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  • Review Article
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Treatments for behavioural disorders in neurodegenerative diseases: drug development strategies

Nature Reviews Drug Discovery volume 5, pages 64–74 (2006)Cite this article

Key Points

  • Neuropsychiatric symptoms are common in neurodegenerative disorders and their effective pharmacological management represents an unmet medical need.

  • Many classes of compounds have effects on behavioural symptoms in neurodegenerative disorders, including agents used for psychotropic purposes in other disorders, cholinesterase inhibitors, NMDA (N-methyl-D-aspartate) receptor blockers and antioxidants.

  • Imaging, genetic and autopsy studies reveal the neurobiological basis of behavioural changes in neurodegenerative disorders. These approaches assist in target identification for new classes of psychotropic agents for these conditions.

  • Improved tools that allow the reliable assessment and validation of behavioural changes in patients with neurodegenerative disorders have evolved. The Neuropsychiatric Inventory allows the assessment of behavioural changes. The Cornell Scale for Depression in Dementia facilitates the evaluation of mood symptoms.

  • Clinical trials evaluating potential new treatments for neurodegenerative disorders should include behavioural measures to provide insights into the effects of the agents on this important disease manifestation.

Abstract

Neuropsychiatric symptoms and behavioural alterations are common in neurodegenerative diseases, and effective treatment of these changes represents an important unmet public health need. Imaging, neuropathological, neurotransmitter and molecular genetic studies increasingly identify specific mechanisms that mediate behavioural changes in neurodegenerative disorders and provide a platform for seeking effective therapeutic interventions. Measuring behavioural outcomes in clinical trials of antidementia agents represents an important means of evaluating treatment effectiveness, and clinical trial methodologies and behavioural instrumentation are evolving to facilitate drug development in this important therapeutic target area.

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Figure 1: Cascade of pathophysiological events in neurodegenerative diseases.
Figure 2: Sources of compounds with potential therapeutic effects in neuro-degenerative diseases.
Figure 3: Steps in drug development for behavioural disturbances in neurodegenerative diseases.

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Authors and Affiliations

  1. Department of Neurology, 710 Westwood Plaza, David Geffen School of Medicine, UCLA, Los Angeles, 90095, California, USA

    Jeffrey L. Cummings

  2. MediChamp, 37 Grayson Lane, Newton, 02462, Massachusetts, USA

    Kate Zhong

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  1. Jeffrey L. Cummings
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  2. Kate Zhong
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Correspondence to Jeffrey L. Cummings.

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Competing interests

J.L.C. has provided consultation to the following pharmaceutical companies: AstraZeneca, Avanir, Bristol–Myers Squibb, Eisai, Forest, Janssen, Lilly, Lundbeck, Memory, Merz, Neurochem, Novartis, Ono, Pfizer, Sanofi-Aventis and Wyeth. K.Z. is a former employee of AstraZeneca.

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DATABASES

OMIM

Alzheimer's disease

Parkinson's disease

Progressive supranuclear palsy

Schizophrenia

Glossary

Neurodegenerative diseases

(NDDs). Conditions characterized by gradually progressive cell loss. Most of the disorders in this class have abnormal production, accumulation or misfolding of proteins.

Delusions

False beliefs that are not explained by the individuals' culture, subculture or religion.

Agitation

Abnormal behaviour with excessive motor and verbal activities that are typically manifested by pacing, shouting, cursing, striking out, kicking and actively resisting care.

Frontotemporal dementias

(FTD). A group of idiopathic or hereditary degenerative disorders that preferentially affect the neurons of the frontal and temporal lobes. Nerve cells could harbour tau or ubiquitin deposits. Pick's disease is one type of FTD.

Progressive supranuclear palsy

A neurodegenerative disorder that is characterized pathologically by the accumulation of tau in brainstem, thalamus and basal ganglia neurons. The clinical symptoms of this disorder are subcortical dementia, extended body posture, supranuclear gaze palsy and pseudobulbar palsy.

Corticobasal degeneration

A neurodegenerative disorder with tau-related nerve-cell loss in basal ganglia and cortical structures. The clinical symptoms comprise asymmetric rigidity and myoclonus, with limb apraxia accompanying progressive intellectual decline.

Disease-modifying treatment

Treatments that alter the course of a neurodegenerative disease by intervening in the pathological process leading to cell death. Neuroprotective agents are examples of disease-modifying therapies.

Biological markers

(Biomarkers). Laboratory or imaging studies that provide an index of disease activity; some biomarkers can serve as surrogate markers for following disease activity or time.

Mild cognitive impairment

(MCI). A clinical syndrome characterized by memory complaints and impairment in one or more cognitive domains, no or limited decline in activities of daily living and an absence of dementia. The syndrome, particularly the form with disproportionate memory loss, is often a harbinger of Alzheimer's disease.

Secretases

Enzymes that cleave the amyloid precursor protein via the benign α-secretase pathway or via the Alzheimer-related β- and γ-secretase pathway.

Amyloid

A peptide that is aggregated in the neuritic plaques of Alzheimer's disease. It is neuro-toxic in its oligomeric form.

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Cummings, J., Zhong, K. Treatments for behavioural disorders in neurodegenerative diseases: drug development strategies. Nat Rev Drug Discov 5, 64–74 (2006). https://doi.org/10.1038/nrd1928

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