PCOM Library / Hot Topics in Research / Internal Medicine / Neurology / Archive for "Alzheimer Disease"

Category: Alzheimer Disease

Hot Topics: Dementia Risk Doubled After Stroke

Jackie Werner Dementia, Hot Topics in Research, Neurology

Stroke and dementia risk: A systematic review and meta-analysis

Kuźma E, Lourida I, Moore SF, Levine DA, Ukoumunne OC, Llewellyn DJ. Stroke and dementia risk: A systematic review and meta-analysis. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. . https://doi.org/10.1016/j.jalz.2018.06.3061.

Stroke is an established risk factor for all-cause dementia, though meta-analyses are needed to quantify this risk.

We searched Medline, PsycINFO, and Embase for studies assessing prevalent or incident stroke versus a no-stroke comparison group and the risk of all-cause dementia. Random effects meta-analysis was used to pool adjusted estimates across studies, and meta-regression was used to investigate potential effect modifiers.

We identified 36 studies of prevalent stroke (1.9 million participants) and 12 studies of incident stroke (1.3 million participants). For prevalent stroke, the pooled hazard ratio for all-cause dementia was 1.69 (95% confidence interval: 1.49–1.92; P < .00001; I2 = 87%). For incident stroke, the pooled risk ratio was 2.18 (95% confidence interval: 1.90–2.50; P < .00001; I2 = 88%). Study characteristics did not modify these associations, with the exception of sex which explained 50.2% of between-study heterogeneity for prevalent stroke.

Stroke is a strong, independent, and potentially modifiable risk factor for all-cause dementia.

Hot Topics: New Technology Could Allow Dementia Patients to Live Alone Longer

Jackie Werner Dementia, Hot Topics in Research, Neurology

Health management and pattern analysis of daily living activities of people with dementia using in-home sensors and machine learning techniques

Enshaeifar S, Zoha A, Markides A, et al. Health management and pattern analysis of daily living activities of people with dementia using in-home sensors and machine learning techniques. PLOS ONE. 2018;13(5):e0195605. https://doi.org/10.1371/journal.pone.0195605.

The number of people diagnosed with dementia is expected to rise in the coming years. Given that there is currently no definite cure for dementia and the cost of care for this condition soars dramatically, slowing the decline and maintaining independent living are important goals for supporting people with dementia. This paper discusses a study that is called Technology Integrated Health Management (TIHM). TIHM is a technology assisted monitoring system that uses Internet of Things (IoT) enabled solutions for continuous monitoring of people with dementia in their own homes. We have developed machine learning algorithms to analyse the correlation between environmental data collected by IoT technologies in TIHM in order to monitor and facilitate the physical well-being of people with dementia. The algorithms are developed with different temporal granularity to process the data for long-term and short-term analysis. We extract higher-level activity patterns which are then used to detect any change in patients’ routines. We have also developed a hierarchical information fusion approach for detecting agitation, irritability and aggression. We have conducted evaluations using sensory data collected from homes of people with dementia. The proposed techniques are able to recognise agitation and unusual patterns with an accuracy of up to 80%.

Hot Topics: Treating Depression May Counteract Cognitive Impairments

Jackie Werner Alzheimer Disease, Geriatrics, Hot Topics in Research, Mood Disorders

Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment

Sugarman MA, Alosco ML, Tripodis Y, Steinberg EG, Stern RA. Neuropsychiatric symptoms and the diagnostic stability of mild cognitive impairment. Journal of Alzheimer’s Disease. 2018:1-15. doi: 10.3233/JAD-170527.

Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer’s disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses.

The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses.

The sample included 6,763 participants from the National Alzheimer’s Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15).

1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia.

The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.




Hot Topics: Alzheimer’s Further Linked to Brain Plaques

Jackie Werner Alzheimer Disease, Hot Topics in Research, Senile Plaques

Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons

Donohue MC, Sperling RA, Petersen R, al e. Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. JAMA. 2017. 317(22):2305-2316. doi: 10.1001/jama.2017.6669.

Importance  Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later Alzheimer-related cognitive decline.

Objective  To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid.

Design, Setting, and Participants  Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Exposures  Individuals were classified at baseline as having normal (n = 243) or elevated (n = 202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid β.

Main Outcomes and Measures  Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 [worst] to 30 [best] points), Clinical Dementia Rating Sum of Boxes (CDR–Sum of Boxes; 0 [best] to 18 [worst] points), and Logical Memory Delayed Recall (0 [worst] to 25 [best] story units).

Results  Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR–Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points [95% CI, 0.94-2.10]; P < .001), MMSE (mean difference, 0.56 points [95% CI, 0.32-0.80]; P < .001), and CDR–Sum of Boxes (mean difference, 0.23 points [95% CI, 0.08-0.38]; P = .002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units [95% CI, −0.02 to 1.48]; P = .056).

Conclusions and Relevance  Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.

A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012

PJ Grier Alzheimer Disease, December, Dementia, Hot Topics in Research

A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012

Importance  The aging of the US population is expected to lead to a large increase in the number of adults with dementia, but some recent studies in the United States and other high-income countries suggest that the age-specific risk of dementia may have declined over the past 25 years. Clarifying current and future population trends in dementia prevalence and risk has important implications for patients, families, and government programs.

Objective  To compare the prevalence of dementia in the United States in 2000 and 2012.

Design, Setting, and Participants  We used data from the Health and Retirement Study (HRS), a nationally representative, population-based longitudinal survey of individuals in the United States 65 years or older from the 2000 (n = 10 546) and 2012 (n = 10 511) waves of the HRS.

Main Outcomes and Measures  Dementia was identified in each year using HRS cognitive measures and validated methods for classifying self-respondents, as well as those represented by a proxy. Logistic regression was used to identify socioeconomic and health variables associated with change in dementia prevalence between 2000 and 2012.

Results  The study cohorts had an average age of 75.0 years (95% CI, 74.8-75.2 years) in 2000 and 74.8 years (95% CI, 74.5-75.1 years) in 2012 (P = .24); 58.4% (95% CI, 57.3%-59.4%) of the 2000 cohort was female compared with 56.3% (95% CI, 55.5%-57.0%) of the 2012 cohort (P < .001). Dementia prevalence among those 65 years or older decreased from 11.6% (95% CI, 10.7%-12.7%) in 2000 to 8.8% (95% CI, 8.2%-9.4%) (8.6% with age- and sex-standardization) in 2012 (P < .001). More years of education was associated with a lower risk for dementia, and average years of education increased significantly (from 11.8 years [95% CI, 11.6-11.9 years] to 12.7 years [95% CI, 12.6-12.9 years]; P < .001) between 2000 and 2012. The decline in dementia prevalence occurred even though there was a significant age- and sex-adjusted increase between years in the cardiovascular risk profile (eg, prevalence of hypertension, diabetes, and obesity) among older US adults.

Conclusions and Relevance  The prevalence of dementia in the United States declined significantly between 2000 and 2012. An increase in educational attainment was associated with some of the decline in dementia prevalence, but the full set of social, behavioral, and medical factors contributing to the decline is still uncertain. Continued monitoring of trends in dementia incidence and prevalence will be important for better gauging the full future societal impact of dementia as the number of older adults increases in the decades ahead.


Kenneth M. Langa, MD, PhD1,2,3,4; Eric B. Larson, MD, MPH5; Eileen M. Crimmins, PhD6; et alJessica D. Faul, PhD3; Deborah A. Levine, MD, MPH; Mohammed U. Kabeto, MS; David R. Weir, PhD 
JAMA Intern Med. Published online November 21, 2016. doi:10.1001/jamainternmed.2016.6807

Visualization of regional tau deposits using 3H-THK5117 in Alzheimer brain tissue

PJ Grier Alzheimer Disease, April, Hot Topics in Research

Visualization of regional tau deposits using 3H-THK5117 in Alzheimer brain tissue


 The accumulation of neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein, starts spreading early in specific regions in the course of Alzheimer’s disease (AD), correlating with the progression of memory dysfunction. The non-invasive imaging of tau could therefore facilitate the early diagnosis of AD, differentiate it from other dementing disorders and allow evaluation of tau immunization therapy outcomes. In this study we characterized the in vitro binding properties of THK5117, a tentative radiotracer for positron emission tomography (PET) imaging of tau brain deposits.


Saturation and competition binding studies of 3H-THK5117 in post-mortem AD brain tissue showed the presence of multiple binding sites. THK5117 binding was significantly higher in hippocampal (p < 0.001) and temporal (p < 0.01) tissue homogenates in AD compared to controls. Autoradiography studies with 3H-THK5117 was performed on large frozen brain sections from three AD cases who had been followed clinically and earlier undergone in vivo 18F-FDG PET investigations. The three AD cases showed distinct differences in regional THK5117 binding that were also observed in tau immunohistopathology as well as in clinical presentation. A negative correlation between in vivo 18F-FDG PET and in vitro 3H-THK5117 autoradiography was observed in two of the three AD cases.


This study supports that new tau PET tracers will provide further understanding on the role of tau pathology in the diversity of the clinical presentation in AD.

Acta Neuropathologica Communications20153:40, DOI: 10.1186/s40478-015-0220-4; Lemoine et al. 2015; Received: 14 June 2015; Accepted: 15 June 2015; Published: 2 July 2015

Schizophrenia risk from complex variation of complement component 4

PJ Grier Dementia, February, Hot Topics in Research, Memory Impairment

Schizophrenia risk from complex variation of complement component 4


Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

Corresponding Author: McCarroll, Steven A.

Nature (2016), doi:10.1038/nature16549, Published online 27 January 2016

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

PJ Grier Brain, Dementia, Hot Topics in Research, Memory Impairment, Neurology

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.


Cho-Yi Chen, Proceedings of the National Academy of Sciences 2015 of the USA ; published ahead of print December 22, 2015, doi:10.1073/pnas.1508249112.