Dementias and Brain Degenerations

Main Text

Preamble

One in three adults over 85 years old suffers from Alzheimer disease or other forms of dementia. New treatments to slow progression of this devastating disease are being developed; most rely on early identification of at-risk individuals before clinical symptoms emerge.

Innovative technologies, such as tau imaging and MR connectivity analyses, represent new, exciting frontiers in the early identification of dementing disorders. While some illustrative case examples are included here, the overall purpose of this chapter is to discuss normal and abnormal brain aging changes on imaging modalities that are generally available to practicing neuroradiologists.

After our discussion of the normal aging brain, we turn our attention to dementias and brain degenerative disorders. Dementia is a loss of brain function that affects memory, thinking, language, judgment, and behavior. Dementia has many causes but most often occurs secondary to degenerative processes in the brain.

Neurodegeneration occurs when neurons in specific parts of the brain, spinal cord, or peripheral nerves die. Although dementia always involves brain degeneration, not all neurodegenerative disorders are dementing illnesses. Some neurodegenerative disorders [e.g., Parkinson disease (PD)] can have associated dementia, but most do not.

The Normal Aging Brain

Introduction to the Normal Aging Brain

Age-related changes take place in virtually all parts of the brain and occur at all ages. Understanding the biology and imaging of normal aging is a prerequisite to understanding the pathobiology of degenerative brain diseases.

Terminology

The term normal aging brain, as used in this chapter, refers to the spectrum of normal age-related neuroimaging findings as delineated by longitudinal population-based studies, such as the Rotterdam Scan Study (RSS).

Genetics

Genetic factors definitely affect brain aging and contribute to age-related cognitive decline. Apolipoprotein E (specifically APOE-ε4) and other risk-associated single-nucleotide polymorphisms are genetic variants that are robustly associated with brain pathology on MR. Epigenetic dysregulation has also been identified as a pivotal player in aging as well as age-related cognitive decline and degenerative disorders.

Pathology

Gross Pathology

Overall brain volume decreases with advancing age and is indicated by a relative increase in the size of the CSF spaces. Widened sulci with proportionate enlargement of the ventricles are common. Although minor thinning of the cortical mantle occurs with aging, the predominant neuroanatomic changes occur in the subcortical white matter (WM).

Microscopic Features

The subcortical WM demonstrates decreased numbers of myelinated fibers, increased extracellular space, and gliosis. Perivascular (Virchow-Robin) spaces in the subcortical and basal ganglia enlarge.

Three histologic markers are associated with dementias: Senile plaques (SPs), neurofibrillary tangles (NFTs), and Lewy bodies. SPs are extracellular amyloid deposits that accumulate in cerebral gray matter. Nearly 1/2 of cognitively intact older individuals demonstrate moderate or frequent SP density.

NFTs are caused by tau aggregations within neurons. Lewy bodies are intraneuronal clumps of α-synuclein and ubiquitin proteins. They are found in 5-10% of cognitively intact individuals.

Clinical Issues

Although the incidence of dementias increases dramatically with aging, nearly 2/3 of patients over 85 years of age remain neurologically intact and cognitively normal.

Imaging the Normal Aging Brain

Imaging plays an increasingly central role in evaluating older patients for “altered mental status” and early signs of dementia.

CT Findings

Screening NECT scans are often obtained in older patients for nonspecific indications, such as “altered mental status.” The normal aging brain demonstrates mildly enlarged ventricles and widened sulci on NECT scans (38-1A). A few scattered patchy WM hypodensities are common, but confluent subcortical hypointensities, especially around the atria of the lateral ventricles, are a marker of arteriolosclerosis (“microvascular disease”).

MR Findings

T1WI

T1-weighted images show mild but symmetric ventricular enlargement and proportionate prominence of the subarachnoid spaces.

T2/FLAIR

WM hyperintensities (WMHs) and lacunar infarcts on T2/FLAIR scans are highly prevalent in older adults. They are associated with cardiovascular risk factors, such as diabetes and hyperlipidemia. “Successfully” aging brains may demonstrate a few scattered nonconfluent WMHs (a reasonable number is one WMH per decade, but the prevalence rises more steeply after age 50).

Perivascular spaces increase in prevalence and size with aging and are seen on T2WI as well-delineated round, ovoid, or linear CSF-like collections in the basal ganglia, subcortical WM, midbrain, etc. (see Chapter 32). Perivascular spaces suppress completely on FLAIR. Between 25-30% may display a thin, smooth, hyperintense rim. Lacunar infarcts typically demonstrate an irregular hyperintense rim around the lesions.

FLAIR scans in normal older patients demonstrate a smooth, thin, periventricular hyperintense rim around the lateral ventricles that probably represents increased extracellular interstitial fluid in the subependymal WM (38-1B). A “cap” of hyperintensity around the frontal horns is common and normal.

T2* (GRE, SWI)

Ferric iron deposition in the basal ganglia increases with age and is best demonstrated on T2* sequences. Hypointensity on T2* scans is normal in the medial globus pallidus (38-1C). Putaminal hypointensity is typically less prominent until the eighth decade. The caudate nucleus shows a scarce iron load at any age. The thalamus does not normally exhibit any hypointensity on T2* sequences.

Microbleeds on T2* scans are common in the aging brain. GRE and SWI sequences demonstrate cerebral microbleeds in 20% of patients over age 60 and 1/3 of patients aged 80 and older. Although common and therefore statistically“normal,” microbleeds are not characteristic of successful brain aging. Basal ganglia and cerebellar microbleeds are usually indicative of chronic hypertensive encephalopathy. Lobar and cortical microbleeds are typical of amyloid angiopathy and are associated with worse cognitive performance.

Differential Diagnosis

The correlation between cognitive performance and brain imaging is complex and difficult to determine. Therefore, the major differential diagnosis of a normal aging brain is mild cognitive impairment (MCI)and early “preclinical”Alzheimer disease (AD). WMHs are markers of microvascular disease, so there is considerable overlap between normal brains and those with subcortical arteriosclerotic encephalopathy.

Dementias

Preamble

The three most common dementias are AD, dementia with Lewy bodies, and vascular dementia (VaD). Together, they account for the vast majority of all dementia cases. Less frequent causes include frontotemporal lobar degeneration (FTLD) (formerly known as Pick disease) and corticobasal degeneration (CBD). It can be difficult to distinguish between the various dementia syndromes because clinical features frequently overlap and so-called mixed dementias are common.

Alzheimer Disease

AD remains the only leading cause of death for which no disease-modifying treatment currently exists and age is by far the greatest risk factor. At least 1/3 of older individuals in the USA will die with dementia, largely due to AD.

Terminology

AD is a progressive neurodegenerative condition that leads to cognitive decline, impaired ability to perform the activities of daily living, and a range of behavioral and psychologic conditions.

There is increasing evidence that AD represents a continuum of severity. The pathogenic process is prolonged and may extend over several decades. A prodromal preclinical/asymptomatic disease (i.e., pathology is present, but cognition remains intact) may exist for years before evidence of MCI develops.

Etiology

General Concepts

AD is characterized by an “amyloid cascade.” Reduced clearance of amyloid-β (Aβ) results in its aggregation in neurons. The Aβ42 residue is both insoluble and highly neurotoxic. Aβ42 clumps form SPs in the cortical gray matter. Aβ42 deposits also thicken the walls of cortical and leptomeningeal arterioles, causing amyloid angiopathy.

Another key feature of AD is tauopathy. Abnormal phosphorylation of a microtubule-associated protein known as “tau” eventually leads to the development of NFTs and neuronal death.

Genetics

Approximately 10% of AD cases have a strong family history of the disorder. The ε4 allele is the ancestral form of apolipoprotein E (APOE) and is associated with both higher absorption of cholesterol at the intestinal level and higher plasma cholesterol levels in carriers. Both the ε4 and MTHFR polymorphisms are known risk factors for late-onset AD (the most common type) and cerebrovascular disease (including VaD; see later discussion).

Pathology

Gross Pathology

Brains affected by AD show generalized (whole-brain) atrophy with shrunken gyri, widened sulci, and ventricular expansion (especially the temporal horns). Changes are most marked in the medial temporal and parietal lobes (38-6). The frontal lobes are commonly involved, whereas the occipital lobes and motor cortex are relatively spared.

Microscopic Features

The three characteristic histologic hallmarks of AD are SPs, NFTs, and exaggerated neuronal loss. All are characteristic of—but none is specific for—AD.

AD also often coexists with other pathologies, such as vascular disease or Lewy bodies. Variable amounts of amyloid deposition in arterioles of the cortex and leptomeninges (amyloid angiopathy) are present in > 90% of AD cases.

Staging, Grading, and Classification

One of the most widely used systems—the Braak and Braak system—is based on the topographic distribution of NFTs and neuropil threads with grades 1-6.

Clinical Issues

Epidemiology and Demographics

AD accounts for ~ 50-60% of all dementias. Age is the biggest risk factor for developing AD. The prevalence of AD is 1-2% at age 65 and increases by 15-25% each decade. In the “oldest-old” patients (> 90 years), mixed pathologies—typically AD + VaD—predominate.

Diagnosis

AD represents a disease spectrum that ranges from cognitively normal individuals with elevated Aβ through those who exhibit the very first, minimal signs of cognitive impairment (MCI) to frank AD.

Historically, the definitive diagnosis of AD was made only by biopsy or autopsy. The clinical diagnosis of AD defines three levels of certainty: Possible, probable, and definite AD. The diagnosis of definite AD currently requires the clinical diagnosis of probable AD plus neuropathologic confirmation.

The Alzheimer Disease Neuroimaging Initiative (ADNI) standardized datasets are currently the most commonly used references for the computer-aided diagnosis of dementia.

Natural History

AD is a chronic disease. Progression is gradual, and patients live an average of 8-10 years after diagnosis. Between 5-10% of patients with MCI progress to probable AD each year.

Imaging

General Features

One of the most important goals of routine CT and MR is to identify specific abnormalities that could support the clinical diagnosis of AD. The other major role is to exclude alternative etiologies that can mimic AD clinically, i.e., “causes of reversible dementia.”

The introduction of radiotracers for the noninvasive in vivo quantification of Aβ burden in the brain has revolutionized the approach to the imaging evaluation of AD.

CT Findings

NECT is used to exclude potentially reversible or treatable causes of dementia, such as subdural hematoma, but are otherwise uninformative, especially in the early stages of AD. Medial temporal lobe atrophy is generally the earliest identifiable finding on CT.

MR Findings

The current role of conventional MR in the evaluation of patients with dementing disorders is to (1) exclude other causes of dementia, (2) identify region-specific patterns of brain volume loss (e.g., “lobar-predominant” atrophy), and (3) identify imaging markers of comorbid vascular disease, such as amyloid angiopathy.

The most common morphologic changes on standard MR are thinned gyri, widened sulci, and enlarged lateral ventricles. The medial temporal lobe—particularly the hippocampus and entorhinal cortex—are often disproportionately affected (38-2), as are the posterior cingulate gyri.

T1-weighted MP-RAGE data can be used to quantify regional brain atrophy using open-source (i.e., FreeSurfer), proprietary, or commercial (i.e., NeuroQuant) automated volumetric analyses (38-3). 7T MR can identify abnormalities in the hippocampal subfields. The most consistent finding is reduction in CA1 volume (specifically CA1-SRLM) (38-4). Volume loss of hippocampal regions with NeuroQuant and Neuroreader is valuable in the prediction of AD from MCI at three-year follow-up compared with other regions.

T2* (GRE, SWI) sequences are much more sensitive than standard FSE in detecting cortical microhemorrhages that may suggest comorbid amyloid angiopathy.

Functional Neuroimaging

fMRI shows decrease in intensity &/or extent of activation in the frontal and temporal regions in cognitive tasks. pMR may demonstrate subtly reduced rCBV in the temporal and parietal lobes in MCI patients.

Nuclear Medicine

F-18 FDG PET demonstrates areas of regional hypometabolism (38-5)and helps distinguish AD from other lobar-predominant dementias (e.g., FTLD). Early-stage AD shows decreased metabolism in the parietotemporal association cortices, posterior cingulate, and precuneus regions. With moderate to severe AD, there is additional frontal lobe involvement.

Amyloid (Aβ) PET using amyloid-binding radiotracers has emerged as one of the best techniques for early AD diagnosis. Aβ deposition occurs well before symptom onset and likely represents preclinical AD in asymptomatic individuals and prodromal AD in patients with MCI. F-18 florbetapir, flutemetamol, and florbetaben tracers are FDA approved for clinical use. A positive Aβ PET scan shows loss of gray matter-WM distinction due to tracer uptake in the cortex, typically temporal, parietal, and frontal lobes (38-7).

Differential Diagnosis

The most difficult distinction is differentiating normal age-related degenerative processes and early “preclinical” AD.

“Mixed dementias” are common, especially in patients over the age of 90 years old. VaD is the most common dementia associated with AD. Lacunar and cortical infarcts are typical findings in VaD. Cerebral amyloid angiopathy often coexists with AD. Cerebral amyloid angiopathy is characterized by WM lesions and multiple T2*/GRE/SWI hypointensities related to hemosiderin. Lewy bodies are sometimes found in AD patients (“Lewy body variant of AD”).

FTLD shows frontal &/or anterior temporal atrophy and hypometabolism; the parietal lobes are generally spared. Dementia with Lewy bodies typically demonstrates generalized, nonfocal hypometabolism. Patients with CBD have prominent extrapyramidal symptoms.

Causes of reversible dementia that can be identified on imaging studies include mass lesions, such as chronic subdural hematoma or neoplasm, vitamin deficiencies (thiamine, B12), endocrinopathy (e.g., hypothyroidism), and normal pressure hydrocephalus.

New Alzheimer Disease Therapies and Imaging

Recently, monoclonal antibodies against Aβ have become available in both clinical trials and early clinical practice for the AD treatment. These new therapies require brain MR imaging to detect contraindications to treatment and to monitor for adverse events associated with treatment. The new agents include monoclonal antibodies: Bapineuzumab, aducanumab, donanemab, lecanemab, and gantenerumab. These therapies have been shown to reduce amyloid plaque.

The main imaging findings of these new treatment complications are called amyloid-related imaging abnormalities (ARIA)and are reported for several agents that target cerebral Aβ burden. ARIA includes ARIA-Efor edema or effusion and ARIA-Hfor microhemorrhages and hemosiderosis.

FLAIR MR of AIRA-E shows parenchymal &/or sulcal hyperintensities (38-8) (38-9A). ARIA-H shows areas of hypointense signal on GRE/T2* or SWI indicative of hemosiderin deposition or superficial siderosis (38-9B). These MR findings typically resolve spontaneously or after the therapy is decreased or discontinued.

The main imaging differential for ARIA is cerebral amyloid angiopathy-related inflammation (CAA-RI). CAA-RI is an inflammatory condition that occurs in patients with cerebral amyloid angiopathy and responds to steroid treatment or immunosuppression. ARIA only occurs secondary to monoclonal antibody therapy. CAA-RI and ARIA have similar imaging findings of sulcal effusion and parenchymal edema as well as microhemorrhages and siderosis. Clinical history is key.

Risk factors for developing ARIA are drug exposure, APOE-ε4 allele carriership, and pretreatment microhemorrhages. It is noted that the risk for developing ARIA is reduced if patients are started at a low drug dose and progressively titrated over time to the higher optimal treatment dose.

Vascular Dementia

Cerebrovascular disease is a common cause of cognitive decline. The burden of “silent” microvascular disease and its long-term deleterious effect on cognition are becoming increasingly well recognized, as is its link with AD as a significant comorbidity.

Terminology

VaD is sometimes also called multiinfarct dementia, vascular cognitive disorder, vascular cognitive impairment, subcortical ischemic VaD, and poststroke dementia.

Etiology

Inherited Vascular Dementias

Monogenic disorders are estimated to cause ~ 5% of all strokes and 10% of VaDs. The most common inherited disorders that can cause VaD are CADASIL and Fabry disease.

Sporadic Vascular Dementias

Most cases of VaD are sporadic and caused by the cumulative burden of cerebrovascular lesions. Risk factors for VaD include hypertension, dyslipidemia, and smoking. Mutations in the MTHFR gene correlate with elevated levels of plasma homocysteine and are associated with both AD and vasculogenic cognitive impairment.

Pathology

Gross Pathology

The most common, readily identifiable gross finding in VaD is multiple infarcts with focal atrophy (38-10). Multiple subcortical lacunar infarcts (38-11)&/or widespread WM ischemia are more common than cortical branch occlusions or large territorial infarcts (38-40).

Microscopic Features

Arteriolosclerosis and amyloid angiopathy are the major underlying pathologies in VaD. So-called microinfarcts—minute foci of neuronal loss, gliosis, pallor, or frank cystic degeneration—are seen at autopsy in nearly 2/3 of patients with VaD and > 1/2 of all cases with other dementing disorders (e.g., AD, dementia with Lewy bodies). Lesions are found in all brain regions and are especially common in the cortex, subcortical WM, and basal ganglia.

Clinical Issues

Epidemiology and Demographics

VaD is the second most common cause of dementia (after AD) and accounts for ~ 10% of all dementia cases in resource-rich countries. VaD is a common component of “mixed” dementias and is especially prevalent in patients with AD.

The incidence of VaD increases with age. Risk factors include hypertension, diabetes, dyslipidemia, and smoking. There is a moderate male predominance.

Natural History

Progressive, episodic, stepwise neurologic deterioration interspersed with intervals of relative clinical stabilization is the typical pattern of VaD.

Imaging

General Features

The general imaging features of VaD are those of multifocal infarcts and WM ischemia.

CT Findings

NECT scans often show generalized volume loss with multiple cortical, subcortical, and basal ganglia infarcts. Patchy or confluent hypodensities in the subcortical and deep periventricular WM, especially around the atria of the lateral ventricles, are typical (38-12).

MR Findings

T1WI often shows greater than expected generalized volume loss. Multiple hypointensities in the basal ganglia and deep WM are typical. Focal cortical and large territorial infarcts with encephalomalacia can be identified in many cases.

T2/FLAIR scans show multifocal diffuse and confluent hyperintensities in the basal ganglia and cerebral WM. The cortex and subcortical WM are commonly affected (38-13) (38-14). T2* sequences may demonstrate multiple “blooming” hypointensities in the cortex and along the pial surface of the hemispheres (38-13C) (38-14C).

Nuclear Medicine

FDG PET shows multiple diffusely distributed areas of hypometabolism, generally without specific lobar predominance (38-13D).

Differential Diagnosis

The major differential diagnosis of VaD is AD. The two disorders overlap and often coexist. AD typically shows striking and selective volume loss in the temporal lobes, especially the hippocampi. The basal ganglia are typically spared in AD, whereas they are often affected in VaD.

CADASIL is the most common inherited cause of VaD. Onset is typically earlier than in sporadic VaD. Anterior temporal and external capsule lesions are highly suggestive of CADASIL.

FTLD is characterized by early onset of behavior changes, whereas visuospatial skills remain relatively unaffected. Frontotemporal atrophy with knife-like gyri is classic. Dementia with Lewy bodies may be difficult to distinguish from VaD without biopsy. FDG PET shows hypometabolism of the entire brain, especially the visual cortex. Cerebral amyloid angiopathy commonly coexists with both AD and VaD and may be indistinguishable without biopsy. It is characterized by multiple microhemorrhages on T2*/GRE/SWI.

Frontotemporal Lobar Degeneration

Terminology

FTLD is a clinically, pathologically, and genetically heterogeneous group of disorders—sometimes called frontotemporal dementias (FTDs)—that principally affect the frontal and temporal lobes. The FTLD spectrum also includes PD with dementia and amyotrophic lateral sclerosis (ALS).

Etiology

Genetics

Mutations in three major genes, MAPT, GRN, and C9orf72, account for most cases of FTLD. Tau protein is the product of MAPT, and abnormal tau accumulation in neurons &/or glia is known as Pick bodies.

Pathology

Gross Pathology

FTLDs are characterized by severe frontotemporal atrophy with neuronal loss, gliosis, and spongiosis of the superficial cortical layers (38-15). The affected gyri are thinned and narrowed, causing the typical appearance of knife-like gyri (38-16). The posterior brain regions, especially the occipital poles, are relatively spared until very late in the disease process (38-16).

Microscopic Features

The three principal FTLD histologies are characterized by neuronal accumulations of aggregated proteins. They are (1) tau, (2) TDP-43, and (3) FUS proteins. Intraneuronal tau occurs as either Pick bodies or NFT-like structures.

Clinical Issues

Epidemiology and Demographics

FTLD is the second most common cause of “presenile dementia,” accounting for 20% of all cases in patients under the age of 65 years. FTLD is the third most common overall cause of dementia (after AD and VaD), constituting 10-25% of all dementia cases. Average age at disease onset is typically around 60 years, younger than seen in AD and other neurodegenerative disorders.

Presentation

Three different classic clinical subtypes of FTLD are recognized. The most common is behavioral variant FTD (bvFTD), which accounts for > 1/2 of all cases. bvFTD shows progressive behavior and cognition deterioration.

Primary progressive aphasia (PPA) syndromes are divided into three separate syndromes. The second, less common syndrome after bvFTD is semantic variant PPA (sv-PPA), previously known as semantic dementia. sv-PPA dementia presents with impaired single-word comprehension and object naming with preserved fluency, repetition, and grammar. It is associated with left frontotemporal dysfunction. The third clinical syndrome is termed progressive nonfluent/agrammatic variant (nfv-PPA), formerly known as progressive nonfluent aphasia. Patients with nfv-PPA present with impaired complex sentence comprehension but preserved single-word comprehension. It is associated with frontotemporal dysfunction. Lastly, there is a controversial logopenic variant (lv-PPA)dementia that presents with impaired word finding and repetition with errors in speech and naming. This variant is more often classified as an atypical variant of AD.

Recently, there has been a shift to include a category of FTD with motor symptoms. Within this category, the following degenerations are included: CBD, progressive supranuclear palsy (PSP), FTD with motor neuron disease, and ALS. However, these entities are discussed later in the chapter.

Imaging

General Features

Neuroimaging features of the FTDs should be assessed according to whether they produce focal temporal or extratemporal (e.g., frontal) atrophy, whether the pattern is relatively symmetric or strongly asymmetric, and which side (left vs. right) is most severely affected. FTLD is characterized by frontal and temporal lobe atrophy that occurs with relative preservation of posterior areas, which is the imaging hallmark of the disease group. Occasionally, focal atrophy manifests with a knife edge appearance due to the marked brain volume loss (38-17).

CT Findings

Abnormalities on CT represent late-stage FTLD. Severe symmetric atrophy of the frontal lobes with lesser volume loss in the temporal lobes is the most common finding.

MR Findings

Whereas standard T1 scans may show generalized frontotemporal volume loss, voxel-based morphometry can discriminate between various pathologic subtypes. For example, FTLD-tau is associated with strongly asymmetric atrophy involving the temporal &/or extratemporal (i.e., frontal) regions. FTLD is characterized by frontal and temporal lobe atrophy that occurs with relative preservation of posterior areas, which is the imaging hallmark of the disease group.

Clinical FTLD subtypes also correlate with frontal vs. temporal and left vs. right atrophy predominance. The bvFTD is characterized by atrophy of the frontal and temporal lobes with involvement of the anterior insula, anterior cingulate, orbitofrontal cortex, and amygdala (38-17). Early changes often affect the right hemisphere. The sv-PPA typically shows left anterior temporal lobe atrophy, though may show the entire temporal lobe involved (38-19). sv-PPA may also involve the frontal lobes. Involvement of the bilateral temporal lobes may be seen as the disease progresses (38-18). nfv-PPA demonstrates bilateral frontal and temporal volume loss, but the left hemisphere is most affected in nfv-PPA. With lv-PPA, there is predominant atrophy of the left posterior temporal cortex and parietal lobe.

Newer MR imaging techniques with DTI show DTI tract differences between bvFTD and the PPAs. The bvFTD shows abnormalities in the uncinate fasciculus, genu, and cingulum. The PPA have abnormalities in the longitudinal fasciculus.

Nuclear Medicine Findings

F-18 FDG PET scans show hypoperfusion and glucose hypometabolism in the frontal and temporal lobes (38-20). Initially, the hypometabolism is within the frontal lobes with progression to include regions of temporal and parietal lobes. The anterior cingulate cortex, frontal insula, caudate nuclei, thalamus may also have hypometabolism bilaterally. There is relative sparing of the motor cortex. Hemispheric metabolic asymmetry may be present in a similar pattern to the MR findings of each type of FTD. This hypometabolism typically occurs before atrophy is visualized on CT or MR.

Differential Diagnosis

The major differential diagnoses of FTLD are AD and VaD. AD shows atrophy of the parietal and temporal lobes and hippocampi more than frontal lobe. Early F-18 FDG hypometabolism in the parietotemporal and posterior cingulate cortices and positivity on amyloid PET helps make the AD diagnosis. VaD is characterized by global atrophy with diffuse WM lesions related to infarcts and chronic microvascular ischemia. Deep gray nuclei lacunar infarcts are also typical.

Miscellaneous Dementias

Creutzfeldt-Jakob Disease

Transmissible spongiform encephalopathies (TSEs), a.k.a. prion diseases, are a group of neurodegenerative disorders that includes Creutzfeldt-Jakob disease (CJD). Animal TSEs include bovine spongiform encephalopathy (“mad cow” disease).

CJD is the most common human TSE and has a worldwide distribution. CJD is unique, as it is both an infectious and neurogenetic dementing disorder. CJD is the archetypal human TSE.

Etiology

CJD is a rapidly progressive neurodegenerative disorder caused by an abnormal, misfolded prion protein, PrP(Sc). The abnormal form propagates itself by recruiting its normal isoform and imposing its conformation on the homologous host cell protein. The conformational conversion of PrP(C) to PrP(Sc) is the fundamental event underlying all prion diseases.

Four types of CJD are recognized: Sporadic (sCJD), familial or genetic (gCJD), iatrogenic (iCJD), and variant (vCJD). sCJD is the most common type. gCJD is caused by diverse mutations in the PRNP gene. iCJD is caused by prion-contaminated materials (e.g., surgical instruments, dura mater grafts). vCJD typically results from the transmission of bovine spongiform encephalopathy from cattle to humans.

Pathology

Gross pathology shows ventricular enlargement, caudate atrophy, and variable cortex volume loss (38-21) with relative sparing of the WM. The classic triad of histopathologic findings is marked neuronal loss, spongiform change, and striking astrogliosis. PrP(Sc) immunoreactivity is the gold standard for the neuropathologic diagnosis of human prion diseases.

Epidemiology and Demographics

CJD now accounts for > 90% of all human prion diseases. Approximately 85% of CJD cases are sporadic (sCJD). Peak age of onset is 55-75 years. gCJD causes most of the remaining cases (5-15%). vCJD and iCJD are now rare.

Clinical Issues

CJD is a progressive, fatal illness. Over 90% of patients progress from normal function to death in under a year. Median survival is ~ 4 months, although vCJD progresses more slowly.

Several clinicopathologic subtypes of sCJD have been identified. In the most common subtype, rapidly worsening dementia is followed by myoclonic jerks and akinetic mutism. In 2/3 of sCJD cases, EEG shows a characteristic pattern of periodic bi- or triphasic complexes. The Heidenhain variant occurs as pure visual impairment leading to cortical blindness.

Imaging

CJD primarily involves the gray matter structures of the brain. MR with DWI is the imaging procedure of choice. T1 scans are often normal but may show faint hyperintensities in the posterior thalami (38-25). FLAIR hyperintensity or restricted diffusion in the caudate nucleus and putamen or in at least two cortical regions (temporal-parietal-occipital “cortical ribboning”) are considered highly sensitive and specific (96% and 93%, respectively) for the diagnosis of sCJD (38-22) (38-23). Occipital lobe involvement predominates in the Heidenhain variant.

T2/FLAIR hyperintensity in the posterior thalamus (pulvinar sign) or posteromedial thalamus (hockey stick sign) is seen in 90% of vCJD cases but can also occur in sCJD (38-24). CJD does not enhance on T1 C+.

Differential Diagnosis

CJD must be distinguished from other causes of rapidly progressive dementia, such as viral encephalitis, paraneoplastic limbic encephalitis, and autoimmune-mediated inflammatory disorders, such as LGI1, NMDAR, or GABA encephalopathies. These CJD “mimics” can usually be excluded with appropriate serologic examination.

Other dementias, such as AD and FTLD, are more insidiously progressive. The basal ganglia involvement in CJD is a helpful differentiating feature. Unlike most dementing diseases, CJD also shows striking diffusion restriction.

CREUTZFELDT-JAKOB DISEASE

Pathology and Etiology

• Most common human transmissible spongiform encephalopathy

• Creutzfeldt-Jakob disease (CJD) is prion disease

 Proteinaceous particles without DNA, RNA (“prions”)

 Misfolded isoform PrP(Sc) of normal host PrP(C)

 Propagated by conformational conversion of PrP(C) to PrP(Sc)

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