Neuropharmacologic approaches to cognitive rehabilitation2 R. Klein et al. / Neuropharmacologic approaches to cognitive rehabilitation progenitor cells that can, under the right conditions,

Behavioural Neurology 17 (2006) 1–3 1IOS Press

Neuropharmacologic approaches to cognitiverehabilitation

Reva Klein, Patrick McNamara and Martin L. Albert∗Harold Goodglass Aphasia Research Center, Department of Neurology, Boston University Medical School and theMedical Research Service, VA Boston Healthcare System, USA

Neuropharmacologic rehabilitation of cognitivedeficits is a field waiting to be created. NIH, withits Roadmap Initiative for Translational Research, ispushing hard, but clinicians and scientists, for the mostpart, have yet to accept the challenge. The goal of thisSpecial Issue is to document the current state of the art.As readers will note, most contributors conclude thefield is just now taking its tentative first steps towardself-definition.

Our aim in this Special Issue is to present a survey ofthe latest developments in pharmacologic treatment ofcognitive deficit in selected clinical disorders, includingthe dementias, Parkinson’s disease (PD), multiple scle-rosis (MS), epilepsy, vascular disorders and traumaticbrain injury (TBI). Our primary interest was to considernot only treatment of acute or subacute disease, butalso approaches to prevention and rehabilitation. Twoprincipal conclusions emerge from these detailedreviews: 1) cognitive disorders associated with eachof these neurologic conditions can be severe anddisabling; 2) effective pharmacologic intervention forsome of these disabling cognitive symptoms are nowemerging, but are understudied.

The first three papers discuss disorders (dementias,vascular disorders and TBI) that share a long traditionof research into cognitive deficits. Thus, studies ofpharmacologic management of cognitive disturbancesin these disorders are considerably more advanced than

∗Corresponding author: Martin L. Albert, M.D., Ph.D., Apha-sia Research Center (12A), VA Boston Healthcare System, 150 So.Huntington Avenue, Boston, MA 02130, USA. Tel.: +1 857 3644775; Fax: +1 617 739 8926; E-mail: [email protected].

those for disorders discussed in the last three papers(PD, MS and epilepsy). Development of effectivetreatments for cognitive disorders in these last threedisorders had to await recognition and typing of thevariety, extent and severity of cognitive deficit. Thisevaluative and classificatory work has largely beenaccomplished only in the last 15 or so years.

In their review of the dementias, Ringman and Cum-mings note that the cholinesterase inhibitors donepezil,rivastigmine, and galantamine have demonstratedefficacy in improving cognition and global status inmild to moderate Alzheimer’s disease. Donepeziland galantamine have also been shown to be mildlyeffective in dementia due to cerebral ischemia. Onlymemantine has demonstrated some efficacy in mod-erate to severe AD. The benefits from these drugs,however, are limited and their long-term effectivenesshas not been well-studied. Unfortunately, there arecurrently no proven treatments directed specificallyat the pathology of frontotemporal dementia and nocurrently proven therapy for the prevention ofdementia.

In their paper on cerebrovascular disorders, Romeroand his colleagues review recent research on basicmechanisms of neuronal injury in the ischemicpenumbra, focusing on new opportunities to promoterecovery after injury or to protect against cellular dam-age in the first place. This basic research has revealedone of the most spectacular finds in the recent historyof the science of neurorehabilitation. The adulthuman brain in the areas of the subventricular zone andthe hippocampal dentate gyrus (deep to the temporallobe) contains populations of undifferentiated

ISSN 0953-4180/06/$17.00 © 2006 – IOS Press and the authors. All rights reserved

2 R. Klein et al. / Neuropharmacologic approaches to cognitive rehabilitation

progenitor cells that can, under the right conditions,proliferate and differentiate (after migrating to theolfactory bulb) into mature brain cells. Followingischemic injury some of these cells may migrate to theperiphery of the infarct as well and thus could theoret-ically facilitate recovery of cellular function. Growthfactors can promote differentiation of progenitor cellsinto mature neurons and represent a promising new areain the treatment of stroke.

In their paper on pharmacotherapy of posttraumaticcognitive impairments, Arciniegas and Silver note thataugmentation of posttraumatic cerebral catecholamin-ergic and cholinergic function has demonstrated someefficacy in improving cognition in patients with TBI.When the posttraumatic impairments are in the areasof arousal, speed of processing, and attention, agentsthat enhance catecholaminergic transmission (such asmethylphenidate, dextroamphetamine, amantadine, orbromocriptine) are more effective than cholinergicagents. In severe cases, modafanil, carbidopa/L-dopa,or other non-standard agents with stimulating proper-ties such as modafinil, protriptytline, or lamotriginehave sometimes been effective. When the predominantposttraumatic impairment is in the domain of memory,cholinergic agents (such as cholinesterase inhibitors)are recommended. The authors are careful to point outthat pharmacotherapy is only one of several possibleinterventions for posttraumatic cognitive impairments,and is at present best regarded as an adjunct tononpharmacologic therapies for such problems.

In their paper on treatment of cognitive deficits inPD, McNamara and Durso note that many patients withPD experience significant cognitive impairment in therealm of executive function, even early in the courseof the disease. These mental impairments are onlypartially responsive to levodopa treatment and are oftenas disabling as the motor impairment, particularly inthe mid and late stages of the disease. Although therehas been only a handful of properly controlled clinicaltrials of intervention targeted at amelioration of mentaldysfunction in PD, catecholaminergic and cholinergicagents have demonstrated efficacy, though not as yetover the long-term.

In their paper on MS, Pierson and Griffith notethat cognitive impairments in multiple sclerosis arenow recognized to be substantial, with the domains ofexecutive function and speed of processing mostseverely affected. While it may be intuitive to linkeffective treatment of fatigue with improvement in cog-nitive performance, studies have yet to bear that out.Emotional well-being and pharmacologic stabilization

of associated affective disorders can have a positiveinfluence on cognitive performance in MS. However,significant deficits may remain even after treatment ofdepression.

In their paper on epilepsy Mula and Trimble note thatit is now acknowledged that disorders of attention andmemory are frequent in patients with epilepsy. Sourcesof these cognitive deficits likely involve some combi-nation of the underlying pathology (e.g. hippocampalsclerosis and/or ictal and interictal neurophysiologicaldisturbances) and antiepileptic drugs themselves.Piracetam and its derivatives, and sabeluzole, havereceived some support for treatment of these cognitivedeficits in epilepsy. The authors highlight the need andpromise of focusing on neuroprotection in futurestudies of epilepsy, and they note that a number ofpsychotropic agents enhance synaptogenesis andneurogenesis while improving cognition.

Striking themes emerge from these reviews: 1) whiledopaminergic and cholinergic agents have the best trackrecords to date (most efficacious in reducing deficit),noradrenergic agents are fast emerging as promisingagents for treatment of cognitive deficits in neurologicdisorders; 2) serotonergic agents have been assessedand found wanting (though they certainly need morethorough evaluations before they can be dismissed asineffective in the cognitive realm); 3) treatment ofdepressive and other mood disorders in these variousneurologic disorders often slightly improves cognitivedysfunction, although significant residual dysfunctionremains, indicating that cognitive deficits in thesedisorders are not due primarily to mood problems;4) pharmacotherapy is typically more effective whencombined with cognitive-behavioral interventions; 5)neuroprotective agents may also enhance cognition;these agents should receive more attention; 6) atypicalantipsychotics that are effective for treatment ofcognitive disorders in schizophrenia may prove usefulfor treatment of both neuropsychiatric complicationsand selected cognitive disorders in the neurologicdisorder reviewed here; 7) side effect profiles for allof the major agents discussed in these papers varyconsiderably across disorders, and, thus, need to becatalogued with each new application of the drug; 8)drug interactions and polypharmacy are unresolvedproblems.

Finally, we propose the establishment of a nationaldatabase on drugs potentially effective in treatingcognitive processes or symptoms in neurologic disor-ders. Currently the neuropharmacologic literature isorganized along traditional medical lines according to

R. Klein et al. / Neuropharmacologic approaches to cognitive rehabilitation 3

disorder. While such an approach to classification iscertainly valuable, an alternative approach that targetsselected subsystems or subprocesses within a largercognitive processing module might be useful as well.Such a database could be clinically useful in helpingto identify promising new treatments across disordertypes. For example, episodic memory lapses arecommon features of many neurologic conditions andperusal of the reviews in this Special Issue suggest thata small class of cholinesterase inhibitors may be effec-tive in treating these memory lapses regardless of theneurologic diagnostic label.

We thank the authors of the papers in this SpecialIssue, and the editors for inviting us to put it together.The clinical cognitive neurosciences are poised forsignificant breakthroughs in treatment of cognitivedysfunction.

Acknowledgements

Supported in part by NIH (NIDCD and NIA) and VAMedical Research Service.

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Neuropharmacologic approaches to cognitive rehabilitation2 R. Klein et al. / Neuropharmacologic approaches to cognitive rehabilitation progenitor cells that can, under the right conditions,

Documents