Elsevier

Neurobiology of Aging

Volume 31, Issue 9, September 2010, Pages 1554-1562
Neurobiology of Aging

Lifespan trajectory of myelin integrity and maximum motor speed

https://doi.org/10.1016/j.neurobiolaging.2008.08.015Get rights and content

Abstract

Objective

Myelination of the human brain results in roughly quadratic trajectories of myelin content and integrity, reaching a maximum in mid-life and then declining in older age. This trajectory is most evident in vulnerable later myelinating association regions such as frontal lobes and may be the biological substrate for similar trajectories of cognitive processing speed. Speed of movement, such as maximal finger tapping speed (FTS), requires high-frequency action potential (AP) bursts and is associated with myelin integrity. We tested the hypothesis that the age-related trajectory of FTS is related to brain myelin integrity.

Methods

A sensitive in vivo MRI biomarker of myelin integrity (calculated transverse relaxation rates (R2)) of frontal lobe white matter (FLwm) was measured in a sample of very healthy males (N = 72) between 23 and 80 years of age. To assess specificity, R2 of a contrasting early-myelinating region (splenium of the corpus callosum) was also measured.

Results

FLwm R2 and FTS measures were significantly correlated (r = .45, p < .0001) with no association noted in the early-myelinating region (splenium). Both FLwm R2 and FTS had significantly quadratic lifespan trajectories that were virtually indistinguishable and both reached a peak at 39 years of age and declined with an accelerating trajectory thereafter.

Conclusions

The results suggest that in this very healthy male sample, maximum motor speed requiring high-frequency AP burst may depend on brain myelin integrity. To the extent that the FLwm changes assessed by R2 contribute to an age-related reduction in AP burst frequency, it is possible that other brain functions dependent on AP bursts may also be affected. Non-invasive measures of myelin integrity together with testing of basic measures of processing speed may aid in developing and targeting anti-aging treatments to mitigate age-related functional declines.

Introduction

The protracted myelination of the human brain results in roughly quadratic (inverted U) trajectories of myelin content and integrity reaching a maximum in mid-life and then declining in older age (Bartzokis et al., 2001, Bartzokis et al., 2003, Benes et al., 1994, Ge et al., 2002, Jernigan and Gamst, 2005, Kemper, 1994, Walhovd et al., 2005). Axon myelination results in saltatory conduction of action potentials (AP) that increases (>10-fold) signal transmission speed (Waxman, 1977) and makes it possible to integrate information across the spatially distributed neural networks that support cognitive and motor functions (Bartzokis et al., 2001, Fuster, 1999, Lutz et al., 2005, Mesulam, 2000, Srinivasan, 1999). Myelination also markedly decreases the refractory time (time needed for repolarization before a new AP can be supported by the axon) by as much as 34-fold (Felts et al., 1997, Sinha et al., 2006). Thus myelin and maintenance of its integrity allows axons to support high-frequency bursts of signals and is necessary for a variety of normal brain processes ranging from high motor speeds, to cortical oscillations and long-term potentiation (LTP) of synaptic transmission (Axmacher et al., 2006, Bartzokis, 2004a, Buzsaki and Draguhn, 2004, Canolty et al., 2006, Kreiman et al., 2006).

Salthouse and others (Hedden et al., 2005, Salthouse, 2000, Schaie et al., 2004) have argued that the age-related decline in cognitive processing speed resources underlies age-related declines in most cognitive functions including memory encoding which depends on high-frequency bursts (up to 200 Hz) to produce LTP of synaptic transmission [(Buhl and Buzsaki, 2005, Yun et al., 2002); for review see (Axmacher et al., 2006)]. In fact, cognitive, sensory, and motor measures of processing speed are all highly related to brain aging and show quadratic-like trajectories over the lifespan, reaching peaks in adulthood (Era, 1988, Hedden and Gabrieli, 2004, Hoyer et al., 2004, Salthouse, 2000, Schaie et al., 2004). The underlying biological substrate of this relationship is not well understood (Hedden and Gabrieli, 2004, Schaie et al., 2004). Peters and others have argued that brain aging may be primarily related to the process of myelin breakdown (Bartzokis et al., 2004, Bartzokis et al., 2006, Braak and Braak, 1996, Marner et al., 2003, Peters et al., 1996, Peters et al., 2001, Peters and Sethares, 2004, Peters and Sethares, 2004, Sloane et al., 2003). To test the hypothesis that processing speed measures are related to myelin integrity (Bartzokis, 2004a, Bartzokis, 2004b) we examined one of the simplest and best understood tests of CNS processing speed: maximal finger tapping speed (FTS).

Like many cognitive tasks the FTS task involves a distributed neural network and high-frequency bursts of APs (Lutz et al., 2005). Single cell recordings in monkey brain have demonstrated that firing rates of motor neurons positively correlate with increasing velocity, force, and acceleration necessary to produce faster finger movements (Ashe and Georgopoulos, 1994, Humphrey, 1972) as well as other fast movements such as visual saccades where similar relationships of movement speed and AP frequency (upwards of 300 Hz) are observed (Berthoz et al., 1986, Krauzlis, 2003, Missal et al., 2002). The tight coupling of FTS with AP firing frequency makes the tapping task dependent on intact myelin to reduce axonal refractory time in order for high AP frequencies to be supported by the neural networks (Felts et al., 1997, Sinha et al., 2006). Thus both its distributed nature and dependence on high neuronal firing rates make FTS dependent on the developmental process of myelination (Garvey et al., 2003, Yeudall et al., 1987) and the maintenance of myelin integrity with aging (Bartzokis, 2004a, Bartzokis et al., 2006).

The structural integrity of myelin sheaths can be indirectly measured in vivo with magnetic resonance imaging (MRI) using transverse relaxation rates (R2), relaxometry measures that are markedly sensitive to small changes in the proportion of tissue water (Oldendorf and Oldendorf, 1988). R2 is related to the transverse relaxation time (T2) through the simple formula R2 = 1/T2 × 1000. Myelination decreases water content (increasing R2) while myelin breakdown and loss increases water content (decreasing R2). R2 measures have been used to assess myelin integrity in development/myelination phase (birth to mid-life) when R2 increases (Bartzokis et al., 2003, Miot-Noirault et al., 1997) as well as in aging and a variety of myelin-damaging conditions when R2 decreases (Bartzokis et al., 2003, House et al., 2006, Neema et al., 2007, Takao et al., 1999, Vermathen et al., 2007). Severity of myelin damage and associated R2 changes are on a continuum that ranges from focal lesions (Neema et al., 2007, Takao et al., 1999, Vermathen et al., 2007) visible to the unaided eye (referred to as T2 “hyperintensities” on radiology reports) to diffuse changes that occur in “normal appearing white matter” detectable only with quantitative R2 measures (Bartzokis et al., 2003, House et al., 2006, Neema et al., 2007, Vermathen et al., 2007). In disease processes such as multiple sclerosis or phenolketonuria myelin destruction is qualitatively observable on MRI images but more subtle changes are also detectable quantitatively in “normal appearing white matter” (Neema et al., 2007, Vermathen et al., 2007). Similarly, age-related R2 changes in normal appearing white matter have been quantitatively demonstrated in healthy aging as well as more pronounced changes associated with genes that increase risk of developing Alzheimer’s disease (AD), pre-AD conditions such as mild cognitive impairment, and AD itself (Bartzokis et al., 2003, Bartzokis et al., 2007, House et al., 2006).

Ultrastructural electron microscopy studies demonstrate that age-related myelin breakdown results in microvacuolations consisting of splits of myelin sheath layers that create microscopic fluid-filled spaces that increase MRI “visible” water and thus decrease R2 (Bartzokis et al., 2004, Peters et al., 1996). These microvacuolations are ultrastructurally very similar to reversible myelinopathies produced by certain toxins (Jackson et al., 1994, Peters et al., 1996, Peyster et al., 1995, Weiss et al., 1994). Animal studies have confirmed that this type of myelin breakdown can be detected with MRI in circumscribed susceptible white matter regions and that the histopathologic changes produced by toxins as well as the recovery process can be thus tracked by MRI with the unaided eye [(Jackson et al., 1994, Peyster et al., 1995, Qiao et al., 2000, Weiss et al., 1994); reviewed in (Cohen et al., 2000)]. Although R2 has not been directly correlated with myelin breakdown due to normal aging (as opposed to the reversible toxin-induced myelin breakdown described above), in humans and primates healthy aging is not associated with neuronal loss [(Gomez-Isla et al., 1997); reviewed in (Peters, 2002, Peters et al., 1998)] while the process of age-related myelin breakdown and loss has been thoroughly demonstrated (Kemper, 1994, Marner et al., 2003, Peters et al., 1996, Peters et al., 2001, Peters and Sethares, 2003, Peters and Sethares, 2004, Sloane et al., 2003, Tang et al., 1997). Herein the terms myelin “integrity” and “breakdown” will be used to refer to R2 measures (Bartzokis et al., 2006).

Age-related myelin breakdown is a generalized process (Bartzokis et al., 2004, Marner et al., 2003, Peters et al., 1996, Peters et al., 2001, Peters and Sethares, 2003, Peters and Sethares, 2004, Sloane et al., 2003) that is most pronounced in more vulnerable later myelinating regions such as frontal lobe white matter (FLwm) that contain higher proportions of smaller thinly myelinated axons (Bartzokis, 2004a, Grieve et al., 2007, Marner et al., 2003, Salat et al., 2005, Sullivan et al., 2008). It is technically difficult to directly assess myelin breakdown of the specific myelin segment(s) limiting the maximal frequency of APs a circuit can support. We therefore chose FLwm to serve as an in vivo biomarker for myelin integrity because its vulnerability makes this region a good surrogate for damage prone regions of the FTS circuitry (Jancke et al., 1998, Lutz et al., 2005). The choice was based on the fact that both post mortem as well as our prior imaging data show FLwm is maximally sensitive to differences in myelin integrity due to aging (Bartzokis et al., 2004, Kemper, 1994, Marner et al., 2003) and that highly reliable and reproducible R2 measures can be obtained from this region (Bartzokis et al., 2003).

We tested the hypothesis that the lifelong quadratic trajectory of myelination and subsequent myelin breakdown is associated with FTS performance across the lifespan. We focused on men because men show consistently higher FTS performance, and we hypothesized that the highest possible tapping speed that requires the highest action potential frequencies would be most sensitive to differences in myelin integrity (Homann et al., 2003, Kauranen and Vanharanta, 1996, Reed et al., 2004).

Section snippets

Subjects

Healthy adult male volunteers that participated in the study were recruited from the community and hospital staff. Potential subjects were excluded if they had a history of neurological disorder, psychiatric illness (including drug or alcohol abuse), or head injury resulting in loss of consciousness for more than 10 min. The subjects were physically very healthy and were excluded if they were obese (defined as body mass index of (BMI) >30 kg/m2), had a history of diabetes or cardiovascular

Results

The estimated regression parameters from the mixed effects regression were used to graph the functions across the age range 23–80 and represent an average of right and left hand tapping. Significant quadratic relationships with age were observed for FLwm R2 (t = 2.42, d.f. = 69, p = .018) and for FTS (t = 2.46, d.f. = 69, p = .016). The Swm did not exhibit a significant linear (r = −0.14, d.f. = 70, p = .25) or quadratic (t = 0.32, d.f. = 69, p = .75) association with age. The results are displayed in Fig. 2. The

Discussion

This is the first study to demonstrate that a functional performance measure (FTS) follows a quadratic lifespan trajectory that is virtually indistinguishable from the trajectory of a sensitive in vivo myelin integrity biomarker (Fig. 2) (Bartzokis et al., 2004). Furthermore, the data show a highly significant correlation between the functional (FTS) and biomarker (FLwm R2) measures that is specific to vulnerable late-myelinating FLwm and is not observed in the early-myelinating Swm contrast

Conflict of interest

The authors have no actual or potential conflicts of interest.

Disclosure statement

All human subjects received written and oral information about the study and signed written informed consents approved by the local institutional review board prior to study participation.

Acknowledgments

This work was supported in part by NIH grants (MH066029; AG027342; EB008281; P50 AG 16570; U54 RR021813); the RCS Alzheimer’s Foundation, Sidell-Kagan Foundation; and the Department of Veterans Affairs.

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