bluuebunny/crossref_metadata_2025 huggingface dataset:
Visit‐to‐visit heart rate variability is associated with cognitive decline in older adults: The S.AGES cohort
Authors: Rouch Laure , Vidal Jean‐Sébastien , Hanon Olivier ,   S.AGES Investigators
Published: December 2020

Background

Visit‐to‐visit blood pressure variability (BPV) has been increasingly recognized as a predictor of cognitive decline and dementia but the impact of long‐term heart rate variability (HRV) on cognition is unknown.

Method

3319 non‐institutionalized subjects from the S.AGES (elderly subjects) cohort underwent clinical examinations every 6 months during 3 years. Visit‐to‐visit HRV was evaluated using standard deviation, coefficient of variation, average real variability, successive variation, variation independent of mean and residual standard deviation. Cognition was assessed using the Mini‐Mental State Examination and incident dementia using the Diagnostic and Statistical Manual of Mental Disorders. Linear mixed models and Cox proportional hazards models were used, respectively to assess the association of HRV with cognitive function over time and incident dementia.

Result

Among the 3319 subjects (mean age, 78 years; 57% female; university level, 20%), 93 (2.8%) developed dementia. Higher HRV was significantly associated with poorer cognition (1‐sd increase of CV: β ± SE = ‐0.18 ± 0.06, p < 0.01) after adjustment for demographics, heart rate, antihypertensive drug use, coronary artery disease, diabetes, chronic heart failure, atrial fibrillation, transient ischemic attack or stroke, smoking and dyslipidemia at baseline. Similar results were observed with all other indicators of variability (p<0.01) except residual standard deviation. After adjustment, higher HRV was not associated with greater risk of dementia (1‐sd increase of CV: HR = 1.03, 95% CI [0.83‐1.28], p = 0.7).

Conclusion

Higher long‐term HRV is associated with cognitive decline in community‐dwelling older adults. Future research is needed to assess whether it could be a therapeutic target for preserving brain health.
A novel care model for dementia: Improving caregiver burden and depression
Authors: Manning Carol A , Boyd Elizabeth , Fields Samantha , Sperling Scott A , Tsang Siny
Published: December 2020

Background

In the United States, people with dementia are cared for by 16,000,000 unpaid caregivers (Alz. Association, 2019). Dementia caregivers have increased morbidity and poorer health than non‐caregivers. Negative biopsychosocial impacts related to caregiving undermine the capacity to provide care, and lead to increased institutional placement, increasing burden on public systems (de Vugt, Verhey, 2013).

Method

This study investigated the efficacy of a novel care model in which participants were assigned care coordinators who provided education, support, guidance and access to existing resources. Participants were 105 people with dementia (54.3% women) and their caregivers (67.3% women). Depression (CES‐D), caregiver burden (Zarit), and healthcare utilization were measured at baseline and twelve months. We used Linear Effects Modeling and the Actor‐Partner Interdependence Model (APIM; Kashy & Kenny, 2000) to examine the extent to which patient/caregiver’s depression at 12 months was affected by their own and partner’s depression at baseline.

Result

Care coordination satisfaction was high. There were significant decreases in caregiver burden and depression over time (both p’s < 0.001). Regarding health care utilization, there was a decrease in the number of nights in the hospital with care coordination relative to before study onset. Most people had no change in the number of doctor visits relative to prior to the study, but of those who had a change, most had fewer visits with care coordination. APIM results showed patients’ and caregivers’ depression at baseline were positively correlated (p < .001). Patients’ depression at baseline predicted their depression at 12‐months (p < .01), taking into account the correlation of depression between patients and caregivers, and the effect of caregivers’ depression at baseline. Caregivers’ depression at 12‐months was not affected by their own nor patients’ depression at baseline.

Conclusion

Patients and caregivers participating in a novel caregiving model involving care coordination showed decreased caregiver burden, depression and hospitalization. Caregiver depression at twelve months was unrelated to caregiver and patient baseline depression, controlling for correlations between caregiver and patient depression at baseline. Care coordination may help alleviate negative impacts related to caregiving, suggesting that this model may improve important elements of dementia care.
Depressive symptoms and risk of dementia in non‐depressed older adults
Authors: Fitzpatrick Annette L. , Lopez Oscar L. , Leary Cindy S. , Semmens Erin O. , Adam Claire , Park Christina , Senter Camilla , Hajat Anjum
Published: December 2020

Background

The relationship between depression and dementia is complex. Whether depression serves as a risk factor, prodromal symptom, or comorbidity of dementia remains unclear. Longitudinal studies that establish temporality of these conditions in late life may shed light on their relationship.

Method

We analyzed data from the Ginkgo Evaluation of Memory Study (GEMS) initiated in 2000 and followed for 8 years to determine incident dementia and its subtypes Alzheimer’s disease (AD) and vascular dementia (VaD). Inclusion criteria for enrollment in GEMS required participants to have a Center for Epidemiology Studies Depression score (CES‐D) <16 or to be on treatment for depression. Dementia was determined by consensus of study neurologists based on standardized criteria using neuropsychiatric testing, MRI imaging, and comorbidities. Cox Proportional Hazards Regression was used to evaluate the associations of dementia (n=515), AD (without VaD, n=348) and VaD (with or without AD, n=145) with number of depressive symptoms at baseline. We determined the optimum cutpoint for depressive symptoms to predict dementia using Receiver Operating Characteristic (ROC) curves. Adjustments for age, gender, race, education, area level income, and study site were included in models.

Result

3,042 participants mean age 78.6 (SD 3.3), 46% women, mean follow‐up time 5.5 (SD 1.6) person‐years, were included in analyses. Mean number of CES‐D depressive symptoms at baseline was 3.5 (SD 3.2) with 525 participants reporting none. Number of depressive symptoms was associated with an increased risk of dementia (HR:1.09, 95% CI:1.06‐1.12, p<0.001), AD (HR:1.10, 95% CI:1.07‐1.13, p<0.001) and VaD (HR:1.05, 95% CI:1.00‐1.10, p=0.04). The optimum cutpoint based on the ROC curve was 2.6 with sensitivity of 0.64 and specificity of 0.49. Participants who reported > 3 depressive symptoms had a 45% increased risk of dementia compared to those with fewer symptoms (HR: 1.45, 95% CI:1.04‐2.04, p=0.03). Effect modification by presence of mild cognitive impairment (MCI) was found (p interaction = 0.008). Results were only significant for those without MCI.

Conclusion

Reporting just a few depressive symptoms in late life may indicate future onset of dementia. These results suggest the need for close clinical follow‐up of cognitive impairment in these non‐depressed older adults.
Genetic context and aging influence anxiety‐like behavior in diverse mouse models of Alzheimer’s disease
Authors: Korgan Austin C. , Doyle Patricia H. , Neuner Sarah M. , Kaczorowski Catherine C. , O'Connell Kristen M.S.
Published: December 2020

Background

Many neuropsychiatric symptoms have been observed in humans with Alzheimer’s disease (AD). Significant changes in anxiety, depression, agitation, and apathy are present in AD patients relative to age‐matched controls, often occurring prior to the onset of cognitive deficits.

Method

Here, we used the elevated plus maze (EPM) to examine anxiety‐like behavior in our AD‐BXD genetic reference panel to determine if sex, age (6 and 14m), or genetic background (28 BXD strains) influence anxiety in 5XFAD carrier (AD‐BXD) and non‐carrier (Ntg‐BXD) mice.

Result

At 6m of age, AD‐BXD strains spent significantly more time in the open arms (anxiolytic) compared to Ntg‐BXD controls, despite no differences in cognitive abilities (presymptomatic). The effect of the 5XFAD transgene on time spent in the open arms was exacerbated with aging, 14m AD‐BXD strains spent significantly more time in the open arms compared to both 6m 5XFAD carriers and non‐transgenic mice at either age. We also found a significant main effect of background strain and a strain by genotype interaction; indicating that the degree to which the transgene increased the time spent in open arms was dependent on individual genetic context. Interestingly, the anxiolytic response in these mice was mirrored by a decrease in locomotor activity (distance traveled).

Conclusion

Contrary to increased anxiety described in human AD patients, we observed a decrease in anxiety‐like behaviors in the AD‐BXDs that exacerbated by age. However, circadian influence on anxiety may limit the translational relevance of this data set, especially considering the impact of strain, age, and genotype on locomotor activity. Ongoing work will investigate non‐anxiety‐like behavior in the EPM (risk‐taking), circadian‐dependent (i.e. morning vs. evening) changes in anxiety‐like behaviors, and gene expression in the hypothalamus as a function of anxiety‐like behavior.
Are early stage tau depositions associated with pyroglutamylated Aβ in Alzheimer’s disease?
Authors: Walker Lauren , Johnson Mary , Thomas Alan J. , Attems Johannes
Published: December 2020

Background

Hallmark lesions observed Alzheimer’s disease (AD) include neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (HP‐
T
) and amyloid β plaques. Pyroglutamylated Aβ (pAβ) is a sub‐species of Aβ, and we have previously demonstrated an association between (pAβ) and HP‐T in human post‐mortem brains, and observed that pAβ predicts the severity of clinical dementia. Several studies in transgenic mouse models have demonstrated Aβ inducing HP‐T pathology and anti‐Aβ antibody treatment eliminated not only parenchymal Aβ deposits but also early stage HP‐T deposits while mature NFTs remained unaltered suggesting that Aβ ‐ HP‐T interaction takes place at an early stage of NFT development. However, these studies did not specifically look for the proportion of pAβ within Aβ and hence data on the interaction between pAβ and stages of NFT development are lacking. We now aim to investigate whether pAβ is associated with tau conformations that represent earlier stages of tangle development, measured by MC1 and CP13 antibodies in human post‐mortem tissue.

Method

Tissue from frontal, temporal, parietal, occipital and entorhinal cortices from 70 post‐mortem brains (35 AD and 35 aged controls) were processed into a tissue microarray blocks for high throughput analysis, and stained for pAβ, MC1, and CP13. Percentage area of immunopositivity calculated using an automated image analysis system.

Result

pAβ, MC1, and CP13 loads were higher in AD cases compared to controls in all regions (all p < 0.05). The burden of pAβ positively correlated with the burden of MC1 and CP13 in all regions (all p < 0.05).

Conclusion

This study provides the first set of results from a larger screening study to determine at which point the interaction between pAβ and tau takes place. Our results suggests pAβ is associated with conformational states of tau that represent early stage tau depositions. Therefore studies investigating whether immunisation using pAβ is capable of removing early stage tau depositions, precluding excessive mature NFT tau accumulations, and attenuating cognitive decline in AD are warranted.
Adverse lipid profiles in older people are associated with lower dementia risk
Authors: van Dalen Jan Willem , Hoevenaar‐Blom Marieke P , van Gool Willem A , van Charante Eric P Moll , Richard Edo
Published: December 2020

Background

Dyslipidaemia in mid‐life is associated with incident dementia but evidence is conflicting on whether dyslipidaemia in late‐life increases dementia risk. This may be due to the large heterogeneity in cholesterol measures and study designs employed. We used detailed data from a large prospective cohort of older people to comprehensively assess the relation between a broad range of cholesterol measures and incident dementia, addressing potential biases, confounders and modifiers.

Method

In 3392 community‐dwelling individuals, without dementia, aged 70‐78 years, total cholesterol, low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), triglycerides and apolipoprotein A1 and B were assessed. Over a median of 6.7 years follow‐up, dementia was established by clinical diagnosis confirmed by independent outcome adjudication. Hazard ratios (HR) for dementia and mortality were calculated using Cox regression.

Result

Dementia occurred in 231 (7%) participants. Dyslipidaemia, particularly high LDL‐C/HDL‐C, was associated with lower dementia risk, independent of age, cardiovascular risk factors, cognitive function, apolipoprotein E genotype and cholesterol lowering drugs. This association was not influenced by the competing risk of mortality. One SD increase in LDL/HDL conveyed a 19% lower dementia risk (HR=0.81, 95%CI=0.69‐0.96) and a 10% lower risk of dementia/mortality combined (HR=0.90, 95%CI=0.82‐0.98). Strong and consistent interactions suggested these associations were predominant in individuals with low BMI and education and potentially reversed in high BMI and education subgroups.

Conclusion

Dyslipidaemia in older individuals conveyed a lower risk of dementia. Differentiating between subgroups seems essential when assessing the risk of poor outcome associated with dyslipidaemia. This may have important implications for dementia risk prediction.
Sensory function, cognition, and brain structure in SCD, MCI, and AD: Initial findings from the COMPASS‐ND Study
Authors: Phillips Natalie , Al‐Yawer Faisal , Giroud Nathalie , Rehan Sana , Pappadatos Zoe , Mick Paul , Wittich Walter , Pichora‐Fuller M. Kathleen
Published: December 2020

Background

There is a strong relationship between sensory and cognitive function in older adults and impairment in hearing, vision, and olfaction are each independently associated with dementia. However, these have rarely been examined together in persons with dementia, nor their concurrent relationship with cognitive function and brain structure. The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study is a large‐scale study of older Canadians who are living with, or are at risk for, dementia, including those with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer’s disease (AD), other causes of dementia, and normal controls. We collect clinical and cognitive data, structural brain imaging, and measures of sensory function.

Method

Complete sensory, cognitive, and brain imaging data have been released on participants with study diagnoses of SCD (n=35; 74% women, mean age = 69.4 years; mean education = 16.6 years), MCI (n=79; 49% women, mean age = 73.5 years; mean education = 15.5 years), and AD (n=21; 10% women, mean age = 75.9 years; mean education = 15.5 years).

Hearing function was assessed by pure tone screening at 25 and 40 dB and with a computerized speech in noise perception task. Vision function was assessed by measuring reading acuity and contrast sensitivity. Olfaction was assessed with a 16‐item olfactory recognition test.

Result

Controlling for age, sex, and education, cognitive performance measures decreased over the groups (SCI>MCI>AD), as expected. The groups differed in contrast sensitivity and olfaction, but not hearing (audiometric category, perceiving digits in noise) or visual reading acuity. Poorer olfaction was associated with poorer auditory episodic memory and lower hippocampal volume. Poorer hearing thresholds were associated with lower right hippocampal volume in SCD participants. Within MCI participants, poorer hearing was associated with a disruption in the relationship between auditory episodic memory and a number of variables, including visual episodic memory and lateralized hippocampal volume.

Conclusion

These results illustrate a complex interplay between sensory‐cognitive‐brain measures in older adults with or at risk for dementia and suggest that sensory status has important implications for brain structure and clinical status.
Identification of dysregulated lipid metabolic pathways in mouse embryonic derived neurons and in a mouse model of Alzheimer's disease
Authors: Costa Ana Paula , Menon Vilas , McIntire Laura Beth
Published: December 2020

Background

Lipidomic data from autopsy brain, human plasma and animal models highlights severe lipid dyshomeostasis in Alzheimer’s disease (AD). The importance of lipid metabolism in AD is supported by GWAS studies which have identified multiple lipid modifying enzymes and interacting proteins. Further, mouse genetic studies have shown benefit of genetic disruption of synaptojanin1 (Synj1), phospholipase A2 (PLA2), and phospholipase D2 (PLD2).

Method

We used high‐content screening for Aß‐triggered synapse loss in mouse embryonic stem cell derived neurons to identify phospholipid modifying enzymes which contributed to synapse loss. In an orthogonal approach we used DESI Imaging Mass Spectrometry to identify lipid metabolic pathways which are dysregulated in brain of a mouse model of AD.

Result

We showed that haploinsufficiency of Synj1, a phosphoinositide phosphatase, and concurrent maintenance of phosphoinositide levels, ameliorated behavioral deficits in a mouse model of AD in spite of pathological amyloid accumulation. Similarly, disruption of phospholipid modifying enzymes PLD2 and PLA2 resulted in rescue of behavioral deficits despite the pathological accumulation of amyloid. It is likely then that specific pathways in lipid metabolism underlie AD disease mechanisms leading to behavioral impairment. Specifically, the loss of polyunsaturated fatty acids among multiple phospholipid classes is common in AD affected human brain and mouse models. Our lipidomic studies show that lipid species are dramatically altered in mouse brain in a regionally specific manner determined by imaging mass spectrometry.

Conclusion

Synthesis of these findings and the fact that disruption of phospholipid modifying enzymes Synj1, PLA2 and PLD2 rescue behavioral deficits in spite of pathological accumulation of amyloid, implicate acyl chain remodeling as a candidate therapeutic target in AD.
Histopathological assessment and staging of large and small vessel disease associated with normal brain aging
Authors: Dallaire‐Théroux Caroline , Saikali Stephan , Duchesne Simon
Published: December 2020

Background

Vascular cognitive impairment is the manifestation of diffuse underlying cerebrovascular disease (CVD) that can be assessed at postmortem examination. However, CVD is nonspecific and therefore common in cognitively intact individuals, as prevalence increases with age. There is also an important overlap between CVD and other neurodegenerative conditions, especially Alzheimer’s disease, with more than 40% of cases being mixed aetiologies. We aimed to validate a histological scale able to assess the natural progression of small and large vessel lesions associated with normal brain aging, and further understand their potential contribution to cognitive impairment.

Method

Brain specimens from 63 cognitively intact participants aged 19 to 84 were examined and rated by two blinded and independent observers using a modified version of the Vascular Cognitive Impairment Neuropathology Guidelines (VCING; Skrobot et al. 2016). The scale focuses on nine anatomical regions and ten histological changes, including vascular wall lesions and secondary tissue damages. Weighted Kappa coefficients were calculated to estimate interrater reliability, and Spearman’s rank correlation test was used to calculate regional gradients of vascular load associated with age.

Result

Preliminary analyses suggest an inter‐observer agreement ranging from 0.39 to 1.00. Atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy and perivascular hemosiderin deposits were significantly correlated with age (ρ = 0.76, 0.74, 0.44 and 0.39, respectively; p < 0.005). There was also a trend in the severity of perivascular retraction and myelin loss associated with age (ρ = 0.26 and 0.31, p = 0.04 and 0.01). In arteriolosclerosis, the strongest regional gradients were observed in deeper brain structures (i.e., basal ganglia and thalamus).

Conclusion

These results suggest an existing cerebrovascular pathology that accumulates with normal aging, the burden of which can be reproducibly estimated with a modified version of the VCING scale. Our results can be used as normative benchmarks to assess the severity of occurrence. While large vessel pathology is a well‐known risk factor for vascular dementia, the contribution of small vessel disease to cognitive impairment has yet to be established. The use of a dedicated standardized histological staging scale is crucially needed to better understand its clinical implications and identify thresholds of pathological states associated with cognitive decline.
Neuropsychiatric symptoms in early onset Alzheimer's disease and frontotemporal dementia
Authors: Stojkovic Tanja , Mandic Stojmenovic Gorana , Stefanova Elka , Kostic Vladimir S.
Published: December 2020

Background

Having in mind a significant percentage of atypical presentations at disease onset (behavioral symptoms, depression, psychotic symptoms or non‐cognitive cognitive deficits), understanding clinical heterogeneity of early onset Alzheimer's disease (EOAD) and frontotemporal dementia (EOFTD) can improve early diagnosis and differentiation between these clinical entities.

Our objective was to investigate the heterogeneity of neuropsychiatric symptoms (NPS) in EOAD and EOFTD spectrum.

Method

Two hundred and seven consecutive patients with EOAD and EOFTD spectrum, diagnosed according to the current clinical criteria, were recruited from the Neurology Clinic, Clinical Centre of Serbia. Sociodemographic and clinical characteristics were evaluated using a pre‐designed semi‐structured questionnaire while neuropsychiatric symptoms (NPS) were evaluated using Neuropsychiatric Inventory (NPI).

Result

EOAD and EOFTD patients did not differ in age, age at disease onset, duration of the disease, gender and education. In comparison to EOAD, patients in the EOFTD spectrum expressed agitation, euphoria, apathy, disinhibition, irritability, aberrant motor behavior and dietary changes more frequently. EOFTD behavioral variant patients expressed apathy, aberrant motor behavior and disinhibition more often than patients with PPA, while in PPA anxiety was represented. In EOAD group total NPI score correlated with clinical dementia rating scale score. In the advanced stages of dementia, EOAD patients expressed agitation and irritability more frequently than at disease onset, while in advanced EOFTD agitation and aberrant motor behavior were more frequent than in the earlier stages of the disease. Amnestic and non‐amnestic presentation of EOAD did not differ in frequency on NPS

Conclusion

NPS are a hallmark of behavioral variant of EOFTD and later stages of EOAD.
Frequency of consumption of food groups for patients with Alzheimer‐type dementia, before the diagnosis of the disease in a second‐level hospital in Guadalajara, Jalisco, Mexico, 2020
Authors: de los Ángeles Vargas‐Rodríguez María , Llamas‐López Leonardo
Published: December 2020

Background

The nutrients obtained through food and the interaction they present with the mechanisms of epigenetics point as a means of prevention and treatment for AD. The identification of food in each population is important considering that each one has aspects that make it unique. The realization of retrospective dietary surveys allows us to know how people's diet were and correlate the existence in the development of a pathology.

Method

Descriptive, observational, retrospective design with mixed approach. With n=15 AD who assisted the service of neurology and n=15 control group, healthy older adults according to the WHO definition and the test modified MMSE (score of 16‐19 points). Both groups over 60 years.

Result

To statistically analyze X2 (p=<0.05) was used, in fig. 1 of the consumption of soda, it can be observed that the AD consumed soda more frequently. Regarding the consumption of vegetables such as nopal, tomato, chayote and consumption of fruits such as apples and bananas, it did not obtain statistical significance, but with guava it did have fig. 2 (p=0.019). The groups of cereals, legumes and dairy products were not statistically significant. While in foods of animal origin (red meat, white meat and egg) there was no statistical significance but it can be seen in fig. 3 as AD have a higher frequency of red meat (p=0.060). While statistical significance was found in the use of lard(p=0.048) being more frequent in the control group. Regarding lifestyle there was no significance. But we found significance in water consumption (p=0.013) and tobacco use (p=0.009).

Conclusion

We can conclude that when looking at the data on food consumption, it seems that they play a role in the development of the disease, not reflecting it statistically, probably due to the small sample that was used. The suspicions of various authors point to a higher consumption of simple carbohydrates, reflected in our study in fig. 1. While the importance of water consumption was demonstrated in our study, the recommended consumption is 2,000 ml, the control group consumed it closer to this amount and tobacco use was of great importance, highlighting greater use in AD.
The epidemiology of the different clinical presentations of early onset dementia
Authors: Chiari Annalisa , Adani Giorgia , Vinceti Giulia , Tondelli Manuela , Galli Chiara , Fiondella Luigi , Costa Manuela , Molinari Maria Angela , Filippini Tommaso , Vinceti Marco , Zamboni Giovanna
Published: December 2020

Background

It is known that patients with Early Onset Dementia (EOD), defined as dementia with symptoms onset before the age of 65, frequently present with atypical clinical syndromes. However, the epidemiology of the different presentations of EOD, including the clinical variants of Alzheimer’s dementia (AD) and frontotemporal dementia (FTD), has never been investigated altogether in the same population‐based study, probably because their characterisation is relatively recent, and subsequent to the advent of AD biomarkers. Epidemiologic data on all‐causes of EOD are also scarce, inconsistent, and mostly based on low‐level clinical assessment.

Method

We investigated the epidemiology of EOD in the province of Modena, Northern Italy (700,000 inhabitants), by identifying newly‐diagnosed EOD patients retrospectively from January 2006 to December 2016, and prospectively from January 2017 to June 2019. Diagnosis was based on extended clinical and neuropsychological assessment, and supported by the use of imaging and cerebrospinal fluid biomarkers in the majority of cases.

Result

EOD age‐ and sex‐adjusted incidence was 6.45/100000 inhabitants/year during the 2016‐2019 period, corresponding to 46 new cases per year in the overall study population. At census day (30th June 2019), there were 258 patients with a clinical diagnosis of EOD (123 males) in the province of Modena. Crude Prevalence was 74.3/100000 (71.2 in males and 77.4 in females) in the population aged 30‐64, and 119.9/100000 (117.1 in males and 122.6 in females) in the population aged 45‐64. Overall crude prevalence was 36.4/100000 inhabitants (35.5/100000 in males, 37.4/100000 in females). The most frequent EOD was the amnestic variant of AD (crude incidence of 21.6/100000 and prevalence of 5/100000 persons aged 30‐64 years), followed by the behavioural variant of FTD (crude incidence of 14.1/100000 and prevalence of 2.8/100000 persons aged 30‐64 years), and logopenic variant of primary progressive aphasia (crude incidence of 5.8/100000 and prevalence of 0.8/100000 persons aged 30‐64 years).

Conclusion

We provide the first report on incidence and prevalence of all the clinical presentations of EOD including different variants of AD and FTD. These epidemiological data will benefit the clinical reasoning of clinicians faced with dementia in young patients and will allow to improve dementia care organisation.
Language changes in Alzheimer's disease in a patient of the Karajá ethnicity
Authors: de Lacerda Maria Carolina Cabral , Caixeta Leonardo Ferreira
Published: December 2020

Background

The influence of an ethnic role in the expression of (AD) alzheimer's disease has been studied by several authors. However, there are practically no studies on mental health in the indigenous elderly.

Method

A male patient, 72 years old, chief of the Karajá indigenous tribe, with a medical diagnosis of Alzheimer's Disease, with language disorders was evaluated both in Portuguese and in the native language Karajá. Was used the Boston Naming Test (BNT), Verbal fluency (semantic category) and board Theft of biscuits. Ten target figures were also used, referring to their natural habitat (turtle, pipes, arrow, gourd, jaguar, fire, banana tree, drum, net and hollow).

Result

The results demonstrated that there is a deterioration of the language in both evaluated languages, worse in Portuguese. In the Boston naming test, of the 60 named figures, the patient named figures in 21 Portuguese language and 28 Karajá linguage figures. In verbal fluency he presented 05 words in Portuguese and 07 in Karajá. In oral production, he demonstrated important anomie, an empty speech with little context, in both languages. Regarding the target figures of their habitat, he showed anomie to a figure (drum) in Karajá, "Weriri".

Conclusion

Further studies aimed at investigating language disorders in different ethnic groups, especially indigenous peoples, allow for early diagnosis of dementia, as well as assisting public policies on quality of life and mental health in this community.
3xTg Alzheimer’s disease mice are more susceptible to induced seizures
Authors: Vyver Maxime Vande , De Bundel Dimitri , Nagels Guy , Engelborghs Sebastiaan , Smolders Ilse
Published: December 2020

Background

Epilepsy is a frequent comorbidity in patients with Alzheimer’s disease (AD).1 Early cellular hyperexcitability and seizures are present in several AD mouse models.2,3 The mechanisms responsible for these changes in excitability, the impact on the disease and how they could be reversed remain largely unknown.

Method

We used the triple‐transgenic (3xTg) mouse model, that has mutations affecting the two main proteins involved in AD: amyloid and tau. Seven‐week‐old female 3xTg (n = 19) and age‐ and gender‐matched wild‐type (n = 19) mice were corneally kindled with the 6 Hz electrical stimulations.4 Corneal kindling is a model of repeated induced seizures, where identical electric stimuli applied to the eyes, give rise to a progressive seizure phenotype. Once a mouse was fully kindled (defined as 10 consecutive generalized seizures), it was treated with several antiseizures drugs (ASDs) to assess their effect. Spontaneous locomotor activity and anxiety‐like behavior was tested with open field. After the experiments, mice were killed and brains were evaluated for amyloid and tau pathology with (immuno)histochemistry.

Result

When subjected to identical stimuli 3xTg mice exhibit more severe seizures compared to wild‐type mice (p < 0.001). This difference is most prominent in the beginning of the kindling process and reduces over time (p < 0.001). Levetiracam and brivaracetam have similar efficacy in reducing seizure severity, lamotrigine is less effective. Seizures in 3xTg mice are more resistant to the three tested ASDs in comparison to wild‐type mice (p < 0.01). Despite being more active during handling after several weeks of corneal kindling, no increased spontaneous locomotor activity nor anxiety‐like behavior was detected in 3xTg mice.

Conclusion

The presence of alterations in both amyloid and tau pathways results in an increase in seizure susceptibility at young age, before neurofibrillary tangles or amyloid plaques are expected to be present. The seizures of the 3xTg mice are more resistant to clinically used ASDs. The 6 Hz corneal kindling in mice is increasingly established as a model of epileptogenesis and an accessible model to assess seizure susceptibility and ASD effect in fully kindled AD mice. References: (1) Subota, 2017. (2) Vossel, 2017. (3) Palop, 2016. (4) Leclercq, 2014.
Brain iron burden is associated with accelerated cognitive decline in Alzheimer’s disease
Authors: Ayton Scott , Portbury Stuart , Kalinowski Pawel , Diouf Ibrahima , Agarwal Puja , Schneider Julie A. , Morris Martha Clare , Bush Ashley I.
Published: December 2020

Background

Brain iron has been reported elevated in Alzheimer’s disease (AD) in mostly small studies that were without extensive clinicopathological classification. Brain iron may be important for disease progression since it can become pro‐oxidant and induce cell death (by ferroptosis) or inflammation (by promoting an inflammatory phenotype of microglia). Here, we report the largest post‐mortem study of brain iron in AD, examining iron in multiple brain regions in a large (645) group across the clinicopathological staging of the disease with extensive cognitive data collected in the decade prior to death.

Methods

Iron was measured in gray matter from inferior temporal, mid frontal, anterior cingulate, and cerebellar cortices from 645 post‐mortem brains (Memory and Aging Project). AD pathology was defined by CERAD criteria. NINCDS‐ADRDA criteria were used to assign AD clinical diagnosis during life. Cognitive performance (test batteries for multiple cognitive domains) was assessed annually in the decade prior to death. Analysis consisted of mixed‐effects models with quadratic and linear variables: iron, age, sex, APOE ε4, plaque counts, neurofibrillary tangle counts, Lewy bodies, vascular infarcts.

Results

This study included 166 pathology‐negative subjects without dementia, 40 pathology‐negative subjects with dementia, 212 subjects with AD pathology but without dementia, and 227 subjects with AD pathology and dementia. In subjects without dementia, iron levels were not associated with pathological status, demonstrating that iron does not elevate in the brain merely with increasing pathology load. Iron was elevated (p = 2 × 10−4) in the inferior temporal cortex of people with AD pathology and clinical dementia, but not in any other region. Nonetheless, the iron status of each region was strongly associated with accelerated cognitive decline in the years prior to death, regardless of whether iron was increased, with a composite of iron values in each region demonstrating the greatest performance (Figure 1).

Conclusions

Iron is regionally elevated in AD brains, but, importantly, iron need not be increased to pathological levels to influence neurodegeneration. Rather, iron burden acts as a risk factor trait in brains with iron levels in the normal range.
Hyperspectral retinal imaging shows amyloid‐like deposits in preclinical Alzheimer’s disease
Authors: Shah Tejal M. , Gupta Sunil M. , Goozee Kathryn , Chatterjee Pratishtha , Sohrabi Hamid , Martins Ralph N.
Published: December 2020

Background

Brain beta‐amyloid deposits in Alzheimer’s disease (AD) are associated with retinal beta‐amyloid deposits post‐mortem, yet, findings from imaging the live human retina provide inconclusive evidence due to confounding factors such as drusen found in age‐related macular degeneration [(AMD), (Kayabasi 2014, Koronyo‐Hamaoui 2017)]. We therefore aimed to identify drusen and retinal amyloid‐like deposits via hyperspectral imaging.

Method

Cognitively normal (n=45) older adults, aged 50‐85 years with known neocortical amyloid burden (NAB) including those at‐risk for AD (SUVR≥1.35), were recruited from our study cohorts in Sydney, New South Wales. All participants completed imaging in the spectral range of 450 to 900nm wavelength at 5nm steps. 11 participants completed optical coherence tomography to confirm presence/absence of drusen. Raw hyperspectral images were visually scanned to identify retinal deposits.

Result

Matched to our reference images, we identified retinal hyperintense ‘nano dots’. The spectral range of drusen and nano dots was between 500 to 635 nm and 450 to 600 nm respectively. Drusen was more around the macula in a clustered fashion. nano dots were seen in abundance in the superior quadrant, scattered along the blood vessels and appeared smaller with well distinct margin. In participants with no history of AMD (n=30), the visual identification of nano dots was possible for 77% in high NAB and no nanodots were visually identified in 70% in low NAB group participants.

Conclusion

Further investigation is required to examine the nano dots to determine whether they have diagnostic significance.
Cognitive training for people with dementia: A Cochrane review
Authors: Bahar‐Fuchs Alex , Martyr Anthony , Goh Anita M Y , Sabates Julieta M , Clare Linda
Published: December 2020

Background

Cognitive training (CT) has been found by previous reviews to be ineffective in relation to cognitive and non‐cognitive outcomes among people with neurodegenerative or vascular dementias (Bahar‐Fuchs et al. 2013). However, the quality of trials has been regarded as low, and numerous new trials have been completed in recent years. Here we present findings of a comprehensive update to this review (Bahar‐Fuchs et al. 2019).

Methods

33 RCTs were eligible for inclusion, 11 of which were included in our 2013 review. Study characteristics and data required for effect size calculations were extracted and Risk of Bias for each study was rated in duplicate. Change from baseline was used to calculate effect estimates (Hedges g), and a random effects meta‐analysis was performed, including investigation of effect moderators. Quality of evidence was evaluated using GRADE.

Results

Figure 1 summarizes risk of bias in various domains. We found moderate quality evidence of a small‐moderate effect of CT relative to control on the primary outcome, global cognition immediately following treatment (SMD=0.42, CI=0.23‐0.62, Figure 2), which was maintained at a medium‐term follow‐up. None of our pre‐specified factors moderated this effect. We also found high‐quality evidence of a moderate effect of CT on verbal semantic fluency (SMD 0.52, 95% CI 0.23‐0.81) at end of treatment, which was maintained in the medium term. No benefits of CT where found compared with an alternative treatment, and the quality of evidence in relation to most other outcomes was low, so we could not determine whether it was associated with meaningful benefits.

Conclusions

This comprehensive updated review suggests, for the first time, that CT is associated with a small to moderate effect on global cognition and semantic fluency in people with mild‐moderate dementia. quality of evidence remains an issue, and confidence in the findings in relation to many meaningful outcomes remains low. References: Bahar‐Fuchs, A., et al. (2013). Cognitive training and cognitive rehabilitation for mild to moderate Alzheimer's disease and vascular dementia. Cochrane Database of Systematic Reviews, Issue 6. Bahar‐Fuchs A, et al. (2019). Cognitive training for people with mild to moderate dementia. Cochrane Database of Systematic Reviews. 2019(3).
Rates of amyloid PET positivity in geriatric HIV
Authors: Milanini Benedetta , Javandel Shireen , Hillis Madeline , Chen Karen , Hellmuth Joanna , Paul Robert , Pohl Kilian M , Valcour Victor
Published: December 2020

Background

Chronic HIV infection and amyloid deposition with aging may represent a double‐hit to the brain. We aimed to define the rate of amyloid positivity among older HIV‐infected adults and contrast the demographic, clinical and neuropsychological features of HIV+ amyloid PET+ individuals compared to HIV+ amyloid PET‐ participants.

Method

Study sample included 52 adults with chronic HIV infection. Participants underwent a standardized neurological and neuropsychological assessment that tapped multiple cognitive domains. HIV diagnostic criteria informed by clinical acumen were applied to diagnose HIV‐associated neurocognitive disorder. None of the participants showed a clinical picture consistent with Alzheimer’s disease (AD). Florbetapir amyloid PET scans were read by trained and certified neurologists as positive (n=5) or negative (n=47) (Johnson et al., 2013). T‐tests and chi‐squared tests were performed to explore differences between the two groups.

Result

We found 10% rate of amyloid positivity in our cohort. The PET‐ and PET+ groups were similar in age, sex and education. The mean (SD; range) age was 67 (5; 60‐86) for PET‐ and 69 (5; 63‐73) for PET+ participants. All participants but two were male (PET‐: 45 (96%); PET+: 5 (100%)). The mean (SD) education was 16 (2) for both groups. No differences were found in clinical HIV‐related variables. For PET‐ participants, mean (SD) nadir and current CD4 count were 165 (126) and 574 (275) versus 188 (116) and 620 (180) in the PET+ group. All participants were on antiretroviral treatment with undetectable HIV RNA in plasma. Cognitively, all participants presented with mild neurocognitive disorder and the two groups performed similarly in all the cognitive domains explored, including memory.

Conclusion

Results reveal a low frequency of amyloid positivity among virally suppressed HIV‐infected individuals over the age of 60, similar to that published among the age‐matched seronegative population (i.e., 12%), suggesting that HIV does not link to a higher amyloid plaque burden. Moreover, older HIV‐infected individuals classified as amyloid positive exhibit a similar profile as their amyloid negative counterparts. While we did not observe an increased amyloid deposition by using PET, further studies are needed to determine if amyloid PET is an effective tool for identifying AD in the setting of HIV.
Reduction of lipid peroxidase levels in EFAD mouse model
Authors: Cacciottolo Mafalda , Thorwald Max A. , Forman Henry J. , Morgan Todd E. , Finch Caleb E.
Published: December 2020

Background

Cerebral microbleeds (MBs) are more prevalent in APOE4 carriers and associated with Alzheimer Disease (AD). Loss of cerebrovascular integrity, blood‐brain barrier breakdown, and reduced Aβ clearance are also shown by APOE4 carrier mice. In AD, increased brain amyloid coupled with increased oxidative stress may synergistically contribute to MBs prevalence. EFAD mice carrying familial dominant AD genes in combination with human apoE alleles are a model for sex differences in AD, with greater amyloid accumulation and microbleeds in female E4FAD mice.

Independently, Aβ and heme from microbleeds contribute to increased oxidative stress. New data suggest increased lipid peroxidation in E4 mice at baseline as measured by 4‐HNE. Peroxiredoxin 6 (Prdx6) and glutathione peroxidase 4 (GPx4) are the only known antioxidant enzymes capable of detoxifying oxidized phospholipids.

Method

Prdx6 and GPx4 were studied by Western blot in cortical lysates of 6mo old EFAD mice. To evaluate Aβ contribution, we analyzed Prdx6 and GPx4 in 2mo old EFAD mice, which show 2 to 10‐fold lower Aβ compared to 6mo EFAD mice, and 6mo old EFAD non carrier siblings (no AD‐transgene).

Result

Prdx6 was decreased in E4FAD mice (M: ‐30%; F: ‐50%) compared to E3FAD mice. GPx4 was decreased only n E4FAD females (M: no change; F: ‐50%). Younger mice did not show differences in either lipid peroxidases at 2mo. Interestingly, Prdx6 but not GPx4 was reduced in 6mo old female E4FAD non carrier siblings.

Conclusion

Our data suggest that the decreased levels of Prdx6 in 6mo old female E4 carrier mice in absence of Aβ might impair their ability to reduce oxidized lipids and predispose them to membrane alteration. Moreover, aging and increase of Aβ load together might contribute to the reduction of GPx4 levels in APOE4 carriers and the accumulation of MBs. Additional studies are required to clarify the underlying interaction sex‐apoE allele in MBs onset and its contribution to the pathogenesis of AD.
Overview of immune system in AD
Authors: Heneka Michael T.
Published: December 2020

Background

The accumulation of neurotoxic amyloid beta peptides along with neurofibrillary tangle formation are key pathological hallmarks of Alzheimer’s disease. The brain has been considered as an immune‐privileged organ, however, increasing evidence from translational, genetic, and pathological studies suggests that activation of distinct innate immune pathways are a third important disease hallmark which, once initiated, actively contributes to disease progression and chronicity.

Method

Representing the innate immune system, microglial cells play a pivotal role in this immune response and are activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors. This immune activation leads to the release of inflammatory mediators, but also distracts microglia cells from their physiological functions and tasks, including debris clearance and trophic factor support. Likewise, the adaptive immune system shows changes that suggest that it actively contributes to the immune processes that are ongoing in the brain during the entire disease trajectory.

Result

Several lines of evidence suggest that immune processes may have protective as well as detrimental consequences. The precise molecular, spatial and temporal characterization of these immune processes will be necessary in order to develop new diagnostics as well as therapeutic interventions.

Conclusion

An overview of the current understanding of immune mechanisms in AD, their link to the microbiome, as well as open questions will be outlined and discussed.