in attention only in the absence of abnormal Aβ burden.

Mitigating cognitive impairment in aging mice: Exploring the therapeutic potential of ischelium

To deeply explore the intervention effects of ischelium on the cognitive memory decline in naturally aging mice and its potential mechanisms, we randomly divided mice into four groups: young control group (C), elderly group (M), ischelium low-dose group (L), and ischelium high-dose group (H). The experiment lasted for 12 weeks. We employed the Y-maze test, open field test, and conditioned fear test to evaluate the memory functions of each group. Through HE staining and electron microscopy, we observed morphological changes in the mouse hippocampus. RT-PCR was used to detect changes in the expression of factors related to cognitive function in the hippocampus of elderly mice. We analyzed the changes in the Nrf2/HO-1 pathway and the inflammatory factors IL-1β and TNF-α using elisa. Additionally, we examined the enzymatic activities of SOD, CAT, GSH-Px, and MDA in the hippocampus and analyzed the compositional changes of gut microbiota in mice using 16S technology. Our results indicate that ischelium effectively ameliorates cognitive impairments in elderly mice.

Longitudinal associations of serum biomarkers with early cognitive, amyloid and grey matter changes.

Blood-based biomarkers have been extensively evaluated for their diagnostic potential in Alzheimer's disease. However, their relative prognostic and monitoring capabilities for cognitive decline, amyloid-β (Aβ) accumulation and grey matter loss in cognitively unimpaired elderly require further investigation over extended time periods. This prospective cohort study in cognitively unimpaired elderly [n = 185, mean age (range) = 69 (53-84) years, 48% female] examined the prognostic and monitoring capabilities of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), Aβ1-42/Aβ1-40 and phosphorylated tau (pTau)181 through their quantification in serum. All participants underwent baseline Aβ-PET, MRI and blood sampling as well as 2-yearly cognitive testing. A subset additionally underwent Aβ-PET (n = 109), MRI (n = 106) and blood sampling (n = 110) during follow-up [median time interval (range) = 6.1 (1.3-11.0) years]. Matching plasma measurements were available for Aβ1-42/Aβ1-40 and pTau181 (both n = 140). Linear mixed-effects models showed that high serum GFAP and NfL predicted future cognitive decline in memory (βGFAP×Time = -0.021, PFDR = 0.007 and βNfL×Time = -0.031, PFDR = 0.002) and language (βGFAP×Time = -0.021, PFDR = 0.002 and βNfL×Time = -0.018, PFDR = 0.03) domains. Low serum Aβ1-42/Aβ1-40 equally but independently predicted memory decline (βAβ1-42/Aβ1-40×Time = -0.024, PFDR = 0.02). Whole-brain voxelwise analyses revealed that low Aβ1-42/Aβ1-40 predicted Aβ accumulation within the precuneus and frontal regions, high GFAP and NfL predicted grey matter loss within hippocampal regions and low Aβ1-42/Aβ1-40 predicted grey matter loss in lateral temporal regions. Serum GFAP, NfL and pTau181 increased over time, while Aβ1-42/Aβ1-40 decreased only in Aβ-PET-negative elderly. NfL increases associated with declining memory (βNfLchange×Time = -0.030, PFDR = 0.006) and language (βNfLchange×Time = -0.021, PFDR = 0.02) function and serum Aβ1-42/Aβ1-40 decreases associated with declining language function (βAβ1-42/Aβ1-40×Time = -0.020, PFDR = 0.04). GFAP increases associated with Aβ accumulation within the precuneus and NfL increases associated with grey matter loss. Baseline and longitudinal serum pTau181 only associated with Aβ accumulation in restricted occipital regions. In head-to-head comparisons, serum outperformed plasma Aβ1-42/Aβ1-40 (ΔAUC = 0.10, PDeLong, FDR = 0.04), while both plasma and serum pTau181 demonstrated poor performance to detect asymptomatic Aβ-PET positivity (AUC = 0.55 and 0.63, respectively). However, when measured with a more phospho-specific assay, plasma pTau181 detected Aβ-positivity with high performance (AUC = 0.82, PDeLong, FDR < 0.007). In conclusion, serum GFAP, NfL and Aβ1-42/Aβ1-40 are valuable prognostic and/or monitoring tools in asymptomatic stages providing complementary information in a time- and pathology-dependent manner.

Lower cerebral blood flow predicts cognitive decline in patients with vascular cognitive impairment.

Chronic cerebral hypoperfusion is one of the assumed pathophysiological mechanisms underlying vascular cognitive impairment (VCI). We investigated the association between baseline cerebral blood flow (CBF) and cognitive decline after 2 years in patients with VCI and reference participants. One hundred eighty-one participants (mean age 66.3±7.4 years, 43.6% women) underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) and neuropsychological assessment at baseline and at 2-year follow-up. We determined the association between baseline global and lobar CBF and cognitive decline with multivariable regression analysis. Lower global CBF at baseline was associated with more global cognitive decline in VCI and reference participants. This association was most profound in the domain of attention/psychomotor speed. Lower temporal and frontal CBF at baseline were associated with more cognitive decline in memory. Our study supports the role of hypoperfusion in the pathophysiological and clinical progression of VCI. Impaired cerebral blood flow (CBF) at baseline is associated with faster cognitive decline in VCI and normal aging. Our results suggest that low CBF precedes and contributes to the development of vascular cognitive impairment. CBF determined by ASL might be used as a biomarker to monitor disease progression or treatment responses in VCI.

Impact of Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, and Escherichia coli Oral Infusions on Cognitive Memory Decline in Mild Cognitive Impairment

Synaptic plasticity is a result of changes in the neuronal circuits which may result in the formation of protein-dependent (long-term memory (LTM) formation) and protein-independent (short-term memory (STM) formation) memories. This STM formation is based on existing proteins, but LTM formation depends on RNA and protein synthesis within the neuronal cells. This RNA and protein synthesis may depend on stimulus exposure like odour, taste, and other environmental stimuli. The present study is aimed to show the impact of oral bacterial infusions on cognitive memory formation through pre and post-infusive behavioural analysis. The results of the study revealed that oral infusions of Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus and Escherichia coli result in impaired cognitive learning and memory formation. This impaired cognitive memory formation is shown with the help of two-step (pre and post-infusive) behavioural analysis. Pre-infusive behavioural study shows no decline in cognitive learning and memory formation before oral microbial infusions in a serene habituated environment. After oral microbial infusions, a post-infusive behavioural analysis may reveal a memory decline in the treated group. Comparative two-step behavioural analysis indicates that P. aeruginosa infusions strongly impact cognitive memory decline compared to the other three groups. This cognitive memory decline may happen due to the production of primary/secondary metabolites within the animal gut and their transportation to the CNS through the blood-brain barrier. The outcome of the present study states that poor oral hygiene plays a significant role in cognitive memory decline concerning mild cognitive impairment (MCI).

Bioenergetic and vascular predictors of potential super‐ager and cognitive decline trajectories – A UK Biobank random forest classification study

AbstractBackgroundAging is often characterized by progressive cognitive decline in memory and executive function. Yet, some adults aged 80 years or older, are “Super‐Agers” that exhibit cognitive performance akin to younger adults. It is unknown if there are adults in mid‐life with similar superior cognitive performance (“positive‐aging”) versus cognitive decline over time, and if there are blood biomarkers that can distinguish between these groups.MethodAmong 1303 participants in UK Biobank, latent growth curve models classified participants into different cognitive groups based on longitudinal Fluid Intelligence (FI) scores over 7‐9 years. Random Forest (RF) classification was then used to predict cognitive trajectory types using longitudinal predictors including demographic, vascular, bioenergetic, and immune factors. Feature ranking importance and performance metrics of the model were reported.ResultDespite model complexity, we achieved a precision of 77% when determining who would be in the “positive‐aging” group. Among the top fifteen features, an equal number were related to either vascular health or cellular bioenergetics but not demographics like age, sex, or socioeconomic status (see figure).ConclusionOur results suggest that optimal cognitive aging may not be driven by age per se, but biological factors that may be amenable to lifestyle or pharmacological changes.

Resilience and Reserve mechanisms underlying clinical‐cognitive progression in Dominant Inherited Alzheimer’s Disease.

AbstractBackgroundPrevention of Alzheimer’s dementia may encompass both avoiding the AD pathological processes (resistance) and coping with AD pathology (resilience). Increasing evidence implicates resistance/resilience factors (e.g., level of education, socio‐economic status [SES], physical activity [PA]) occurring through life as potential modifiers of age at symptom onset (AAO) and rate of cognitive decline to dementia. The extent to which life course factors may influence disease progression in Dominantly Inherited Alzheimer’s Disease (DIAD) remains unknown.MethodsWe aimed to examine the influence of life‐course factors on clinical‐cognitive decline and MRI hippocampal volume in individuals with DIAD enrolled in the Dominantly Inherited Alzheimer Network. A total of 310 mutations carriers (195 asymptomatic and 111 symptomatic [CDR&gt;0]) self‐reported education, work complexity, SES, and PA at baseline and completed longitudinal clinical‐cognitive measures, CSF biomarker studies (Aβ‐42, p‐tau‐181, t‐tau), structural MRI and Aβ‐PET imaging. The influence of life‐course risk factors on AAO, cognitive performances, and hippocampal volume were analyzed using linear mixed models.ResultIn mutation carriers (MC), adjusting for age, PiB‐PET SUVR, and sex, lower clinical disease severity as measured by CDR‐SB was associated with higher levels of education (p = 0.04), PA (p = 0.01) and SES (0.002). Similarly, MC with higher educational levels (p = 0.02) and SES levels (p = 0.001) exhibited larger hippocampal volume despite no differences in PiB‐PET SUVR. Longitudinally, MC with higher levels of education, PA, and SES showed better performance and slower cognitive decline in memory and executive function prior to symptom onset (CDR&gt;0), but a similar decline rate after symptom onset.ConclusionLife‐course factors, like higher education, PA, and SES may promote brain resistance and clinical resilience to AD pathology in DIAD. A model of cognitive reserve in DIAD may help to identify how social and behavioral factors influence the progression of AD pathophysiology and explain how a variety of factors may enhance resistance to pathology, delay AAO, and cognitive decline rate.

Bioenergetic and vascular predictors of potential super-ager and cognitive decline trajectories-a UK Biobank Random Forest classification study.

Aging has often been characterized by progressive cognitive decline in memory and especially executive function. Yet some adults, aged 80years or older, are "super-agers" that exhibit cognitive performance like younger adults. It is unknown if there are adults in mid-life with similar superior cognitive performance ("positive-aging") versus cognitive decline over time and if there are blood biomarkers that can distinguish between these groups. Among 1303 participants in UK Biobank, latent growth curve models classified participants into different cognitive groups based on longitudinal fluid intelligence (FI) scores over 7-9years. Random Forest (RF) classification was then used to predict cognitive trajectory types using longitudinal predictors including demographic, vascular, bioenergetic, and immune factors. Feature ranking importance and performance metrics of the model were reported. Despite model complexity, we achieved a precision of 77% when determining who would be in the "positive-aging" group (n = 563) vs. cognitive decline group (n = 380). Among the top fifteen features, an equal number were related to either vascular health or cellular bioenergetics but not demographics like age, sex, or socioeconomic status. Sensitivity analyses showed worse model results when combining a cognitive maintainer group (n = 360) with the positive-aging or cognitive decline group. Our results suggest that optimal cognitive aging may not be related to age per se but biological factors that may be amenable to lifestyle or pharmacological changes.

Alzheimer cafè: toward bridging the gap between cure and care in patients with dementia

Background Alzheimer’s disease (AD) is the most common form of degenerative dementia, whose symptoms usually appear in the pre-senile age. In the early stages, patients present social difficulties due to the general cognitive decline in memory, language and executive domains. These problems also affect patients’ quality of life, emotions, and mood, leading to social isolation. Objective The aim of this study is to evaluate the effects of Alzheimer’s Cafè (AC) on the cognitive and behavioral outcomes of AD patients. Methods Twenty patients diagnosed with AD, who attended the Cognitive and Behavioral Rehabilitation Laboratory of the IRCCS Centro Neurolesi ‘Bonino-Pulejo’ of Messina, Italy, from December 2017 to December 2018, were enrolled in this study. As these patients belonged to the experimental group (EG: n = 20), they received specific cognitive-behavior training using the AC modality. The patients were assessed by a neuropsychological evaluation at the beginning and at the end of the program. Their outcomes were compared to a matched group of patients with neurodegenerative dementia (CG: 20) receiving conventional cognitive training. Results The pre-post comparisons showed that both CG and EG had a significant improvement in global cognitive functioning (MoCA p < 0.001) and in perceived quality of life (<0.001). However, only in the EG, we observed a significant increase in social functioning (SASS p < 0.00), the perception of mental well-being (SF-12 Mental p < 0.00), and a reduction in the depressive state (GDS p < 0.00). Conclusions The present study suggests the importance of AC for patients with AD and the potential effect on psychological and social well-being.

Variability in Cardiometabolic and Inflammatory Parameters and Cognitive Decline

The relationship between variability in cardiometabolic and inflammatory parameters and cognitive changes is unknown. This study investigates the association of visit-to-visit variability in BMI, mean arterial pressure, total cholesterol, triglycerides, HbA1c, high-sensitivity C-reactive protein, ferritin, and fibrinogen with cognitive decline. This population-based cohort study included 2,260 individuals (mean age=63.0 [SD=7.5] years) free of cognitive diseases who underwent ≥3 clinical measurements from 2004 to 2019. Variability was expressed as variability independent of the mean across visits. Participants were divided on the basis of quartiles of variability score, a scoring system generated to explore the composite effect of parameter variability (range=0-24), where 0 points were assigned for Quartile 1, 1 point was assigned for Quartile 2, 2 points were assigned for Quartile 3, and 3 points were assigned for Quartile 4, each for the variability of 8 parameters measured as variability independent of the mean. Linear mixed models evaluated the longitudinal associations with cognitive decline in memory and verbal fluency. All analyses were conducted in 2020-2021. Higher BMI, mean arterial pressure, total cholesterol, HbA1c, and ferritin variability were linearly associated with cognitive decline irrespective of their mean values. In addition, participants in the highest quartile of variability score had a significantly worse cognitive decline rate in memory (-0.0224 points/year, 95% CI= -0.0319, -0.0129) and verbal fluency (-0.0088 points/year, 95% CI= -0.0168, -0.0008) than those in the lowest quartile. A higher variability in cardiometabolic and inflammatory parameters was significantly associated with cognitive decline. Stabilizing these parameters may serve as a target to preserve cognitive functioning.

The effect of intracranial stenosis on cognitive decline in a memory clinic cohort

Intracranial stenosis (ICS) is a risk factor for cognitive impairment and dementia in cross-sectional studies. However, data examining the effect of ICS on cognitive decline is limited. We investigated the effect of ICS on cognition over a period of three years in a memory-clinic cohort. Patients were recruited from the National University Hospital in Singapore. Data was collected using a standardised questionnaire, physical examination and 3T MRI at baseline. ICS was defined as arterial narrowing that exceeded 50% of the luminal diameter in any intracranial vessel. Cognition was measured at baseline and annually for 3 years using the mini-mental state examination, Montreal cognitive assessment, and a detailed neuropsychological test battery. The association between ICS and cognitive decline was analysed using generalized estimating equations. 364 patients were included in the analysis. The mean (±SD) age was 71.9 (±8.0) years and 164 (45.1%) patients were male. A total of 66 (18.1%) patients had ICS. ICS was associated with worse executive function (β:-0.37; [95%CI:-0.68;-0.05]; p=0.022) and modified the effect of follow-up time on memory (p=0.005) and visuomotor speed (p=0.047). These results remained significant after controlling for demographics, overall diagnosis, cardiovascular risk factors, and MRI markers of cerebrovascular disease. ICS was independently associated with worse executive function across all time points, and cognitive decline in memory and visuomotor speed over three-years of follow-up. This suggests that ICS may be a useful indicator of vascular brain damage leading to cognitive decline, and may warrant consideration of anti-atherosclerotic treatment in clinical trials.

Poor lung function accelerates cognitive decline in middle-aged and older adults: Evidence from the English Longitudinal Study of Ageing

Background/objectivePrevious studies have linked lung function to cognitive performance. However, it is not clear whether baseline lung function has an effect on the trajectory of cognitive decline during normal aging. This study aimed to examine the association of baseline lung function with long-term changes in cognition among the middle-aged and older adults. MethodsLung function as indicated by forced expiratory volume 1 s (FEV1) and forced vital capacity (FVC), was measured at the baseline examination. Cognition, including memory, time orientation, executive function and processing speed, were tested four times over six years. Generalized estimating equation (GEE) models were used to test the associations between baseline lung function and four visits of cognition in 6080 participants aged 50 years or over from the English Longitudinal Study of Ageing (ELSA). ResultsCompared to participants with higher lung function, those who had lower lung function at baseline experienced a faster rate of decline in memory (joint test: χ2interaction = 12.07, df = 3, P = 0.007 for FVC), time orientation (joint test: χ2interaction = 9.49, df = 3, P = 0.023 for FVC) and executive function (joint test: χ2interaction = 9.13, df = 3, P = 0.028 for FEV1 and joint test: χ2interaction = 12.76, df = 3, P = 0.005 for FVC). No association was found between baseline lung function and the rate of decline in processing speed (joint test: χ2interaction = 1.29, df = 3, P=0.733 for FEV1 and joint test: χ2interaction = 2.35, df = 3, P = 0.503 for FVC). ConclusionsPoor lung function at baseline predicted a faster rate of cognitive decline in memory, time orientation and executive function. The mechanism for this association deserves further investigation.

Spatial patterns of tau deposition are associated with amyloid, ApoE, sex, and cognitive decline in older adults

PurposeThe abnormal deposition of tau begins before the onset of clinical symptoms and seems to target specific brain networks. The aim of this study is to identify the spatial patterns of tau deposition in cognitively normal older adults and assess whether they are related to amyloid-β (Aβ), APOE, sex, and longitudinal cognitive decline.MethodsWe included 114 older adults with cross-sectional flortaucipir (FTP) and Pittsburgh Compound-B PET in addition to longitudinal cognitive testing. A voxel-wise independent component analysis was applied to FTP images to identify the spatial patterns of tau deposition. We then assessed whether tau within these patterns differed by Aβ status, APOE genotype, and sex. Linear mixed effects models were built to test whether tau in each component predicted cognitive decline. Finally, we ordered the spatial components based on the frequency of high tau deposition to model tau spread.ResultsWe found 10 biologically plausible tau patterns in the whole sample. There was greater tau in medial temporal, occipital, and orbitofrontal components in Aβ-positive compared with Aβ-negative individuals; in the parahippocampal component in ε3ε3 compared with ε2ε3 carriers; and in temporo-parietal and anterior frontal components in women compared with men. Higher tau in temporal and frontal components predicted longitudinal cognitive decline in memory and executive functions, respectively. Tau deposition was most frequently observed in medial temporal and ventral cortical areas, followed by lateral and primary areas.ConclusionsThese findings suggest that the spatial patterns of tau in asymptomatic individuals are clinically meaningful and are associated with Aβ, APOE ε2ε3, sex and cognitive decline. These patterns could be used to predict the regional spread of tau and perform in vivo tau staging in older adults.

&lt;p&gt;Early-onset Alzheimer’s disease patient with prion &lt;em&gt;(PRNP)&lt;/em&gt; p.Val180Ile mutation&lt;/p&gt;

Background: In this study, a known PRNP mutation, Val180Ile (c.G538A), was reported in a 58 years old female patient, clinically diagnosed with Alzheimer’s disease (AD).Case report: The patient presented slowly progressive cognitive decline in memory and visuospatial domain. Neuroimaging showed hippocampal atrophy in MRI and mild amyloid positivity in PET scan. Even though her cerebrospinal fluid (CSF) was positive for 14–3-3 protein, no sign of Creutzfeldt-Jakob diseases symptoms was observed. In addition, reduced Aβ42 and elevated total-Tau and phospho-Tau in CSF also proved the AD diagnosis. The mutation may disturb the hydrophobic core of prion protein, and result in abnormal intramolecular interactions. Due to 23andMe, PRNP Val180Ile could not be categorized either as a mutation with complete penetrance, or as neutral variant, and could have a possible role in neurodegeneration. Pathological overlap was observed between prion diseases and other neurodegenerative diseases, including AD or frontotemporal dementia.Conclusion: Whole exome sequencing and pathway analysis of patient revealed rare or possible risk variants in AD associated genes, such as SORL1 or ABCA7. Along with PRNP, AD risk genes may play a role in negative regulation of amyloid formation. Dysfunctions in these genes could possibly be associated in reduced neuroprotection and amyloid clearance.

Hearing Impairment and Incident Dementia and Cognitive Decline in Older Adults: The Health ABC Study.

Age-related peripheral hearing impairment (HI) is prevalent, treatable, and may be a risk factor for dementia in older adults. In prospective analysis, we quantified the association of HI with incident dementia and with domain-specific cognitive decline in memory, perceptual speed, and processing speed. Data were from the Health, Aging and Body Composition (Health ABC) study, a biracial cohort of well-functioning adults aged 70-79 years. Dementia was defined using a prespecified algorithm incorporating medication use, hospital records, and neurocognitive test scores. A pure-tone average in decibels hearing level (dBHL) was calculated in the better hearing ear using thresholds from 0.5 to 4kHz, and HI was defined as normal hearing (≤25 dBHL), mild (26-40 dBHL), and moderate/severe (>40 dBHL). Associations between HI and incident dementia and between HI and cognitive change were modeled using Cox proportional hazards models and linear mixed models, respectively. Three-hundred eighty seven (20%) participants had moderate/severe HI, and 716 (38%) had mild HI. After adjustment for demographic and cardiovascular factors, moderate/severe audiometric HI (vs. normal hearing) was associated with increased risk of incident dementia over 9 years (hazard ratio: 1.55, 95% confidence interval [CI]: 1.10, 2.19). Other than poorer baseline memory performance (difference of -0.24 SDs, 95% CI: -0.44, -0.04), no associations were observed between HI and rates of domain-specific cognitive change during 7 years of follow-up. HI is associated with increased risk of developing dementia in older adults. Randomized trials are needed to determine whether treatment of hearing loss could postpone dementia onset in older adults.

Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model.

Severe progressive neurological paediatric disease mucopolysaccharidosis III type C is caused by mutations in the HGSNAT gene leading to deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulphate. To understand the pathophysiology of the disease we generated a mouse model of mucopolysaccharidosis III type C by germline inactivation of the Hgsnat gene. At 6-8 months mice showed hyperactivity, and reduced anxiety. Cognitive memory decline was detected at 10 months and at 12-13 months mice showed signs of unbalanced hesitant walk and urinary retention. Lysosomal accumulation of heparan sulphate was observed in hepatocytes, splenic sinus endothelium, cerebral microglia, liver Kupffer cells, fibroblasts and pericytes. Starting from 5 months, brain neurons showed enlarged, structurally abnormal mitochondria, impaired mitochondrial energy metabolism, and storage of densely packed autofluorescent material, gangliosides, lysozyme, phosphorylated tau, and amyloid-β. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase causes lysosomal accumulation of heparan sulphate in microglial cells followed by their activation and cytokine release. They also show mitochondrial dysfunction in the neurons and neuronal loss explaining why mucopolysaccharidosis III type C manifests primarily as a neurodegenerative disease.

CEREBRAL OXYGENATION/PERFUSION, CARDIAC HEMODYNAMICS DURING EXERCISE AND COGNITIVE FUNCTIONS IN OBESE PATIENTS

Obesity is associated with an accelerated rate of cognitive decline in memory, attention, processing speed and executive functions resulting in a higher risk of dementia and Alzheimer’s disease (AD) in later life. In cardiac patients showing mild cognitive impairments, cerebral O2Hb correlates with VO2 peak and left ventricular ejection fraction, reflecting a link between cardiac output and cerebral O2Hb during maximal exercise. Objectives:1) To compare cerebral oxygenation/perfusion (COP), central hemodynamics, VO2 peak and cognitive functions in obese patients (OB) and age-matched healthy controls (AMHC) 2) to study the relationships between VO2 peak, cardiac output (CO),cognitive functions in OB. 21 AMHC and 33 OB subjects were recruited. VO2 peak (ml/min/LBM), cardiac hemodynamics (impedance cardiography) and COP (near-infrared spectroscopy) were measured during a maximal incremental ergocycle test. Cognitive function assessments (standard battery, paper-pen tests) included: short term-working memory, perceptual abilities, processing speed, inhibition and mental flexibility and long-term verbal memory. Compared to AMHC, OB had a lower VO2 peak, lower ejection fraction (EF%), and higher end-systolic and end-diastolic volume indexes (P<0.05), but the ΔHHb was lower in OB (P<0.05). Cognitive function was similar between groups when defining obesity as % body fat. VO2 peak was related to cognitive functions (short term-working memory, processing speed, inhibition and mental flexibility: R=-0.32 to 0.43, P<0.05) but not cardiac index (CI). 1) OB subjects have a lower VO2 peak (including VO2 peak adjusted for lean body mass) compared to AMCH, indicating lower cardiorespiratory fitness. 2) Cognitive function was similar between groups when defining obesity as % body fat. However, visceral adiposity defined by % of trunk fat mass correlated significantly with short-term memory(Forward Empan), inhibition and mental flexibility (stroop 3 and stroop 4). 3) Because of similar ΔO2Hb during exercise between groups and because ΔHHb (mM) was significantly reduced in OB, these results suggest a reduced O2Hb extraction in OB. However, reduced ΔHHB in OB was not associated with impaired cognitive function. 4) In all subjects, parameters assessing the main executive functions were correlated to VO2 peak but not the CO or CI.

The effects of breast cancer treatment on cognitive functions

11531 Background: We have started a longitudinal study to investigate if a) the effects of being given a breast cancer (bc) diagnosis may affect cognitive functions in women, b) if adjuvant therapy may have detrimental effects on cognition, c) if subjects with substantial cognitive impairment after therapy may benefit from a cognitive training program. Methods: The study is dimensioned for 140 subjects. The subjects are recruited consecutively and prospectively from the mammography-screening program at Sodersjukhuset, Stockholm. According to the results of the diagnostic process the patients are divided in two main groups by “biological” randomization; healthy subjects and women with bc (n=70 in each group). All participants are examined by a web-based battery of neuropsychological tests at four times: at inclusion and before diagnosis, after diagnosis (two months), after treatment (six months), and follow-up after an additional three months. Subjects who score one standard deviation below the mean compared to baseline, in any of four cognitive domains (response speed, processing speed, memory and attention) after treatment will be offered to participate in a randomized trial of cognitive training versus control. Results: We have so far included 65 subjects. 30 have completed the third test session. Preliminary results show that patients with a recent bc diagnosis and subsequent surgery demonstrate a tendency toward a cognitive decline in attention. There is a significant cognitive decline in memory in the bc group after treatment p=0.029 (repeated measures ANOVA) and inclination of mild impairment in processing speed. Conclusions: The preliminary results may be interpreted to suggest that receiving a bc diagnosis and/or surgery may be associated to a substantial cognitive decline in a subgroup of patients. After six months of treatment a subgroups of patients have a significant decline in memory, which is not dependent on other cognitive functions, depression or anxiety. Women with bc receiving adjuvant chemotherapy often report difficulties with memory, attention and concentration difficulties. We believe that the fact that bc is the most common cancer among women and specially among women of working age in Sweden may, in itself, motivate a study of cognitive effects of its treatment. No significant financial relationships to disclose.