The physical and mental activity can counteract the neurodegenerative disease


A physically and mentally active lifestyle confers resilience to frontotemporal dementia (FTD), even in people whose genetic profile makes the eventual development of the disease virtually inevitable, according to new research by scientists at the UC San Francisco Memory and Aging Center.

The research aligns with long-standing findings that exercise and cognitive fitness are one of the best ways to prevent or slow Alzheimer’s disease, but is the first study to show that the same types of behaviors can benefit people with FTD, which is caused by a distinct form of brain degeneration.

FTD is a neurodegenerative disease that can disrupt personality, decision-making, language, or movement abilities, and typically begins between the ages of 45 and 65. It is the most common form of dementia in people under 65 (accounting for 5 to 15 percent of dementia cases overall) and typically results in rapid cognitive and physical decline and death in less than 10 years.

There are currently no drugs to treat FTD, though numerous clinical trials for the disease are underway at UCSF Memory and Aging Center and elsewhere.

“This is devastating disease without good medical treatments, but our results suggest that even people with a genetic predisposition for FTD can still take actions to increase their chances of living a long and productive life.

Their fate may not be set in stone,” said Kaitlin Casaletto, PhD, assistant professor of neurology at the UCSF Memory and Aging Center and corresponding author of the new study, published January 8, 2020 in Alzheimer’s and Dementia.

‘If This Were a Drug, We Would Be Giving it to All Our Patients’

About 40 percent of people with FTD have a family history of the disease, and scientists have identified specific dominant genetic mutations that drive the development of the disease in roughly half of these cases. But even in these individuals, the disease can have very different courses and severity.

There’s incredible variability in FTD, even among people with the same genetic mutations driving their disease. Some people are just more resilient than others for reasons we still don’t understand,” said, Casaletto, a member of the UCSF Weill Institute for Neurosciences.

“Our hypothesis was that the activities people engage in each day of their lives may contribute to the very different trajectories we see in clinic, including when the disease develops and how it progresses.”

To test this hypothesis, Casaletto and colleagues studied how lifestyle differences affected FTD progression in 105 people with dominant, disease-causing genetic mutations who were mostly asymptomatic or had experienced only mild, early-stage symptoms.

The research participants were drawn from two large multisite studies, called ARTFL and LEFFTDS (recently combined into a study known as ALLFTD), led by co-authors Adam Boxer, MD, PhD, and Howie Rosen, MD, also of the UCSF Memory and Aging Center.

As part of these larger studies, all participants underwent initial MRI scans to measure the extent of brain degeneration caused by the disease, completed tests of thinking and memory, and reported on their current levels of cognitive and physical activity in their daily lives (e.g., reading, spending time with friends, jogging).

At the same time, their family members completed regular gold-standard assessments of how well the study participants were functioning in their lives — managing finances, medications, bathing themselves, and so on.

All of these measures were repeated at annual follow-up visits to track the long-term progression of participants’ disease.

Even after only two to three visits (one to two years into the ongoing study), Casaletto and her team have already begun to see significant differences in the speed and severity of FTD between the most and least mentally and physically active individuals in the study, with mentally and physically active lifestyles showing similar effects across participants.

Specifically, the researchers found that functional decline, as assessed by participants’ family members, was 55 percent slower in the most active 25 percent of participants compared to the least active five percent.

“This was a remarkable effect to see so early on,” Casaletto said. “If this were a drug, we would be giving it to all of our patients.”

The researchers found that participants’ lifestyles did not significantly alter the inexorable degeneration of brain tissue associated with FTD, as measured by follow-up MRI scans a year into the study. But even among participants whose brain scans revealed signs of atrophy, the most mentally and physically active participants continued to perform twice as well as the least active participants on cognitive tests. These results suggest that active lifestyles may slow FTD symptoms by providing some form of cognitive resilience to the consequences of brain degeneration.

Findings Could Illuminate Biology of Brain Resilience Across Dementias

The researchers anticipate seeing even larger differences in cognitive decline between more and less active groups as the merged ALLFTD study continues to follow these participants over time.

“We’ve seen such significant effects in just the first year or two in people with very mild disease — if these results hold, we may see that an active lifestyle sets individuals on a different trajectory for the coming years,” Casaletto said.

Specifically, the researchers found that functional decline, as assessed by participants’ family members, was 55 percent slower in the most active 25 percent of participants compared to the least active five percent.

The next step for the research is to include more detailed and objective assessments of participants’ physical and mental activity — including fitting them with wearable FitBit activity sensors — to begin to estimate exactly how much activity is needed to promote cognitive resilience.

Casaletto cautions that the results, though exciting, so far only report a correlation: “It is possible that some participants have less active lifestyles because they have a more severe or aggressive form of FTD, which is already impacting their ability to be active.

Clinical trials that manipulate cognitive and physical activity levels in people with FTD mutations are needed to prove that lifestyle changes can alter the course of the disease.”

With this caveat in mind, Casaletto hopes the findings will not only encourage care teams and individuals with family histories of FTD to adopt lifestyle changes that could provide more productive years of life, but also that the ongoing study will lead to a better biological understanding of the drivers of resilience in people with FTD.

“We can see that lifestyle differences impact people’s resilience to FTD despite very penetrant genetics, so now we can start to ask more fundamental questions, like how these behaviors actually affect the brain’s biology to confer that resilience.”

Casaletto said. “Is that biological effect something we could replicate pharmacologically to help slow the progression of this terrible disease for everyone?”

Authors: The study’s co-senior authors were Howie Rosen, MD, a professor of neurology in the UCSF Memory and Aging Center, and Kristine Yaffe, MD, a professor of psychiatry, neurology and epidemiology and the Roy and Marie Scola Endowed Chair and Vice Chair of Research in Psychiatry with the UCSF Memory and Aging Center. Yaffe is also Chief of Neuropsychiatry and the director of the Memory Disorders Clinic at the San Francisco Veteran’s Affairs Medical Center. Other UCSF co-authors include Adam Staffaroni, Amy Wolf, Fanny Elahi, Jamie Fong, Hilary Heuer John Kornak, Joel Kramer, Bruce Miller, and Adam Boxer. For a full list of authors, see the study online.

Funding: The LEFFTDS and ARTFL studies are funded by grants from the National Institute on Aging (NIA) of the US National Institutes of Health (NIH) (U01AG045390, U54NS092089). Casaletto’s work is also supported by the NIA (K23AG058752, L30AG057123) and by the Larry L. Hillblom Fellowship (2017-A-004-FEL).

Disclosures: Casaletto declares no conflicts of interest. See study online for full list of disclosures.

Brain Plasticity, Adult Neurogenesis, and Physical Activity

The brain capacity to adapt to ever-changing conditions, known as brain plasticity, depends on the ability of neurons to modify the strength and composition of their connections in response to both external and internal stimuli.

The long-term potentiation (LTP) in synaptic efficacy constitutes the physiologic base for learning and memory.

An important way for regulating neuronal function is the activity-dependent synapse-to-nucleus signalling, that can arise both in the post-synaptic and in the presynaptic element [34,35,36,37,38].

These signals are generated through different mechanisms, such as: (i) Calcium waves due to calcium-induced calcium release (CIRC) from the endoplasmic reticulum (ER) [35,39,40]; (ii) retrograde transport of proteins (e.g., Jacob, CREB Regulated Transcriptional Coactivator 1, CRTC1); Abelson-interacting protein 1, Abi1; the amyloid precursor protein intracellular domain associated-1 protein, AIDA-1; and the nuclear factor kappa-light-chain-enhancer of activated B cells, NF-κB); these proteins are post-translationally modified following synaptic activity, and transported to the nucleus, where they act on gene transcription, and thereafter on synaptic plasticity [34,35,36,37,38,41,42]; (iii) formation and microtubule-dependent trafficking of mRNA-protein complexes, that, after exiting the nucleus, move to neuronal periphery, where the mature transcripts localize in a repressed state, in response to local signalling, through activity-dependent activation of specific enzymes, the regulatory proteins can be then modified, for example, by phosphorylation, and the mRNAs can be translated; some of the newly synthesized proteins can accumulate at the synapse, while others can shuttle back to the nucleus to modify chromatin structure and expression [43].

By regulating synapse-to-nucleus signalling, all these events are crucial for allowing synapse activity to result in the specific gene expression programs necessary for learning and memory.

In agreement with this idea, the impaired function of these signalling proteins brings about intellectual disability, psychiatric disorders, or neurodegeneration [37,38,42]. On the other hand, we can hypothesize that an increase of their function, for example as a response to PA, could also enhance brain functions and plasticity.

In the past, it was generally accepted that new neurons could not be generated in the adult to replace dying cells, and this limitation was also considered to be the main cause of neurodegeneration as well as of cognitive decline in the elderly population. However, since the 1960s, many researchers presented data suggesting that, in all the mammals analysed, new neurons could be generated in the sub-granular zone (SGZ) of the dentate gyrus of the hippocampus, and in the sub-ventricular zone (SVZ) of the lateral ventricles, in the postnatal and adult life [44,45,46,47,48,49,50].

In particular, neurons born in the SGZ were shown to differentiate and integrate into the local neural network of the hippocampus. These findings are extremely important since the hippocampus is fundamental for the formation of certain types of memory, such as episodic memory and spatial memory [51,52,53,54].

In addition, hippocampus-dependent learning is one of the major regulators of hippocampal neurogenesis [55]: living in environments which stimulate learning enhances, in rats, the survival of neurons, born in the adult from neural stem cells (NSCs) [52].

Now, increasing evidence suggests that PA, largely due to factors released by contracting muscles (Section 3Figure 1), can improve brain functions, such as memory and attention, in both children and adults [56,57,58,59,60,61,62,63,64].

A few examples of single studies (first three rows) and reviews/meta-analyses (second three rows), aimed at ascertaining any relationship between PA and learning/memory, are given in Table 1.

The data reported in Table 1 clearly indicate that PA has a positive effect on mental health and abilities, especially in adolescents; however, as reported in the “Conclusions” column (sentences in bold letters), most authors agree on the fact that the previous studies do not yet give uniform indications on the relationships between the type/intensity/frequency of exercise and the brain health outcomes; these limitations derive, on one hand, from the wide range of conditions set in the exercise programs, and on the other hand, the differences from study to study also depend on the variability of the parameters chosen to evaluate mental health.

We also have to add to these considerations the poor knowledge we still have of ‘mind’ and of ‘mental health’. Thus, many laboratories are now focusing on exercise-dependent cellular and molecular modifications of brain cells activity, in the attempt to uncover the mechanisms underlying PA–mental health biochemical relationships.

At the cellular level, it was found that treadmill exercise can increase hippocampal neurogenesis in aged mice [68]. Interestingly, exercise can also affect the proliferation [69,70], as well as size and function, of astrocytes [71]. These latter events regulate, in turn, the number and localization of neuronal synapses, and might influence LTP and episodic memory formation [72].

Many researchers suggested that all these effects are also regulated by the brain capillaries (BC, Figure 1) that reach the neurogenic niche, supplying angiogenetic growth factors, such as the growth and differentiation factor 11 (GDF11), the vascular endothelial growth factor (VEGF) [59], and BDNF, that activates a cellular survival pathway involving the serine-threonine kinase AKT and CREB, thus inducing the transcription of genes responsible for almost all the aspects of neuroplasticity [59,72].

The neurogenic niche also receives axonal inputs from both local and distant neurons, which release a variety of neurotransmitters, such as serotonin, glutamate, and GABA [59]. For example, glutamate, through interaction with NMDARs, is thought to regulate LTP in response to exercise [73].

Many epidemiologic studies, mostly in the last two decades, also revealed a link between PA, human brain health (and longevity) and epigenetic modifications of the genome, even leading, on one hand, to the concept of “epigenetic age” or “DNA methylation age” (essentially measured, however, as blood cells DNA methylation) [74,75,76,77,78], and, on the other hand, to the acknowledgment that epigenetic mechanisms induced by PA can build up an “epigenetic memory” that affects long-term brain plasticity, neurogenesis, and function [79,80,81,82]. Intriguingly, it has been proposed that epigenetic modifications caused by lifestyle and diet, as well as the effects of PA can be heritable (discussed in [83]).

Epigenetic processes modify eukaryotic chromatin structure, and hence gene expression, without changing the underlying DNA sequence, through at least three mechanisms:

(i) DNA methylation/demethylation, and post-translational modifications (such as methylation/demethylation and acetylation/deacetylation), of histones on specific residues of their N-terminal tails;

(ii) substitution of some histone isotypes with other histone variants;

(iii) sliding and/or removal of the basic chromatin structural organization elements (nucleosomes), due to specific ATP-dependent chromatin remodelling complexes [84,85,86,87].

Specific proteins are then able to “read” and bind DNA and histone tail modifications, thus creating synergic complexes which can activate or depress transcription [88,89,90,91,92]. Importantly, in some of these remodelling events, long noncoding RNAs (lncRNAs) also play a role [93].

Finally, gene expression can be regulated by short noncoding RNAs, called microRNAs (miRNAs), which are able to pair with sequences mainly present in the 3′-UTR of their target mRNAs, thus inducing inhibition of their translation or even their degradation [94,95,96].

In summary, while the genome of an organism is relatively stable over the lifespan, its expression (i.e., the phenotype) is influenced by many epigenetic factors.

Most important, we now know that inactivity is epigenetically deleterious: for example, it has been reported that nine days of bed rest can induce insulin resistance in otherwise healthy subjects.

The analysis of the pathways affected revealed a significant downregulation of 34 pathways, mainly involving genes associated with the mitochondrial function, including the peroxisome proliferator-activated receptor γ co-activator 1α (PPARGC1A, or PGC-1α). An increase of PPARGC1A DNA methylation was also reported, and this epigenetic modification was not completely reversed after four weeks of retraining, thus highlighting the importance of daily physical activity [76,97].

Media Contacts:
Nicholas Weiler – UCSF

Original Research: Open access
“Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH‐EXAMINER as a potential clinical trial endpoint”. Kaitlin Casaletto et al.
Alzheimer’s & Dementia doi:10.1016/j.jalz.2019.01.012.


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