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Archive for the ‘Aging’ Category

An important paper from Füger et al last month, in which they labelled individual microglia in mouse brains and tracked their locations over 1.5 years. Here were some of their major findings:

  • The median lifespan of microglia was estimated to be approximately 2.5 years, which is close to the mean lifespan of the mice that they were studying. So, it is fair to think of microglia as long-lived tissue macrophages. It is also clear how changes in microglia epigenetics in earlier life could affect late-life cognitive outcomes.
  • Microglia died at a higher rate in older mice, suggesting that aging may lead to alterations in microglia function that could affect neurodegenerative disease.
  • In APPPS1 mice, microglia proliferate 3x more than usual in areas of the cortex without amyloid plaque, but only proliferate a normal amount in areas of the cortex with amyloid plaque. This suggests that any increase in microglia near plaque is likely due to migration, not local proliferation.
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Idiopathic normal pressure hydrocephaus (NPH) is a diagnosis of occult hydrocephalus with normal CSF pressure on LP that was first described in 1965 and is often considered one of the treatable causes of dementia.

The original paper used the now uncommon brain imaging technique of pneumoencephalography, which involved draining the CSF, injecting air as a contrast medium, and performing a brain xray:

Screen Shot 2017-09-17 at 10.48.34 AM

Figure 2 from Adams et al 1965 showing uniformly enlarged ventricles; doi: 10.1056/NEJM196507152730301

At my med school we learned NPH by the triad of “wet, wobbly, and wacky”, referring to its classic triad of symptoms: urinary incontinence, gait disturbance, and cognitive impairment.

Like many symptom triads, these symptoms are non-sensitive, with the full triad seen in <60% of patients. It is also non-specific, as urinary incontinence is seen in ~20-40% of those over 60, gait impairment is seen in ~20% over those over 75, and mild cognitive impairment is seen in ~35% of those over 70.

Espay et al explain all of this in the introduction of their critical literature review of idiopathic NPH. One of their major points is that ventricle enlargement is also non-specific, as it is common in other neurodegenerative diseases such as AD, DLB, and PSP.

Here are some of their other points:

  • There are no specific clinical, imaging, or neuropathologic findings in NPH.
  • The determination of ventricle enlargement on MRI is subjective and not standardized.
  • A “true” diagnosis is dependent upon a treatment response to CSF diversion via a ventriculoperitoneal shunt (VPS), which is circular and problematic.
  •  There has never been a well-defined RCT to evaluate the use of VPS in NPH.
  • Because many patients diagnosed with NPH may in fact have NPH that is secondary rather than a precursor to other neurodegenerative diseases, the fact that VPS may lead to short-term cognitive amelioration even in these patients suggests that VPS should still be considered as a way to improve cognition even in patients that are diagnosed with these neurodegenerative diseases.

Overall, this paper is well worth a read for people interested in treatments for dementia.

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Over the last few years researchers have figured out how to transform iPS cells into dopamine-producing neurons, raising the possibility of transplanting dopaminergic cells into the brains of patients with Parkinson’s disease (PD).

Kikuchi et al. looked at the effect of dopaminergic cell transplantation into the putamen on PD symptoms in monkeys treated with MPTP, which is a model of PD.

Compared to placebo injections, the stem cell transplantation improved symptoms. Notably, it did so somewhat less well than L-DOPA, but it seems plausible that this therapy could be eventually used once L-DOPA has failed, as L-DOPA tends to do over time in PD.

Screen Shot 2017-09-11 at 5.47.25 PM

Extended Data Fig 2K/I; doi:10.1038/nature23664

Perhaps the best news from this study is that they identified no markers of cancer formation in the transplanted brains after more than a year post-transplant. It’s always good news when your proposed therapy turns out to be less likely to cause brain cancer as a side effect.

Clinical trials will apparently start soon — from which we will have much to learn, and hopefully some good news.

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In everyday life, your muscles, metabolism, and nervous system work together to ensure that your cerebral blood flow meets the metabolic needs of your various brain regions. So if you are trying to scrutinize an impressionist painting, your body will likely relocate more blood flow to your visual cortex.

Following a stroke, this cerebral blood flow regulation is impaired. But, the degree and spread of the impairment is unknown. To investigate this, Hu et al. measured systemic blood pressure (BP) and used a transcranial doppler to measure cerebral blood flow velocity (BFV) at the same time.

In their model, better regulation of cerebral blood flow corresponds to a sharper phase shift between blood pressure (BP) and cerebral blood flow velocity (BFV). Individuals with the highest score of a 9 on their autoregulation index (ARI) have more regulation than those with the lowest score of 0, which corresponds to no phase shift.

When they compared patients who had experienced MCA infarcts (a common type of stroke) and healthy controls, they found that stroke patients had significantly less phase coupling between blood pressure and cerebral blood flow. This effect was pronounced over a wide range of blood pressure oscillation frequencies.

Given enough time and the right conditions, can the body repair its ability to regulate cerebral blood flow following a stroke? When the researchers examined this, they found no statistically significant difference between the BFV-BP phase difference and time since stroke.

But, that doesn’t mean that there’s a statistically significant lack of difference. So, further longitudinal studies will be needed to help clarify whether, in certain people in certain environments, the brain improves its cerebral regulation following stroke.

Reference

Hu K, Lo M-T, Peng C-K, Liu Y, Novak V (2012) A Nonlinear Dynamic Approach Reveals a Long-Term Stroke Effect on Cerebral Blood Flow Regulation at Multiple Time Scales. PLoS Comput Biol 8(7): e1002601. doi:10.1371/journal.pcbi.1002601

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How does the connection morphology of motor neuron axons and muscle fiber endplates change with age? Chai et al recently published some results addressing, in part, this question.

Their study compared young 3 month and geriatric 29 month old mice, which, as the authors note, correspond to roughly 20 and 80 years in humans, respectively. However, it’s always important to keep in mind that mice differ from humans in many important ways.

The researchers cut out muscle tissue, sectioned it in 20 um segments, and double stained with antibodies for both synaptophysin (to detect pre-synaptic nerve terminals) and α-bungarotoxin (to detect postsynaptic muscle endplates).

They then classified neuromuscular junctions that stained positive for both synaptophysin and α-bungarotoxin as innervated, and classified junctions positive for α-bungarotoxin only as denervated. Below is an example of a confocal image of a double stained tissue slice.

EDL = extensor digitorum longus; synaptophysin = red; α-bungarotoxin = green; overlay = yellow; white circle = example of endplate positive for only α-bungarotoxin; scale bars = 75 um; doi:10.1371/journal.pone.0028090.g002 part d-f

Across all samples analyzed, ~7 +/- 2% of neuromuscular junctions were fully denervated in 3 month old mice and ~20 +/- 3% of neuromuscular junctions were fully denervated in 29 month old mice. Such denervation could help account for any age-related decrease in muscle function.

Interestingly and importantly, the researchers did not find a similar trend in the soleus. The lack of concordance underscores some of the variability across tissues of the same type in aging.

Reference

Chai RJ, Vukovic J, Dunlop S, Grounds MD, Shavlakadze T (2011) Striking Denervation of Neuromuscular Junctions without Lumbar Motoneuron Loss in Geriatric Mouse Muscle. PLoS ONE 6(12): e28090. doi:10.1371/journal.pone.0028090

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In their review of the “neuroproteome” associated with aging and cognitive decline, VanGuilder and Freeman discuss some of the technical approaches and findings in the field.

This illustrative figure shows some of the major cellular players involved and lists some example proteins involved in four important pathways:

"numerous cell types (microglia (green), astrocytes (orange), oligodendrocytes (blue), and neurons (violet)) and subcellular components (mitochondria (brown), endoplasmic reticulum (green), cytoskeleton (orange/red), and synaptic machinery) are affected by brain aging"; doi: 10.3389/fnagi.2011.00008

As you can see, many proteins have been implicated, although the degree of up-/down-regulation of these proteins is not fully elucidated.

The authors mention the value of standardizing efforts to profile the proteome in important brain regions across the lifespan of rodent models. This step would make these results more robustly quantitative and help iterate towards a consensus.

Reference

VanGuilder H. D. and Freeman W. M (2011) The hippocampal neuroproteome with aging and cognitive decline: past progress and future directions. Front. Ag. Neurosci. 3:8. doi: 10.3389/fnagi.2011.00008

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More neurons are born than necessary, and synaptic pruning is the process by which neurons that have not made as many functional synaptic connections with other neurons are preferentially degraded.

Abitz et al counted cells in the medial thalamus of newborn and adult brains using a optical fractionator and Giemsa staining which binds to phosphate groups of DNA. They distinguished small neurons from glial cells on the basis of chromatin pattern, the size / shape of the nucleus, and the visibility of the nucleolus. Here’s an example of the Giemsa stained  cells via micrographs:

scale bar = 10 micrometers, doi:10.1093/cercor/bhl163

They found an average of 11.2 million neurons in the newborn MD thalamus, which decreased to an average of 6.43 million neurons in adults, probably as a result of synaptic pruning. On the other hand, they found 36.3 million glial cells in adults, much higher than the 10.6 million they found in newborns, suggesting that glial progenitor cells still have a few proliferation cycles to undergo in development.

Elsewhere, Elston et al measured the number of spines in the average pyramidal cell of macaque brains in the primary visual cortex (V1), the inferior temporal gyrus (TE), and the prefrontal cortex (PFC) at different stages of development. They found an inverted U shaped curve of spine number with log age:

doi:10.1523/JNEUROSCI.5216-08.2009

The authors conclude that “synaptic activity thresholds that reinforce synapses and stabilize dendritic spines may vary across cortex.” It is interesting that the regions follow the same general trend in each region, peaking at 3.5 months.

References

Maja Abitz , Rune Damgaard Nielsen , Edward G. Jones , Henning Laursen , Niels Graem , and Bente Pakkenberg. Excess of Neurons in the Human Newborn Mediodorsal Thalamus Compared with That of the Adult. Cerebral Cortex Advance Access published on January 11, 2007, DOI 10.1093/cercor/bhl163.

Guy N. Elston, Tomofumi Oga, and Ichiro Fujita. Spinogenesis and Pruning Scales across Functional Hierarchies.  J. Neurosci. 29: 3271-3275; doi:10.1523/JNEUROSCI.5216-08.2009

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