An Overview of Primary Dementias as Clinicopathological Entities

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.

Delirium Superimposed on Dementia in Perioperative Period and Intensive Care

“…In primary dementia, the cause of nerve cell degeneration is most often (but not in all cases) the deposition of proteins in the brain, having a pathological β-sheet structure—in the case of Alzheimer’s disease (AD), it is amyloid-β, for dementia with Lewy bodies (DLB) and dementia in Parkinson’s disease (PDD) α-synuclein [ 16 , 17 ]. These deposits provoke an inflammatory reaction and activation of microglia through TLRs (Toll-like receptors) [ 18 ].…”

“… Pathophysiology of dementia [ 17 ]. AD—Alzheimer’s Disease, FTD—Frontotemporal Dementia, LBD—Lewy Body Dementia, PDD—Parkinson’s Disease Dementia, MSA—Multiple System Atrophy.…”

Identifying dementia in Down syndrome with the Severe Impairment Battery, Brief Praxis Test and Dementia Scale for People with Learning Disabilities

“…Identification of incipient dementia is difficult in the adult DS population as the order of which domains of cognition are affected earliest remains unclear. Frontal lobe functions, such as personality and affective changes, may be observed before memory impairments (Ball et al 2006a), in contrast to the temporal evolution of deficits in AD that notably begins with early episodic memory impairments followed later by personality and affective changes (Salardini 2019). However, declining memory has also been identified in individuals with DS years before dementia diagnosis (Devenny et al 2002).…”

Immunotherapies for Aging-Related Neurodegenerative Diseases—Emerging Perspectives and New Targets

“…Whereas there remains some debate as to whether protein accumulation is pathogenic or merely a byproduct of disease [16] (Fig. 1), the majority of therapeutic research has been focused on clearing these aggregates [17][18][19][20]. AD, DLB, PD, and FTD are thus often defined as proteinopathies of the aging population that display selective degeneration of neuronal circuitries and progressive accumulation of specific proteins such as amyloid beta (Aβ), tau, α-synuclein (α-syn), TAR DNA-binding protein 43 (TDP43), and repeat-associated non-ATG (RAN) [10,[21][22][23][24][25] among many others ( Fig.…”