The functional brain favours segregated modular connectivity at old age unless affected by neurodegeneration

AbstractBrain’s modular connectivity gives this organ resilience and adaptability. The ageing process alters the organised modularity of the brain and these changes are further accentuated by neurodegeneration, leading to disorganisation. To understand this further, we analysed modular variability—heterogeneity of modules—and modular dissociation—detachment from segregated connectivity—in two ageing cohorts and a mixed cohort of neurodegenerative diseases. Our results revealed that the brain follows a universal pattern of high modular variability in metacognitive brain regions: the association cortices. The brain in ageing moves towards a segregated modular structure despite presenting with increased modular heterogeneity—modules in older adults are not only segregated, but their shape and size are more variable than in young adults. In the presence of neurodegeneration, the brain maintains its segregated connectivity globally but not locally, and this is particularly visible in dementia with Lewy bodies and Parkinson’s disease dementia; overall, the modular brain shows patterns of differentiated pathology.

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The functional brain favours segregated modular connectivity at old age unless targeted by neurodegeneration

10.1101/463810 ◽

2018 ◽

Author(s):

Luis R Peraza ◽

John T O’Brien ◽

Andrew Blamire ◽

Marcus Kaiser ◽

John-Paul Taylor

Keyword(s):

Older Adults ◽

Young Adults ◽

Human Brain ◽

Brain Regions ◽

Functional Brain ◽

Highly Active ◽

The Brain ◽

Universal Pattern ◽

Segregated Structure ◽

Shape And Size

AbstractBrain’s modular connectivity gives this organ resilience and adaptability. The ageing process alters the human brain, leading to modifications to its organised modularity and these changes are further accentuated by neurodegeneration, leading to disorganisation. To understand this further, we analysed modular variability—heterogeneity of modules—and modular dissociation—detachment from segregated connectivity—in two ageing cohorts and a mixed cohort of neurodegenerative diseases. Our results revealed that the brain follows a universal pattern of modular variability that matches highly active and metacognitive brain regions: the association cortices. We also proved that in ageing the brain moves towards a modular segregated structure despite presenting with increased modular heterogeneity—modules in older adults are not only segregated but their shape and size are more variable than in young adults. In the presence of neurodegeneration, the brain maintains its segregated connectivity globally but not locally; the modular brain shows patterns of differentiated pathology.

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A lifespan program of mouse synaptome architecture

10.1101/838458 ◽

2019 ◽

Author(s):

Mélissa Cizeron ◽

Zhen Qiu ◽

Babis Koniaris ◽

Ragini Gokhale ◽

Noboru H. Komiyama ◽

...

Keyword(s):

Young Adults ◽

Old Age ◽

Mouse Brain ◽

Protein Composition ◽

Brain Regions ◽

Intellectual Ability ◽

Brain Circuits ◽

Brain Circuitry ◽

Wide Scale ◽

The Brain

AbstractHow synapses change molecularly during the lifespan and across all brain circuits is unknown. We analyzed the protein composition of billions of individual synapses from birth to old age on a brain-wide scale in the mouse, revealing a program of changes in the lifespan synaptome architecture spanning individual dendrites to the systems level. Three major phases were uncovered, corresponding to human childhood, adulthood and old age. An arching trajectory of synaptome architecture drives the differentiation and specialization of brain regions to a peak in young adults before dedifferentiation returns the brain to a juvenile state. This trajectory underscores changing network organization and hippocampal physiology that may account for lifespan transitions in intellectual ability and memory, and the onset of behavioral disorders.One sentence summaryThe synaptome architecture of the mouse brain undergoes continuous changes that organize brain circuitry across the lifespan.

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Neural Reorganization and Compensation in Aging

Journal of Cognitive Neuroscience ◽

10.1162/jocn_a_00783 ◽

2015 ◽

Vol 27 (7) ◽

pp. 1275-1285 ◽

Cited By ~ 46

Author(s):

Alexa M. Morcom ◽

Wendy Johnson

Keyword(s):

Older Adults ◽

Young Adults ◽

Cognitive Function ◽

Old Age ◽

Functional Imaging ◽

Current Evidence ◽

Imaging Studies ◽

Functional Reorganization ◽

Theories Of Aging ◽

The Brain

According to prominent theories of aging, the brain may reorganize to compensate for neural deterioration and prevent or offset cognitive decline. A frequent and striking finding in functional imaging studies is that older adults recruit additional regions relative to young adults performing the same task. This is often interpreted as evidence for functional reorganization, suggesting that, as people age, different regions or networks may support the same cognitive functions. Associations between additional recruitment and better performance in older adults have led to the suggestion that the additional recruitment may contribute to preserved cognitive function in old age and may explain some of the variation among individuals in preservation of function. However, many alternative explanations are possible, and recent findings and methodological developments have highlighted the need for more systematic approaches to determine whether reorganization occurs with age and whether it benefits performance. We reevaluate current evidence for compensatory functional reorganization in the light of recent moves to address these challenges.

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Inefficient Encoding as an Explanation for Age-Related Deficits in Recollection-Based Processing

Journal of Psychophysiology ◽

10.1027/0269-8803/a000122 ◽

2014 ◽

Vol 28 (3) ◽

pp. 148-161 ◽

Cited By ~ 12

Author(s):

David Friedman ◽

Ray Johnson

Keyword(s):

Older Adults ◽

Young Adults ◽

Cognitive Processes ◽

Brain Activity ◽

Memory Performance ◽

Brain Regions ◽

Semantic Retrieval ◽

Age Related ◽

The Face ◽

Episodic Memories

A cardinal feature of aging is a decline in episodic memory (EM). Nevertheless, there is evidence that some older adults may be able to “compensate” for failures in recollection-based processing by recruiting brain regions and cognitive processes not normally recruited by the young. We review the evidence suggesting that age-related declines in EM performance and recollection-related brain activity (left-parietal EM effect; LPEM) are due to altered processing at encoding. We describe results from our laboratory on differences in encoding- and retrieval-related activity between young and older adults. We then show that, relative to the young, in older adults brain activity at encoding is reduced over a brain region believed to be crucial for successful semantic elaboration in a 400–1,400-ms interval (left inferior prefrontal cortex, LIPFC; Johnson, Nessler, & Friedman, 2013 ; Nessler, Friedman, Johnson, & Bersick, 2007 ; Nessler, Johnson, Bersick, & Friedman, 2006 ). This reduced brain activity is associated with diminished subsequent recognition-memory performance and the LPEM at retrieval. We provide evidence for this premise by demonstrating that disrupting encoding-related processes during this 400–1,400-ms interval in young adults affords causal support for the hypothesis that the reduction over LIPFC during encoding produces the hallmarks of an age-related EM deficit: normal semantic retrieval at encoding, reduced subsequent episodic recognition accuracy, free recall, and the LPEM. Finally, we show that the reduced LPEM in young adults is associated with “additional” brain activity over similar brain areas as those activated when older adults show deficient retrieval. Hence, rather than supporting the compensation hypothesis, these data are more consistent with the scaffolding hypothesis, in which the recruitment of additional cognitive processes is an adaptive response across the life span in the face of momentary increases in task demand due to poorly-encoded episodic memories.

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Effects of a Motor Imagery Task on Functional Brain Network Community Structure in Older Adults: Data from the Brain Networks and Mobility Function (B-NET) Study

Brain Sciences ◽

10.3390/brainsci11010118 ◽

2021 ◽

Vol 11 (1) ◽

pp. 118

Author(s):

Blake R. Neyland ◽

Christina E. Hugenschmidt ◽

Robert G. Lyday ◽

Jonathan H. Burdette ◽

Laura D. Baker ◽

...

Keyword(s):

Older Adults ◽

Graph Theory ◽

Community Structure ◽

Resting State ◽

Brain Networks ◽

Brain Network ◽

Functional Brain ◽

Network Community ◽

Functional Brain Networks ◽

The Brain

Elucidating the neural correlates of mobility is critical given the increasing population of older adults and age-associated mobility disability. In the current study, we applied graph theory to cross-sectional data to characterize functional brain networks generated from functional magnetic resonance imaging data both at rest and during a motor imagery (MI) task. Our MI task is derived from the Mobility Assessment Tool–short form (MAT-sf), which predicts performance on a 400 m walk, and the Short Physical Performance Battery (SPPB). Participants (n = 157) were from the Brain Networks and Mobility (B-NET) Study (mean age = 76.1 ± 4.3; % female = 55.4; % African American = 8.3; mean years of education = 15.7 ± 2.5). We used community structure analyses to partition functional brain networks into communities, or subnetworks, of highly interconnected regions. Global brain network community structure decreased during the MI task when compared to the resting state. We also examined the community structure of the default mode network (DMN), sensorimotor network (SMN), and the dorsal attention network (DAN) across the study population. The DMN and SMN exhibited a task-driven decline in consistency across the group when comparing the MI task to the resting state. The DAN, however, displayed an increase in consistency during the MI task. To our knowledge, this is the first study to use graph theory and network community structure to characterize the effects of a MI task, such as the MAT-sf, on overall brain network organization in older adults.

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Neuropsychological Differences Related to Age in Dementia with Lewy Bodies

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000477296 ◽

2017 ◽

Vol 7 (2) ◽

pp. 188-194 ◽

Cited By ~ 2

Author(s):

Yasuhiro Nagahama ◽

Tomoko Okina ◽

Norio Suzuki

Keyword(s):

Old Age ◽

Memory Impairment ◽

Dementia With Lewy Bodies ◽

Memory Performance ◽

Oldest Old ◽

Age Groups ◽

Lewy Bodies ◽

Age Group ◽

Recent Memory ◽

Better Than

Background/Aims: To examine the influence of age on neuropsychological performances in dementia with Lewy bodies (DLB) and Alzheimer disease (AD) patients. Methods: We examined memory, executive, and visuo-constructional performances in 202 DLB patients and 236 AD patients. We divided the subjects into three age groups (65–74, 75–84, and 85–95 years old), and evaluated the differences in neuropsychological performances. Results: Recent memory in the DLB group was significantly better than that in the age-matched AD group when comparing the age groups 65–74 years and 75–84 years; however, memory impairment in the DLB patients in the age group 85–95 years was comparable with that in the age-matched AD patients. In contrast to recent memory, the other assessed neuropsychological performances, such as visuospatial and executive functions, showed no significant change in differences between the DLB and AD groups with advancing age. Conclusion: Our study revealed that the nature of memory impairment in DLB patients changes according to age. DLB patients in the young-old and old-old age groups showed significantly better memory performance than the age-matched AD patients, whereas memory performance of the DLB patients in the oldest-old age group was similar to that of the age-matched AD patients. This may be associated with the increased rate of coexisting AD pathology in DLB patients with older age.

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Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies

npj Vaccines ◽

10.1038/s41541-021-00424-2 ◽

2022 ◽

Vol 7 (1) ◽

Author(s):

Changyoun Kim ◽

Armine Hovakimyan ◽

Karen Zagorski ◽

Tatevik Antonyan ◽

Irina Petrushina ◽

...

Keyword(s):

Dna Vaccines ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Lewy Bodies ◽

Amyloid Β ◽

The Elderly ◽

Brain Regions ◽

Dependent Manner ◽

Lewy Neurites ◽

The Brain

AbstractAccumulation of misfolded proteins such as amyloid-β (Aβ), tau, and α-synuclein (α-Syn) in the brain leads to synaptic dysfunction, neuronal damage, and the onset of relevant neurodegenerative disorder/s. Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are characterized by the aberrant accumulation of α-Syn intracytoplasmic Lewy body inclusions and dystrophic Lewy neurites resulting in neurodegeneration associated with inflammation. Cell to cell propagation of α-Syn aggregates is implicated in the progression of PD/DLB, and high concentrations of anti-α-Syn antibodies could inhibit/reduce the spreading of this pathological molecule in the brain. To ensure sufficient therapeutic concentrations of anti-α-Syn antibodies in the periphery and CNS, we developed four α-Syn DNA vaccines based on the universal MultiTEP platform technology designed especially for the elderly with immunosenescence. Here, we are reporting on the efficacy and immunogenicity of these vaccines targeting three B-cell epitopes of hα-Syn aa85–99 (PV-1947D), aa109–126 (PV-1948D), aa126–140 (PV-1949D) separately or simultaneously (PV-1950D) in a mouse model of synucleinopathies mimicking PD/DLB. All vaccines induced high titers of antibodies specific to hα-Syn that significantly reduced PD/DLB-like pathology in hα-Syn D line mice. The most significant reduction of the total and protein kinase resistant hα-Syn, as well as neurodegeneration, were observed in various brain regions of mice vaccinated with PV-1949D and PV-1950D in a sex-dependent manner. Based on these preclinical data, we selected the PV-1950D vaccine for future IND enabling preclinical studies and clinical development.

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Noninvasive Detection of Misfolded Proteins in the Brain Using [11C]BF-227 PET

Bioinformatics ◽

10.4018/978-1-4666-3604-0.ch025 ◽

2013 ◽

pp. 438-445

Author(s):

Nobuyuki Okamura ◽

Shozo Furumoto ◽

Manabu Tashiro ◽

Katsutoshi Furukawa ◽

Hiroyuki Arai ◽

...

Keyword(s):

Protein Misfolding ◽

Protein A ◽

Lewy Bodies ◽

Protein Aggregates ◽

Brain Regions ◽

Postmortem Brain ◽

In Vivo Detection ◽

Misfolding Diseases ◽

The Brain

Alzheimer’s disease (AD) and many other neurodegenerative disorders belong to the family of protein misfolding diseases. These diseases are characterized by the deposition of insoluble protein aggregates containing an enriched ß-sheet structure. To evaluate PET amyloid-imaging tracer [11C]BF-227 as an agent for in vivo detection of various kinds of misfolded protein, a [11C]BF-227 PET study was performed in patients with various protein misfolding diseases, including AD, frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS). BF-227 binds to ß-amyloid fibrils with high affinity. Most of the AD patients showed prominent retention of [11C]BF-227 in the neocortex. In addition, neocortical retention of BF-227 was observed in the subjects with mild cognitive impairment who converted to AD during follow-up. DLB patients had elevated [11C]BF-227 uptake in the neocortex. However, FTD and sCJD patients showed no cortical retention of [11C]BF-227. Patients with multiple system atrophy had elevated BF-227 binding in the putamen. Finally, GSS patients had elevated BF-227 uptake in the cerebellum and other brain regions. This chapter confirms that BF-227 can selectively bind to a-synuclein and prion protein deposits using postmortem brain samples. Based on these findings, [11C]BF-227 is not necessarily specific for ß-amyloid in AD patients. However, this tracer could be used to detect various types of protein aggregates in the brain.

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Profiles of matrix metalloproteinases and their inhibitors in plasma of patients with dementia

International Psychogeriatrics ◽

10.1017/s1041610207005790 ◽

2008 ◽

Vol 20 (1) ◽

pp. 67-76 ◽

Cited By ~ 35

Author(s):

Stefan Lorenzl ◽

Katharina Büerger ◽

Harald Hampel ◽

M. Flint Beal

Keyword(s):

Matrix Metalloproteinases ◽

Brain Tissue ◽

Dementia With Lewy Bodies ◽

Constitutive Expression ◽

Lewy Bodies ◽

Postmortem Brain ◽

Plasma Samples ◽

Postmortem Brain Tissue ◽

The Brain ◽

Circulating Levels

ABSTRACTBackground: Matrix metalloproteinases (MMPs) are elevated in the brain tissue of patients with dementia and may play a role in the pathophysiology of dementia. MMP-9 and tissue inhibitors of MMPs (TIMPs) are elevated in postmortem brain tissue of patients with Alzheimer's disease (AD). In a previous study we showed that circulating levels of MMP-9 are elevated in AD patients. The aim of the present study was to examine circulating levels of MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 in the plasma of patients with mild cognitive impairment (MCI), AD, vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD), to determine, whether plasma profiles of MMPs and TIMPs differ in various types of dementia.Methods: Gelatinolytic activity (MMP-2 and MMP-9) was measured in all plasma samples by zymography. Levels of MMP-2, MMP-9, MMP-1 as well as TIMP-1 and TIMP-2 were measured by ELISA.Results: We found constitutive expression of MMP-1, -2 and -9 as well as TIMP-1 and -2 in all the samples investigated. As shown previously, MMP-9 was significantly elevated in the plasma of AD patients (p = 0.004) as compared to controls and MCI patients. Plasma levels of TIMP-1 were significantly lower in VD samples as compared to all other groups. Levels of TIMP-2 were significantly lower in patients with FTD as compared to AD, VaD and MCI patients. There were no significant changes of MMP-1 and MMP-2 levels in the samples.Conclusion: These findings suggest that circulating levels of MMP-9, TIMP-1 and TIMP-2 and changes in the MMP/TIMP balance in plasma differ in various types of dementia.

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