An Overview of Primary Dementias as Clinicopathological Entities

Arash Salardini, MD

Disclosures

Semin Neurol. 2019;39(2):153-166. 

In This Article

Different Types of Primary Dementias

We can classify primary dementias according to their neuropathological phenotype, neuropsychological presentation, and by their clinical features (Table 2):

• Neuropathological phenotype: Proteinopathies are characterized by different misfolded protein aggregates:

   – AD is a double proteinopathy with pathology related to both amyloid β and hyperphosphorylated tau.

   – Tau is also implicated in several other pathologies, including Pick's disease (or FTLD-tau), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP).

   – Frontotemporal lobar degeneration (FTLD) is seen in relations to TDP-43 (FTLD-TDP) and FUS (FTLD-FUS), and in addition to tau (FTLD-tau or Pick's disease).

   – α-Synuclein is associated with PDD and LBD, and the two may be considered as parts of the spectrum of the same disease.

   – In vascular dementia, several pathological findings often coexist, including large vessel atherosclerosis, small vessel arteriosclerosis, and cerebral amyloid angiopathy.[18]

• Neuropsychological presentation: Each neurodegenerative disease has a predilection for a particular part of the brain and for certain brain networks. The spread of pathology in the early stages of disease is mostly along the connections of one or few of these brain networks. For example, pathology in AD begins in the mesial temporal area but spreads to parts of the parietal lobe which are also part of a network called the default mode network.[23] As a result, each primary dementia has several typical presentations relating to the brain networks it favors. In time, pathology spreads to the rest of the brain and the clinical picture becomes less distinct.[24]

• Clinical features: A patient's functional status has great practical significance in the clinical management of primary dementias. Functional status is expressed in terms of clearly defined disease stages:

   – Prodromal stage in which there is no discernable cognitive decline.

   – MCI stage in which cognition can be demonstrated to have declined but the subject continues to function independently.

   – Mild dementia stage in which an individual requires help with their IADLs.

   – Moderate dementia stage when the patient starts requiring help with their BADLs.

   – Severe stage when the patient is completely dependent.[25]

Several other clinical terms are used in the diagnosis of primary dementias, such as early onset (<65 years) versus late onset (>65 years) and familial versus sporadic. Familial and early onset primary dementias are less common than late onset sporadic disease.

Alzheimer's Disease

• Neuropathology: AD is the most common form of primary dementia. AD is characterized by the presence of amyloid β plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic loss, and neuroinflammation. The accumulation of amyloid and tau precedes the onset of symptoms by many years. The presence of amyloid is required for a pathological diagnosis of AD; however, the distribution of NFT more closely correlates with cognitive symptoms.[26]

• Clinical phenotypes: Four clinical presentations are common in AD[27] (Figure 3):

Figure 3.

A 57-year-old woman with MOCA 8/30 and severe short-term memory deficits. (A) Parasagittal MRI image showing widespread cortical atrophy especially in the parietal region. (B) This is a graph of pTau vs. ATI (amyloid tau index) which shows very low amyloid and very high pTau unambiguously consistent with a diagnosis of Alzheimer's disease. (C) The panel shows the average L and R hippocampal volume as a percentage of intracranial volume. The parallel lines drawn are age norms expressed in terms of percentage, assuming a normal distribution. Our patient is in the bottom 5% of her peers. This is consistent with a diagnosis of Alzheimer's disease.

   – Amnestic or typical AD: By far the most common one is the amnestic presentation, also called "typical AD." In this presentation, problems with episodic memory predominate and changes to the mesial temporal area occur early. Other domains may also be affected, most commonly visuospatial cognition as exemplified by an inability to navigate. When more than one domain is involved, the presentation is a multidomain amnestic presentation.

   – Visual variant or posterior cortical atrophy: A visual variant of AD called posterior cortical atrophy affects visual areas of the brain. In these patients, visual perception is compromised in the absence of any ophthalmological problems. An inability to recognize objects or faces or an inability to judge the relative position of objects in space may occur, with relative preservation of episodic memory.

   – Language variant or logopenic dementia: A language variant of AD affects the brain's phonemic lexicon, leading to impaired naming, hesitation in speech, and changes to spelling. Memory deficits and anxiety often coexist.

   – Executive variant or frontal AD: Executive variant of AD presents with executive dysfunction and behavioral symptoms. It is relatively rare and is frequently misdiagnosed as frontotemporal dementia. It is sometimes called frontal variant of AD but this is a misnomer because the frontal lobes are not necessarily involved in the executive variant of AD.

• Genetics and other risk factors: A minority of individuals with AD have a familial form of the disease which is transmitted in an autosomal dominant fashion. The genes involved, APP, PSEN1, and PSEN2, code for proteins which are involved in amyloid metabolism and can be tested in the clinic using available commercial laboratories. Familial forms of AD form a much greater proportion of early onset AD compared with later onset forms.[28] Most AD is sporadic. The main risk factor for sporadic AD, as with all primary dementias, is advanced age. Several other risk factors such as low education, cardiovascular risk factors, APOE4 genotype, and head injuries have been demonstrated for sporadic AD.[29] Genome-wide association studies have uncovered several susceptibility genes which are relatively rare and have small effects on overall risk. Models which use these genes in addition to APOE4 to predict future risk of dementia have been promising.[30]

• Biomarkers: Compared with other primary dementias, the greatest advances have been made in the field of AD. The most tangible result has been the development of several biomarkers which can be used to diagnose AD in vivo. The current research framework proposed by NIA-AA uses biomarker status as a way of classifying AD. It identifies three biomarkers: amyloid (A), tau (T), and neurodegeneration (N)[19,31] (see Table 3).

   – Amyloid positivity may be gauged either by CSF analysis or by PET imaging using amyloid directed radioligands: florbetapir, florbetaben, and flutemetamol. These ligands do not require onsite cyclotron synthesis, which means amyloid PET scans can now be performed in most nuclear medicine sites. Sadly, insurance does not cover the costs, so amyloid PET does not have widespread use outside of research and tertiary settings. CSF studies are widely available and significantly cheaper. A positive amyloid biomarker is represented by low levels of amyloid β 42 in the CSF. The ratio of amyloid β 42 to amyloid 40 may be used instead, when available, to increase diagnostic specificity.[32] CSF sampling has the advantage of being available to measure other biomarkers such as phosphorylated tau. PET scans, on the other hand, demonstrate amyloid distribution in addition to overall levels.[33]

   – Hyperphosphorylated tau: CSF is also used for measurement of hyperphosphorylated tau. A raised level represents pathology. Tau PET ligands are in advanced stages of development but are not yet clinically available. Similar to amyloid PET, tau PET has the added advantage of showing the topographic distribution of NFTs. This is even more important in the case of tau because tau localization and regional distribution correlates well with clinical symptoms.[34]

   – Neurodegeneration: The third proposed biomarker, "neurodegeneration," is a less specific biomarker. It is represented by any biomarker which documents neuronal damage. Measures of atrophy on MRI[35] and hypometabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET) are the most common methods for ascertaining neurodegeneration. Hippocampal atrophy can be measured using automated computer algorithms. It can also be visually rated by clinicians. FDG-PET uses radioactive glucose to find areas of reduced metabolism, which corresponds to neuronal dysfunction and loss. Total tau (as opposed to phosphorylated tau) measured in the CSF is also a measure of "neurodegeneration"[36] (see Figure 4).

Figure 4.

These are reconstructed FDG-PET images of three patients with atypical presentation of Alzheimer's disease. The darker areas are areas of hypometabolism when compared with age-matched normal controls. Each column represents a single patient, with left hemisphere on top. PCA images show significant posterior parietooccipital and occipitotemporal hypometabolism. Executive variant AD shows frontal and temporoparietal hypometabolism on the right. This is not a typical pattern compared with the literature. lvPPA shows mainly left sided temporoparietal hypometabolism. AD, Alzheimer's disease; FDG-PET, fluorodeoxyglucose-positron emission tomography; lvPPA, logopenic variant primary progressive aphasia; PCA, posterior cortical atrophy.

• Treatments: Presently, no disease-modifying medications exist for the treatment of AD, but several strategies have been advanced including immunotherapy directed against amyloid, inhibition of amyloid synthesis, and immunotherapy against extracellular tau. Of these, monoclonal antibodies against amyloid seem to show the greatest promise. Pharmacological interventions for symptomatic management of AD are based on the effect of pathology on several neurotransmitter systems, including acetylcholine, norepinephrine, and serotonin. Cholinesterase inhibitors are Food and Drug Administration approved to manage symptoms of AD, and work by increasing acetylcholine neurotransmission. Nonpharmacological interventions aimed at curtailing excess disability consist of patient education, cognitive interventions, and lifestyle modifications.[37]

Frontotemporal Lobar Degeneration

• Neuropathology: Frontotemporal dementias are a group of pathologies with overlapping clinical phenotypes. The most common protein aggregates in these conditions include tau, TDP-43, and FUS. The corresponding designations are FTLD-tau, FTLD-TDP, and FTLD-FUS, respectively. Tau protein has six isoforms due to alternative splicing of the gene product of its gene MAPT. These isoforms can be divided into two groups based on the number of repeat motifs found in the microtubule-binding domains. There are three isoforms of tau which have three repeat motifs (3R tau), and the other three isoforms have four repeat motifs (4R tau). CBD and PSP are caused by 4R tau. Pick's disease is associated with 3R tau. FTLD-FUS is relatively rare, with FTLD-TDP and FTLD-tau comprising the majority of cases that reach biopsy.[38,39]

• Clinical phenotype: FTLD has a wide range of neuropsychological presentations, which often overlap, increasing diagnostic uncertainty in the clinical setting. Common neuropsychological presentations include:[40,41]

   – Behavioral variants of FTLD (bvFTLD): Patients with bvFTLD present executive and behavioral deficits. Loss of social graces, disinhibition, and changes in personality are the classic signs of bvFTLD. Also common are apathy and loss of motivation and executive dysfunction. Psychosis can be seen in on presentation. New onset psychosis in the elderly is rarely due to primary psychiatric disease, except for depression with psychotic features. Extrapyramidal symptoms may be present in this group. Pathologically, most bvFTLDs are FTLD-TDP43 and FTLD-tau.[42]

   – Language variants of FTLD or primary progressive aphasia (PPA): At presentation, several phenotypes may be recognized:[43]

   ∘ Nonfluent PPA (nfPPA) resembles a slowly progressive Broca's aphasia with some differences. At the outset, naming and repetition may be relatively intact. The patient has problems with sentence formation and uses telegraphic speech which is noted for its agrammatism. There is often coexistent apraxia of speech, which causes the speech to sound flat and aprosodic. There is often difficulty with pronouncing longer words. In time, all language functions are affected and behavioral changes may follow. A high proportion of nfPPA are FTLD-tau.

   ∘ Semantic variant PPA (svPPA) is characterized by atrophy of temporal lobes bilaterally. The patient loses semantic information including meaning of words and may have problems with visual agnosia. Writing and reading deficits occur early in the disease. svPPA may be associated with behavioral problems. There is a high proportion of FTLD-TDP amongst this group.

      ▪ Richardson syndrome (RS): Steele, Richardson, and Olszewski first described the clinical feature of PSP. In this, the patient presents with ocular motor difficulties, cognitive findings, parkinsonian features, and gait instability. Ocular findings include loss of vertical gaze, problems with optokinetic reflex, loss of convergence, and eye-opening apraxia. Presence of an akinetic-rigid form of parkinsonism is the most frequent extrapyramidal presentation. Gait is unstable, and progressively worsening freezing of gait is common. Cognitively, frontal findings and subcortical deficits are found. These include executive dysfunction and mood disorders. With the progression of disease, patients may develop compulsive behaviors, palilalia and apraxia of speech, disinhibition, or apathy. Most cases of RS are due to the characteristic neuropathology of PSP. However, other pathologies such as CBD and Pick's disease can also present this way. Conversely, a person with PSP pathology may present with syndromes which may involve mostly gait or cognition. Some may mimic idiopathic Parkinson's disease or corticobasal degeneration. Most will begin to resemble RS as the disease progresses.[44]

   – Corticobasal syndrome (CBS): This is a clinical syndrome first described in relation to CBD, a 4R tau pathology which frequently presents with this syndrome. CBS is characterized by ideomotor apraxia, parkinsonism, dystonia, visuospatial defect, myoclonus, and alien hand syndrome. CBS can be caused by several pathologies including PSP, AD, and FTLD-TDP. Conversely, CBD may present with RS, nf-PPA, and a behavioral-spatial syndrome characterized by personality change, executive dysfunction, and visuospatial defects.[30,45]

   – Frontotemporal lobar degeneration–motor neuron disease (FTLD-MND): FTLD and MND are commonly seen together. Most patients with FTLD have MND on electromyography. Some progress to clinical disease. Familial forms of this are associated with C9orf72 gene repeat expansion. The disease can be rapidly progressive, presenting similar to amyotrophic lateral sclerosis but affecting the bulbar muscles early.[46]

• Genetics and other risk factors: Several genes implicated in FTLD are available clinically. A family history of dementia should prompt referral to a geneticist. The most common gene mutation in this group is C9orf72 which is due to hexanucleotide expansion in the noncoding region. It is most common in families with history of FTLD-MND. Along with progranulin, valosin-containing protein, and TARDBP, C9orf72 is associated with TDP-43 pathology. Whereas MAPT mutations are associated with tauopathy. MAPT H1 haplotype is a risk factor for 4R tauopathies.[18,40]

• Biomarkers: FTLD-specific CSF biomarkers are not presently available in the clinic. Imaging modalities such as MRI, FDG-PET, and tau-PET can determine the pattern of distribution of brain atrophy, hypometabolism, and tau deposition. These patterns support clinical diagnosis. Patterns may include bifrontal (bv-FTLD), bilateral temporal poles (sv-PPA), more limited frontal including left inferior frontal lobe (nf-PPA) and predominantly temporal (CBD or PCA). Ruling out AD using biomarkers may improve diagnostic confidence[47] (see Figure 5).

Figure 5.

MRI images of a patient with nonfluent primary progressive aphasia variant frontotemporal dementia due to progranulin mutation. (A) Transverse FLAIR slice shows the asymmetrical L > R in this case. (B) Atrophy of the temporal pole is accompanied by the so-called "knife sign" where the slender temporal tissue resembles a knife. (C) FDG-PET shows hypometabolism in frontotemporal areas L > R. FDG-PET, fluorodeoxyglucose-positron emission tomography; FLAIR, fluid attenuation inversion recovery; MRI, magnetic resonance imaging.

• Treatments: Cholinesterase inhibitors are of limited efficacy, and in some instances, may be associated with adverse behavioral changes. Selective serotonin reuptake inhibitors are commonly used for reducing affective symptoms. Otherwise, treatment options are limited to nonpharmacological and behavioral interventions.[40]

Lewy Body Dementia and Parkinson's Disease Dementia

• Neuropathology: Both LBD and PDD are characterized by the accumulation of α-synuclein in neurons to form Lewy bodies. These are overlapping clinical syndromes which are on the spectrum of the same disease. In PDD, Lewy bodies begin by affecting subcortical structures including the brainstem, thalamus, and basal ganglia before spreading to the cortex. Subsequently, the deficits seen in PDD include attentional issues, slowness of mentation, and executive dysfunction associated with involvement of the dorsolateral prefrontal cortex. LBD, on the other hand, has earlier cortical involvement, often coexists with AD or vascular pathologies, and affects posterior parts of the brain. As a result, the characteristic cognitive deficits include arousal and visuospatial dysfunction.[48,49]

• Clinical phenotypes: The two phenotypes are LBD and PDD. They are both associated with rapid eye movement (REM) behavior disorder, a sleep disorder which causes the patient to act out their dreams while still sleeping. LBD is associated with fluctuations, parkinsonism, visuospatial deficits, and hallucinations. Hallucinations, called peduncular hallucinosis, are classically of children and animals and are brightly colored. In our clinic, visions of people standing around while silent and other visual illusions are common. Visual illusions occur especially in poor lighting. Most LBD hallucinations are not threatening to the patient. Episodic memory is often affected less and later than is the case with AD. PDD starts with motor symptoms, slowness of mentation, and problems with memory retrieval, and goes on to include visuospatial problems seen in LBD.[50]

• Genetics and other risk factors: Certain pesticides, vitamin D, and traumatic brain injury have been implicated in Parkinson's disease, therefore PDD and to a lesser extent LBD. Some genes associated with genetic forms of Parkinson's disease such as SNCA and LRRK2 are also associated with LBD. The gene implicated in Gaucher's disease, GBA1, appears in 10% of individuals with Parkinson's disease and increases the risk of LBD. Given that there are other pathologies present in patients with LBD, it is not surprising that both vascular risk factors and APOE4 are most frequent in individuals with LBD than the general population.[51]

• Biomarkers: Loss of dopaminergic neurotransmission can be demonstrated by a dopamine transport scan or a DAT scan. When distinguishing LBD from AD, the presence or absence of amyloid is not useful, because both often have amyloid pathology. However, the pattern of amyloid deposition is different in LBD. A sparing of the posterior cingulate cortex, the so-called island sign, on amyloid PET is fairly specific to LBD. Another difference is on FDG-PET, where LBD affects the occipital lobe, this is spared in AD[52] (see Figure 6).

Figure 6.

The patient has Lewy body dementia. (A) The FDG-PET scan shows the presence of occipital hypometabolism. The darker areas superimposed on the CT represent areas of hypometabolism compared with age-matched controls. (B) DAT-SPECT scan shows a loss of dopaminergic innervation in the striatum. The superimposed lighter signal is dopamine transporter uptake signal. CT, computed tomography; DAT-SPECT, dopamine transporter single-photon emission computed tomography; FDG-PET, fluorodeoxyglucose-positron emission tomography.

• Treatment: Treatment of cognitive symptoms in LBD and PDD centers around cholinesterase inhibitors reduces fluctuations and hallucinations and improves cognition in general. Judicious treatment of motor symptoms can be attempted, with the knowledge that cognitive symptoms may worsen with dopaminergic medications. Depression and anxiety are common in these diseases and need to be treated.[52]

Vascular Dementia

• Neuropathology: Vascular dementia is a general term applied to dementia caused by vascular pathology. Cognitive impairment can occur after multiple infarcts, a large infarct, or a strategically placed infarct. These infarcts can be hemorrhagic or ischemic. The dementia due to these causes is commonly referred to as poststroke dementia. Hypoperfusion causing laminar necrosis can also cause cognitive decline. However, most vascular dementia is due to chronic cerebral small vessel disease. This form of vascular dementia progresses insidiously, causing chronic white matter changes, cortical and subcortical microinfarcts, lacunar infarcts, microbleeds, and superficial siderosis. The two most common causes of small vessel disease are arteriosclerosis and cerebral amyloid angiopathy. In arteriosclerosis, the vessels lose their elasticity and have lumenal narrowing . Cerebral amyloid angiopathy is caused by deposition of amyloid in vessel walls. This damages the vessel wall and increases the risk of bleeding. These bleeds are in the form of microhemorrhages and large lobar bleeds. Cerebral amyloid angiopathy also has an inflammatory form which presents as an RPD.[53,54]

• Clinical phenotypes: The clinical stage of vascular dementia which corresponds with MCI is vascular cognitive impairment. The clinical phenotype of poststroke dementia is determined by the location and extent of the stroke. Small vessel disease is more diffuse and affects cognitive domains, which neurologists have traditionally referred to as "subcortical." These include speed of information processing, complex attention, and some executive functions. Additionally, there is a high rate of problems with memory retrieval, gait apraxia, urinary urge, and psychiatric manifestations. The psychiatric manifestations include depression, abulia, and apathy.[55,56]

• Genetics and risk factors: Vascular risk factors such as hypertension, obesity, hypercholesterolemia, smoking, and family history are closely linked to the risk of stroke and therefore poststroke dementia. The risk of dementia in stroke depends on the location of the strokes as well as the presence of reduced cognitive reserve (advanced age and low education, and coexistence of AD pathology). There is a correlation between small vessel disease and traditional vascular risk factors, but the link is not as strong as that seen in large vessel disease. Several genetic conditions cause small vessel disease, the most common being cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADSIL) in which the patient presents with cognitive deficits in their 40s and 50s. There is some evidence that nondisease causing variations in several genes associated with hereditary small vessel diseases can be risk factors for sporadic small-vessel disease.[57,58]

• Biomarkers: Presently there are no good biomarkers for vascular dementia due to small vessel disease. Several lesion types, including lacunar infarcts, perivascular space enlargements, white matter hyperintensities, microhemorrhages, superficial siderosis, and microinfarcts, are associated with the severity of small vessel disease. However, they are very poor at predicting cognitive outcomes. MRI techniques measuring cerebrovascular reactivity (to CO2) and structural connectivity using diffusion tensor imaging (DTI) are being studied as possible biomarkers for small vessel disease. Presence of amyloid and tau, which is common, will worsen the severity of the dementia[59] (see Figure 7).

Figure 7.

MRI showing evidence of advance small vessel disease. Panels (A) and (B) (FLAIR coronal and transverse, respectively) show confluent white matter hyperintensities affecting predominantly the corona radiata. Panel (C)(transverse section SWI) shows the presence of hypertensive microbleeds in the basal ganglia and thalamus. Panel (D) (transverse section T2) shows the presence of enlarged perivascular spaces best seen in the putamen. This is an example of état criblé or cribriform state found in classic neurological literature. FLAIR, fluid attenuation inversion recovery; MRI, magnetic resonance imaging; SWI, susceptibility-weighted imaging.

• Treatment: Treatment is well established for large vessel disease in the brain and includes antiplatelet therapy or thrombolysis in the acute setting followed by secondary prevention to reduce the risk of reoccurrence. Apart from control of blood pressure, these interventions do not appear to be as effective in slowing the progression of small vessel disease.[53]

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