Commentary to cognitive and behavioral heterogeneity.

Dr. Cummings reviews the cognitive and behavioral heterogeneity of AD, noting that variation in the regional distribution of pathological changes may be largely responsible for the differences in clinical features observed. In support of this notion, he reviews functional imaging studies in which the distribution of abnormalities within the brain appear to correspond to differing cognitive and behavioral deficits. He suggests that animal models of AD that focus on cognitive and behavioral features may provide additional insights into the neurobiological bases of AD and may also have a role in assessing disease-modifying and symptomatic interventions. In addition to providing an overview of the various ways in which AD can manifest, Dr. Cummings has done a good job of highlighting the degree to which alterations in behavior can dominate the clinical picture of this disease. He has provided an up-to-date review of functional imaging in AD and has stressed the potential utility of animal models and the need for better collaboration between basic and clinical scientists. A few issues deserve further consideration. Firstly, the view of AD as a single disease entity which presents a heterogeneous clinical picture is probably inaccurate. It is clear that we are dealing with a group of Alzheimer’s diseases that lead to similar, although heterogeneous, clinical manifestations. Thus, even for the genetic form of the illness, mutations at a number of different genetic loci (chromosomes 21, 14, 1) have been identified. It is likely that further clarification of the proximal molecular genetic mechanisms of the illness, rather than exploration of regional variations in pathologic involvement, will be most productive in better understanding phenotypic heterogeneity. This argument probably holds as well for the nonautosomal dominant forms of AD, in which influences of multiple genes are probably critical in determining the ultimate clinical expression. Another factor likely contributing to the observed clinical heterogeneity of AD is the fact that many cases do not have pure AD pathology, but have coexistent vascular, Lewy body or other pathologic involvement. A second important issue is that our current abilities to assess regional neuropathologic involvement in the brain is limited and may, therefore, yield limited data for clinicopathologic correlations. Most studies have produced inconsistent results regarding the relationship between the distribution and density of pathologic (e.g., neuritic plaques, neurofibrillary tangles) changes in AD and the type and severity of clinical features, including cognitive and behavioral manifestations. Perhaps there are molecular or biochemical changes that are not currently measurable that are better pathologic markers? The entity dementia with Lewy bodies was largely overlooked, for example, until the advent of ubiquitin and alpha-synuclein staining techniques. Thus, Dr. Cummings proposal to more carefully study regional differences in pathology to better explain clinical heterogeneity may not be particularly fruitful due to the absence of “gold standard” neuropathologic techniques. How can we be sure that certain regions are or are not pathologically involved beyond the likely superficial and primitive examinations currently available? A third issue relates to the importance of accurately defining the clinical phenomenology of AD. Some aspects of the clinical heterogeneity discussed by Dr. Cummings, such as agitation, apathy or depression, may be particularly difficult to define or diagnose in patients with dementia. It is obvious that defining such symptoms in experimental animals is extremely problematic and establishing a firm link between animal and human behavior is very difficult. Problems with phenomenology have also been evident when describing so-called “extrapyramidal” features of AD. We have pointed out, for example, that published papers describing motor abnormalities in AD subjects rarely distinguish true parkinsonian signs (lead pipe rigidity, bradykinesia) from the pseudo-parkinsonian signs (paratonic rigidity, apraxia) that often occur in cortical disorders [1]. As with behavioral changes, motor abnormalities observed in animal models may not reflect those seen in humans. * Corresponding author. Tel. 11-716-275-7937; fax: 11-716-473-4678. E-mail address: kurlan@neuron.mct.rochester.edu (R. Kurlan). www.elsevier.com/locate/neuaging Neurobiology of Aging 21 (2000) 863–864