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Dementia: Advanced Topics

Notes

Dementia: Advanced Topics

Sections







Overview

Here we will address advanced topics in dementia.

See the Board Review Questions at the end for clinical cases.

Dementia Etiologies

Although numerous dementia etiologies exist, and you will see varying lists of potential causes, here we will present a working list of common etiologies and etiologies that are pre-mortem (and potentially reversible).

We will present 4 categories of dementia:

  • Neurodegenerative
  • Vascular
  • Reversible Causes
  • Infectious

Neurodegenerative

Let's start with neurodegenerative causes. This category covers two of the top three causes of dementia (Alzheimer's disease and Lewy body dementia). Indicate the following:

Neurodegenerative Causes

Alzheimer's disease

Denote that Alzheimer's disease most often begins with short-term memory loss. It is the most common cause of dementia, by far, followed by vascular dementia.

Lewy body dementia

Denote that Lewy body dementia is best remembered as a combination of dementia plus parkinsonism.

Frontotemporal dementia (FTD)

Frontotemporal dementia (FTD) involves frontotemporal lobar pathologic degeneration with prominent behavior and/or language dysfunction (aphasia).

We address Alzheimer's disease and Lewy body dementia in our general dementia tutorial.
Let's address frontotemporal dementia, now. At the end, we'll address advanced topics in Alzheimer's disease histopathology.

Frontotemporal dementia (FTD)

Frontotemporal lobar degeneration

Frontotemporal dementia (FTD) typically affects individuals in their 50s to 60s. It manifests with behavioral or cognitive (including language) dysfunction out-of-proportion to memory loss. It is autosomal dominant in ~ 40% of cases with the remaining being sporadic.

The nomenclature for the frontotemporal dementias is incredibly challenging to decipher, so we'll present a fairly simplified widely-held heuristic that has good clinically utility.

First, indicate that what unites the various frontotemporal dementia is, in fact, the finding of frontotemporal lobar degeneration. To distinguish them, we rely on their molecular signature.

Molecular Classes

Indicate that, at present, three key molecular classes are:

  • Tau (Pick bodies).
    • Pick bodies are round-shaped, intraneuronal inclusions of tau protein that are argyrophilic (they have affinity for silver staining).
  • TDP-43 (TAR DNA-binding protein of 43kDA)
  • FUS (Fused in Sarcoma)

Clinical Subtypes

Now, let's walk through the various subtypes of FTD.

We'll address behavioral variant FTD (bvFTD), progressive nonfluent aphasia (aka nonfluent agrammatic variant of primary progressive aphasia (PPA)), and semantic variant primary progressive aphasia (PPA).

Behavioral variant FTD (bvFTD)

First, let's focus on bvFTD, which we'll introduce with some clinical-anatomical correlations for apathy and impulsivity.

  • Draw the anterior/medial surface of a brain and show profound frontal lobe cortical atrophy, and specify that emotional apathy that stems pathology in this region.
  • Now, show atrophy of the frontal and temporal lobes in lateral view (with preserved cortical bulk in the parietal and occipital lobes).
  • Specify that impulsivity stems from disease in the orbitofrontal cortex.

Behavioral variant FTD is a progressive neurodegenerative disorder that involves behavior and/or cognitive dysfunction with prominent involvement of any of the following symptoms:

  • Impulsivity (disinhibition) (think: orbitofrontal degeneration)
  • Apathy (think: anterior cingulate gyrus)
  • Loss of empathy (think: amygdala and temporal atrophy)
  • Perseverative/stereotyped behavior (think: frontal and temporal lobes (eg, complex partial seizures))
  • Hyperorality (think: amygdala and Kluver Bucy syndrome)
  • Executive dysfunction (think: prefrontal cortices)

Primary Progressive Aphasias (Nonfluent & Fluent)

Next, let's address the two primary progressive aphasias, which basically divide into motor and sensory aphasias.

Nonfluent

Consistent with the localization of Broca's aphasia, show that progressive nonfluent aphasia localizes to the inferior frontal lobe.
The deficit begins as a transcortical motor aphasia with progression to Broca's aphasia. It is agrammatic, hesitant, nonfluent with preservation of word meaning but dysfunction in understanding complex grammatical arrangements.

Fluent

Show that semantic variant PPA localizes to the anterior temporal lobe (with profound anterior temporal pole atrophy being a key finding).
The deficit begins as a transcortical sensory aphasia with progression to Wernicke's aphasia. There is a loss of word meaning, meaning the fluency and melody of speech is preserved but the content is empty. There is a lack of understanding of basic definitions and a substitution of content with jargon phrases. There is an ultimate progression towards word salad: nonsensical sentences devoid of meaning.

Hypokinetic Movement Disorder Classification

FTD is often categorized along with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), which we address in the hypokinetic movement disorders tutorial.

Vascular

Vascular Etiologies

Next, let's address vascular causes.

Multi-infarct dementia

Multi-infarct dementia involves small vessel, ischemic, silent infarcts.

Cerebral amyloid angiopathy.

Cerebral amyloid angiopathy involves microhemorrhages and lobar hemorrhages.

CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Genetics

Indicate that this occurs secondary to a chromosome 19q13, notch 3 gene mutation.

Presentation

It manifests with strokes individuals who are younger than would be expected for frequent strokes (typically in their 40s). They typically also have significant migraines. Ultimately, the progression of strokes results in dementia.

Anterior temporal lobe atrophy

Draw an axial section through the brain that depicts the anterior temporal lobes. Demonstrate prominent anterior temporal lobe white matter changes and confluent white matter disease beyond these regions. Indicate that as a helpful distinguishing factor, there is prominent anterior temporal lobe involvement, early on.

Reversible Causes

Here, we include a variety of diagnoses that have varying degrees of reversibility.

Reversible Causes

Normal pressure hydrocephalus (NPH)

Indicate the classic normal pressure hydrocephalus (NPH) triad: "wacky, wobbly, wet", which underscores the characteristic dementia, gait apraxia, and bladder incontinence that can occur.

Nutritional & Endocrine

Indicate a few key entities: thiamine (B1) deficiency, B12 deficiency, thyroid disorders.

Psychiatric

Indicate pseudodementia (aka the "dementia of depression"), which is the term for depression that masks itself as dementia. Notably, patients with depression are more likely to complain about memory loss than patients with dementia (who often classically deny having memory problems!).

Look for psychomotor slowing and poor effort as potentially signs of depression. Note that patients with Parkinson's disease may exhibit similar behaviors. Parkinson's disease patients develop depression and ultimately dementia during their disease course.

Autoimmune

Indicate Hashimoto's encephalopathy (aka Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis (SREAT) presents with subacute, progressive delirium (confusion and altered levels of consciousness) and may produce seizures or myoclonus (it is easy to confuse this potentially reversible condition with CJD). It is associated with high anti-TPO-Ab titers (thyroperoxidase) antibodies, and it characteristically responds well to steroid therapy.

  • Note that the pathogenesis of the disorder and whether any relationship exists to autoimmune thyroid disease remains unknown.
  • Note that this diagnosis should remind us to consider autoimmune causes of cognitive dysfunction, more broadly, as well.

Normal pressure hydrocephalus (NPH)

Ventriculomegaly with minimal cortical atrophy

Draw an axial MRI slice through the basal ganglia healthy gyral folds with a normal-sized ventricular system. Next to it, redraw the view but here show enlargement of the ventricles, again with healthy gyral folds (no atrophy).

The most common cause of ventriculomegaly is cortical atrophy (called hydrocephalus ex vacuo) in which ventriculomegaly is secondary to brain atrophy; in NPH, there is hydrocephalus with minimal brain atrophy (with the idea being that the ventriculomegaly is not secondary to brain shrinkage but rather a true ventricular pathological process).

Wacky, Wobbly, Wet

Wacky refers to the dementia, which, as a simplicity, manifests with a prefrontal subcortical dementia in which there is attentional impairment, along with prominent executive dysfunction, as well as memory loss and anomia.

Wobbly refers to the gait apraxia; we show a patient with a symmetrically wide base standing above a magnetic, which keeps the feet "glued" to the floor, which results, at least in part, from stretching on the medial frontal cortex. It affects gait initiation, turning, and transitions, and results in tripping and falls.

Wet refers to urinary urgency and incontinence, secondary to pathologic stretching (with resultant distortion and ischemia) of widespread supraspinal micturition pathways within the brainstem (especially the pontine micturition center), medial frontal lobe (anterior cingulate gyrus and prefrontal cortex), hypothalamus, and other regions.

Diagnosis and treatment

Treatment involves a CSF shunt. So, draw the abdominal peritoneum and show that most often a ventriculoperitoneal shunt is used. It is placed in one of the lateral ventricles and drains into the abdominal peritoneum.

As a diagnostic work-up for NPH, patients undergo large volume lumbar punctures to look for improvement in gait following CSF drainage.

Epidemiology/Controversy

Note that despite how often radiologists call-out this diagnosis, the actual incidence of the disease is unknown and by certain estimates it may be as low as 2 per million, and some clinicians question whether it even truly exists.

  • For a thorough review of the controversial nature of this diagnosis, refer to the following articles:
    • Espay AJ, Da Prat GA, Dwivedi AK, Rodriguez-Porcel F, Vaughan JE, Rosso M, Devoto JL, Duker AP, Masellis M, Smith CD, Mandybur GT, Merola A, Lang AE. Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration. Ann Neurol. 2017 Oct;82(4):503-513. doi: 10.1002/ana.25046. Epub 2017 Oct 4. PMID: 28892572.
    • Espay AJ, Lang AE. Is there even such a thing as "idiopathic normal pressure hydrocephalus"? Ann Neurol. 2017 Dec;82(6):1032. doi: 10.1002/ana.25097. Epub 2017 Dec 4. PMID: 29136297.

Infectious

Finally, lets address a couple of standout infectious etiologies. Note, however, that any chronic brain infection will cause cognitive dysfunction, so if we are considering an infectious etiology, we should cast a broad net with our testing.

Prion disease, Creutzfeldt-Jakob disease (CJD)

Creutzfeldt-Jakob disease (CJD) is the foremost cause of rapidly progressive dementia.

Neurosyphilis

Syphilitic dementia (aka dementia paralytica or "general paresis of the insane") is a late-stage manifestation of neurosyphilis. Patients develop a psychotic dementia with certain motor features, including limb hypotonia and intention tremors.

  • Note that it is a separate syndrome from tabes dorsalis, which presents with posterior column spinal cord disease and, notably, Argyll-Robertson pupils.
  • Importantly, especially in patients with syphilitic dementia, there may be worsening after the onset of treatment secondary to a Jarisch-Herxheimer reaction.

Creutzfeldt-Jakob disease (CJD)

CJD is a prion disease (a proteinaceous infectious particle).

Pathogenesis

Draw the two prion-related proteins (PrP):
First, the non-pathogenic, cellular (C) form. Show that PrPC has an alpha-helix-rich secondary protein structure.
Next, prion-related protein (PrP) scrapie (Sc). Show that PrPSc has a beta-pleated sheet-rich structure.
Note that the conformational difference in these prions is based on the difference of their secondary protein structures (their primary protein structures are the same).
Show that, in short, PrPSc captures PrPC and then refolds it into the PrPSc conformation (the alpha-helices are converted to beta-sheets).

Models exist to explain the exponential dissemination of PrPSc (they are beyond the scope of this tutorial).

Histopathology

Next, show a nucleus in neuropil with adjacent, clear vacuoles to illustrate that the term spongiform encephalopathy is used to describe the sponge-like vacuolation of the cerebral gray matter that is consistently observed in prion disease.

Diagnosis

Now, let's review some key diagnostic tools for the pre-mortem diagnosis of CJD.
In regards to MRI, draw an axial slice, aDWI (diffusion-weighted imaging) MRI sequence; it is the most sensitive and specific test in CJD (~ 90% sensitive, ~ 95% specific).

  • First, show brightness within the head of the caudate to illustrate striatal hyperintensity,
  • Next, show brightness within medial thalamus to illustrate the hockey-stick sign (aka pulvinar sign).
  • Lastly, show cortical brightness to illustrate cortical ribboning, which may be the earliest presenting sign.

Next, indicate that an elevated CSF 14-3-3 protein finding is indicative of CJD. Its utility is argued because of its poor sensitivity and specificity. It probably shouldn't be used in the extremes of pretest probability (less than 20% or greater than 90%), meaning when the clinician is most confident the patient has CJD or has little suspicion of CJD.

Now, let's introduce the characteristic pathologic EEG finding: periodic sharp-triphasic waves at ~ 1Hz frequency (0.5 to 2 Hz), which also has poor sensitivity (~ 65%) and specificity (~ 75%). Show that they consist of sharp, biphasic or triphasic periodic waves. They have mixed spikes with a maximal amplitude in the fronto-precentral region.

Management

To date, there are no curative treatments for prion disease.

Alzheimer's Disease Histopathology

Before we conclude, let's return to Alzheimer's disease, the most common cause of dementia, and take a deeper look at Alzheimer's histopathology.

Amyloid Plaques & Neurofibrillary tangles

Overview

Amyloid Plaques

As a reminder, amyloid beta plaques (senile plaques) are extracellular aggregates of fibrillar amyloid beta peptide. Importantly, they stain red with Congo red staining – the classic amyloid stain – they are found both extracellularly and also in blood vessel walls, we saw that they produce amyloid angiopathy.

Tau Neurofibrillary Tangles

Tau neurofibrillary tangles (tau is a microtubule-stabilizing protein), comprise intracellular conglomerations of hyperphosphorylated tau (a microtubule stabilizing protein); they are the cornerstone to a great deal of neurodegenerative diseases.

Amyloid Cascade Hypothesis

Overview

Although the amyloid cascade hypothesis is no longer widely accepted (in part due to failure of medications that specifically clear amyloid plaques), it is still the most universally understood theory and will still provide us with a solid foundation for the science of Alzheimer's disease.

Indicate amyloid precusor protein (APP). It is the physiologic precursor for the toxic amyloid byproducts that we'll introduce.

Then, indicate tau neurofibrillary tangles.

Pyramidal neuron, hippocampus, CA1

Next, draw a pyramidal neuron of the hippocampus, specifically CA1, since this is the site of the most severe and earliest neurodegeneration in Alzheimer's disease.

  • Start with the triangular-shaped cell body (aka perikaryon or soma). Include its nucleus.
  • Next, show that a long, thick apical dendrite extends from its apical surface. Note that it branches into an apical tuft of dendrites (not shown here).
  • Now, indicate some basal dendrites.
  • Next, show its small axon (as compared to the motor neurons we drew in the neuromuscle section).
  • Remember that hippocampal pyramidal neurons are where Hirano bodies (intracellular eosinophilic rod-shaped structures) are most often found.

Amyloid precursor protein & products

Now draw amyloid precursor protein, which is a cell surface protein, so draw a plasma membrane and indicate the extracellular and intracellular spaces.

Next, indicate that a series of secretases: alpha, beta, and gamma splice the APP into various pieces. Normally, amyloid-beta is removed from APP and degraded outside of the cell. In Alzheimer's pathology, however, amyloid-beta peptides accumulate, instead.

So, let's indicate some toxic amyloid peptide components.

  • First, represent the amyloid-beta-42 oligomer, which is a 42-residue amyloid beta-protein fragment. Amyloid-beta-42 is considered a particularly "sticky", soluble form of amyloid peptide and, thus, in pathologically high concentrations, it aggregates.
    • Place this oligomer in our diagram both intraneuronally and also outside of the cell, as it is found in both spaces.
  • Next, draw an amyloid fibril, which is a larger, less soluble aggregation of amyloid-beta peptide.
  • Then, draw an amyloid-beta plaque, which are called senile or neuritic plaques. They comprise deposits of numerous, aggregated amyloid fibrils. When broken down, the major cleavage products include amyloid-beta 42 and amyloid-beta 40. Show that amyloid-beta plaques are extracellular – they lie outside of the neuron; they are even less soluble than the amyloid fibrils.

Amyloid histopathology

Classic descriptions of amyloid plaques indicate that they have a dense core of amyloid with a less dense halo and that they stain with Congo red (elsewhere, we've seen that Congo red is a classic amyloid stain).

  • It's now understood that these plaques are often are not spherical and and also lack a dense core.
  • Techniques other than Congo red are now used to identify them, such as silver stains and immunohistochemistry.
  • As alluded to earlier, unfortunately, clearance of these plaques has not led to the reversal of dementia that researchers had hoped for.

Cerebral amyloid angiopathy

As mentioned, these amyloid plaques are also found in cerebrovasculature in cerebral amyloid angiopathy, as well. Cerebral amyloid angiopathy is unrelated to the systemic amyloidoses.

Tau neurofibrillary tangles

The pathophysiology of tau neurofibrillary tangle formation lies within the site of the microtubules in the axons and dendrites.

Draw a microtubule and show that tau is a microtubule-stabilizing protein.

  • Indicate that hyperphosphorylation of tau weakens the affinity of tau for the microtubules.
  • Show that these detached tau proteins aggregate and form paired helical filaments: they have a double-helix pattern (or "twisted ribbon" appearance, per more modern accounts).
  • Show that these paired helical filaments conglomerate as densely compacted neurofibrillary tangles. They are insoluble aggregates that crowd the neuronal cell body and extend into the apical dendrite.

Board Review Questions

Diagnostics/Pathophysiology

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