An Overview of Primary Dementias as Clinicopathological Entities

Arash Salardini, MD

Disclosures

Semin Neurol. 2019;39(2):153-166. 

In This Article

General Considerations

Dementia

A diagnosis of dementia requires two conditions: chronic cognitive decline and subsequent functional decline in daily life.[5] Differing diagnostic criteria vary mostly in how cognitive decline is defined, for example, what neuropsychological cut-off to use, or how many and which cognitive domains need to be involved. The basic principles remain the same and may be expressed as follows:

• Presence of cognitive decline:

   – Cognitive concern: The patient or their spouse reports decline in cognitive abilities or work performance. The patient may alternatively be referred after the primary physician raises concern about cognition on history or cognitive screening.

   – Objective demonstration of cognitive decline: The gold standard for cognitive testing is neuropsychological examination. Cognitive performance is expressed in terms of standard deviation (SD) from the mean performance of previously tested cohorts of cognitively normal individuals. The score is normalized for age and level of education. Performances which are 1, 1.5, or 2 SD below the mean represent borderline, minor, or major cognitive decline, respectively.[10]

• There is chronic functional decline:

   – Cognitive changes interfere with independent living. The activities of daily living are divided into two sets of tasks: basic activities of daily living (BADL) which refer to basic self-care tasks such as bathing, feeding, toileting, and dressing, and instrumental activities of daily living (IADL) which are more complex tasks such as managing finances, medication management, managing transportation, shopping, and meal preparation, as well as house chores. A loss of function may be exemplified by an inability to perform IADLs. In later stages of dementia BADLs are also affected (Table 1).[11,12]

• The decline in cognition not explained in terms of delirium or psychiatric illness: delirium and psychiatric illnesses can be associated with significant cognitive symptoms. These causes should be ruled out before a diagnosis of dementia is made.[5]

Mild Cognitive Impairment

The current definition of MCI, based on Petersen's criteria, has two parts: (1) cognitive decline in excess of that which is expected for age and (2) relative preservation of function as evidenced by the ability to perform most IADLs. MCI was originally conceived as a functional stage of dementia. Over time, researchers observed that although most individuals with MCI progressed to dementia, there were smaller groups of individuals who were either stable clinically or reverted back to normal cognition after a time. For a time, MCI was reconceived not as an early stage of dementia, but instead a risk state for future incidence of dementias. Certain phenotypes of MCI such as ones that mostly affected episodic memory appeared to have an even higher risk of conversion to Alzheimer's dementia.[13]

With the advent of reliable biomarkers, this view has been superseded by a more biological conception where cognitive impairment is one risk factor amongst several other biomarkers which can be used to predict the likelihood of an individual's progression to dementia. The concept is most fully developed with regard to AD, for which there are widely available biomarkers. For example, an individual with minor cognitive deficits, positive cerebral amyloid angiopathy, and evidence of mesial temporal atrophy on magnetic resonance imaging (MRI) is at a very high risk of progressing to Alzheimer's dementia (see Figure 1), whereas a person who has cognitive impairment without any biomarkers is at a much lower risk of progression to Alzheimer's dementia. This approach, for the moment, falls short of diagnosing progression to dementias other than AD, because reliable biomarkers are not available for other primary dementias. This will change in the near future.[14]

Figure 1.

MRIs of a patient with mild cognitive problems who is at high risk of progression to dementia. (A) A FLAIR coronal section just anterior to the pons. The arrow directs the eye to the salient locale. The choroid fissure and the inferior horn of the lateral ventricle are enlarged. The hippocampus shows significant loss of height. This is a sign of advanced mesial temporal atrophy.(B) An SWI transverse slice through the corona radiata showing multiple punctate hemorrhages consistent with amyloid angiopathy. FLAIR, fluid attenuation inversion recovery; SWI, susceptibility-weighted imaging.

Clinically, MCI is divided into amnestic and nonamnestic types depending on whether episodic memory is involved or not. Another distinction is made between single-domain and multidomain MCIs, referring to the number of cognitive domains affected. By far the most common cause of amnestic single-domain MCI is AD. Rapid forgetting which characterizes amnestic disorders is associated with hippocampal dysfunction.[15] A rare alternative diagnosis is "age-related hippocampal sclerosis," which is a new clinicopathological entity that presents much like AD but lacks the characteristic pathological changes. It occurs in the very elderly patients and is associated with TDP-43, a protein that is more commonly seen in frontotemporal dementias.[16] Amnestic multidomain MCI can be caused by AD, small vessel disease, and some frontotemporal dementias. Nonamnestic MCI can frequently be due to Lewy body disease, frontotemporal dementia, and atypical AD.[13]

Primary Dementias

Primary dementias are a group of diseases whose principle manifestation is cognitive decline. Most but not all primary dementias are neurodegenerative proteinopathies. In proteinopathies certain misfolded proteins form toxic inclusions and lead to neurodegeneration, glial reaction, and neuroinflammation.[17] Primary dementias include AD, frontotemporal dementia, and prion diseases. Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) are proteinopathies which present with significant extrapyramidal motor symptoms; however, because they are also common causes of dementia, they are included with primary dementias. Vascular dementia is not a proteinopathy, but it is the second most common cause of dementia in the elderly population and is also included in this category.[2]

The present model of primary dementia is as clinicopathological entity. These conditions are defined by three factors: clinical presentation, severity of cognitive-related disability, and neuropathological diagnosis based on histopathology and characteristic changes (Figure 2). For example, an individual with severe cognitive problems and a presentation typical for AD would be considered to have probable AD. The presence of Alzheimer biomarkers strengthens the probability of a correct diagnosis.[18] A newer research framework by National Institute of Aging–Alzheimer's Association (NIA-AA) does away with the clinical and neuropathological parameters. This biological framework classifies AD according to biomarker status. This model will standardize dementia research and in the future, may lead to a model where interactions between different biomarkers and pathologies, like vascular and Alzheimer's pathologies, are taken into account. The biological framework is meant for research only at this stage and is not for the moment a practical approach to primary dementias in the clinic.[19] In this article, our conception of primary dementia is based on the clinicopathological model.

Figure 2.

A conceptual model of proteinopathies, where risk factors lead to an accumulation of misfolded proteins, causing neurodegeneration which manifests as cognitive decline. AD, Alzheimer's disease; FTD, frontotemporal dementias; LBD, Lewy body dementia; MSA, multi-system atrophy; PDD, Parkinson disease dementia.

Rapidly Progressive Dementias

RPDs are conditions which progress from normal cognition to dementia in 1 to 2 years. As a category, the term was first used for prion diseases and their differential diagnoses. RPDs often have features other than cognitive decline such as behavioral problems, pyramidal or extrapyramidal symptoms, electroencephalogram (EEG) changes, and myoclonus. Crudely, we can categorize RPDs into prion diseases, atypical presentation of other primary dementias, autoimmune diseases including autoimmune encephalitis, and secondary encephalopathies (including toxic metabolic encephalopathy). The relative frequency of these conditions depends on the setting. In tertiary referral centers, prion diseases may predominate. In a community setting, secondary encephalopathies are more likely to be worked up as RPD.[7]

Primary dementias which present as RPDs are more likely to be young onset and often have long tract signs, white matter changes, myoclonus, and behavioral changes.[20] For Alzheimer-related RPDs, the presence of amyloid pathology in cerebrospinal fluid (CSF) or on positron-emission tomography (PET) imaging can help establish the diagnosis, especially in the younger patients. For Lewy body disease, a careful history, evidence of neuroleptic sensitivity, and in some cases dopamine transporter imaging will help. For others, especially frontotemporal dementia, many other causes need to be ruled out before a diagnosis is made.[21]

Secondary encephalopathies represent some rarer causes of delirium. Vascular causes include inflammatory cerebral amyloid angiopathy, primary central nervous system angiitis, or Behçet disease. Diffuse neoplasms and infections such as human immunodeficiency virus, herpes encephalitis, syphilis, Whipple's disease, and Lyme disease may also present as RPDs. Some other causes include gastrointestinal-related pathologies such as celiac disease and vitamin malabsorption (e.g., Wernicke's encephalopathy). Finally, difficult-to-detect temporal lobe epilepsies and nonconvulsive seizures, especially with status epilepticus, can mimic RPDs.[22]

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