Determining the underlying etiology and significance of memory loss in older persons without dementia can be a challenge. Memory loss is most often linked to prodromal Alzheimer’s disease (AD), whereas cerebral infarcts are often assumed to be related to executive rather than memory dysfunction. In this Neurology paper, Blum and colleagues used neuroimaging to study the role of cerebral infarcts and hippocampal volume on memory and other cognitive functions in a group (n = 658) of non-demented older individuals from the Washington Heights-Inwood Columbia Aging Project (average age = 80). Though only 5 percent of the cohort had a clinical diagnosis of stroke, over 25 percent had cerebral infarcts on MRI. The authors found that cerebral infarcts were related to lower hippocampal volumes, and that both infarcts and hippocampal volume were independently related to memory function. The infarcts were related to poorer memory as well as worse performance in multiple other cognitive domains. Hippocampal volume was related to poorer memory, but not to impairment in other cognitive...  Read more

Determining the underlying etiology and significance of memory loss in older persons without dementia can be a challenge. Memory loss is most often linked to prodromal Alzheimer’s disease (AD), whereas cerebral infarcts are often assumed to be related to executive rather than memory dysfunction. In this Neurology paper, Blum and colleagues used neuroimaging to study the role of cerebral infarcts and hippocampal volume on memory and other cognitive functions in a group (n = 658) of non-demented older individuals from the Washington Heights-Inwood Columbia Aging Project (average age = 80). Though only 5 percent of the cohort had a clinical diagnosis of stroke, over 25 percent had cerebral infarcts on MRI. The authors found that cerebral infarcts were related to lower hippocampal volumes, and that both infarcts and hippocampal volume were independently related to memory function. The infarcts were related to poorer memory as well as worse performance in multiple other cognitive domains. Hippocampal volume was related to poorer memory, but not to impairment in other cognitive domains.

These data have important implications. First, they suggest that memory loss in older persons without dementia is not a specific indicator of hippocampal disease, such as prodromal Alzheimer’s disease. Memory loss may also occur in the context of subclinical cortical or subcortical infarcts. Second, cerebral infarcts (or the associated vascular disease) may also be related to a reduction in hippocampal volume, an imaging marker most commonly interpreted as a marker of AD pathology. Finally, these data suggest that vascular pathology at least partially accounts for memory loss in non-demented older persons.

These findings, of course, do not negate the role of AD pathology as an important factor in memory loss in aging. Indeed, pathologic studies suggest that subclinical AD pathology is also very common in non-demented older persons and is related to cognitive dysfunction (1). Moreover, in pathologic studies, we showed that mixed AD and infarct pathology is important in both MCI and dementia (2). It is likely that, in some individuals, both AD and vascular pathologies are contributing even at the earliest stages of cognitive impairment.

There are still many unanswered questions. First, a pivotal question in these imaging studies surrounds the etiopathogenesis of the hippocampal volume loss. Though most commonly attributed to AD pathology, a spectrum of age-related pathologies appears to cause hippocampal volume loss, including, but not limited to, AD, hippocampal sclerosis, vascular disease, and TDP-43 pathology (3). Disentangling the various etiologies of hippocampal volume loss and more specific biomarkers of vascular and neurodegenerative diseases are needed. Second, though our understanding of the importance of subclinical macroscopic vascular disease is expanding, there is little known regarding the role of subclinical microvascular disease in memory and cognitive impairment in aging. Pathologic studies suggest microscopic infarcts are at least as important as macroscopic infarcts, if not more important, in the evolution of dementia in aging (4). It will be important to develop biomarkers of microvascular disease to further study the spectrum and significance of vascular pathologies in older persons.

Regardless of these unanswered questions, it is becoming apparent from these and other studies that vascular disease is of paramount importance in the evolution of both memory loss and cognitive impairment in aging and dementia, and should be a public health and research focus for prevention, diagnosis, and treatment.

References:
1. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006:66:1837-1844. Abstract

2. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed Brain Pathologies Account for Most Dementia Cases in Community-Dwelling Older Persons. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed Brain Pathologies Account for Most Dementia Cases in Community-Dwelling Older Persons. Neurology. 2007 Dec 11;69(24):2197-204. Abstract

3. Josephs KA, Whitwell JL, Knopman DS, Hu WT, Stroh DA, Baker M, Rademakers R, Boeve BF, Parisi JE, Smith GE, Ivnik RJ, Petersen RC, Jack CR Jr, Dickson DW. Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology. 2008 May 6;70(19 Pt 2):1850-7. Abstract

4. White L. Brain lesions at autopsy in older Japanese-American men as related to cognitive impairment and dementia in the final years of life: a summary report from the Honolulu-Asia aging study. J Alzheimers Dis. 2009;18(3):713-25. Abstract

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