An Overview of Primary Dementias as Clinicopathological Entities

Arash Salardini, MD

Disclosures

Semin Neurol. 2019;39(2):153-166. 

In This Article

Abstract and Introduction

Abstract

Dementia is a state of cognitive dysfunction which leads to functional decline. It is a syndrome caused by several medical and neurological causes, but most cases of dementia are due to "primary dementias." Primary dementias are neurological diseases whose manifestations are predominantly cognitive. Most primary dementias are caused by neurodegenerative proteinopathies where an accumulation of misfolded proteins leads to neuronal loss, neuroinflammation and glial reaction. Each proteinopathy is characterized by the type of protein implicated in its pathophysiology. Neurodegenerative dementias include the most prevalent cause of dementia—Alzheimer's disease—as well as Lewy body dementia, Parkinson's disease dementia, frontotemporal dementias, and prion diseases. Vascular dementia, especially small vessel disease, though not a neurodegenerative condition, is often grouped together with primary dementias. Each type of proteinopathy, characterized by the location and nature of misfolded protein accumulation, may correspond to a particular clinical phenotype. The correspondence between pathologies and clinical phenotypes is not exclusive, and there is a large degree of overlap. Although in the research setting the clinicopathological construct is on the wane, in the clinic it is the most practical way of approaching primary dementias. In this article, we introduce the clinicopathological construct, the understanding of which will form the basis of the other articles in this volume.

Introduction

Among adult neurological disorders, dementia has the highest economic cost, and is only second to cerebrovascular disease as a cause of death.[1] Alzheimer's pathology and vascular disease, alone or in combination, account for the vast majority of dementia cases worldwide (70–80%).[2] The remainder are made up of Lewy body disease (5%)[3] and a large number of pathologies with low prevalence. Genetic forms of primary dementias comprise a very small portion of cases. Sporadic onset primary dementias are likely due to complex interactions between an array of genetic susceptibilities and the environment. Of all the known risks for sporadic dementia, age, an unmodifiable risk factor, dwarves all others including APOE4 status and vascular risk factors.[4] Therefore, as life expectancy increases around the world the prevalence of dementia will continue to rise.

Sadly, there are no disease-modifying medications available for the treatment of Alzheimer's disease (AD) and most other primary dementias. However, this should not bias the practitioner toward fatalism. Many common diseases such as chronic obstructive pulmonary disease and sickle cell anemia lack a disease-modifying treatment, yet they are expertly and unapologetically managed by the relevant specialties. Most dementias are manageable by addressing symptoms and maximizing daily function. These strategies delay the onset of dementia; in other words, for a given burden of pathology a patient is enabled to function at a higher level if he or she is given the tools and is medically optimized.

The "optimization/harm minimization" approach is superficially similar to the practice of dementia care going back decades. The difference is that contemporary neurologists, geriatricians, and psychiatrists are much better at diagnosis, symptomatic treatment, and case management than their erstwhile predecessors. Giant strides have been made in our understanding of the pathophysiology, natural history, biomarker biology, and neuropsychology of primary dementias. Neurologists whose training affords them familiarity with neurobiology, neuroanatomy, and neuroimaging have especially benefitted from the entry of sophisticated testing modalities into the clinic. Parallel to advances in neuroscience, there is significant progress in models of care, functional assessment, nonpharmacological interventions, and symptom management. In these, geriatricians and geriatric psychiatrists will continue to excel.

Although most interventions required for severe dementia are agnostic vis-à-vis pathological diagnosis, patients in the earlier stages of the disease require diagnosis and disease-specific interventions. Neurologists are more likely to be in charge of care early in the course of dementia. It is therefore important for all neurologists to have a working knowledge of different dementia-causing pathologies and their clinical phenotype, i.e., primary dementias as clinicopathological entities. This paper intends to introduce and expand on this idea.

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