linear CSF-like collections in the basal ganglia, subcortical WM, midbrain, etc. (see Chapter 28) (33-3). PVSs suppress completely on FLAIR. Between 25 and 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 (33-4). A "cap" of hyperintensity around the frontal horns is common and normal.

T2* (GRE, SWI). Brain iron is not present at birth but gradually accumulates as part of normal development. Iron accumulation is greatest in the pars reticulata of the substantia nigra (SN), followed by the globus pallidus (GP), where iron deposition progresses from medial to lateral. The red nucleus and putamen are other common sites where ferritin normally accumulates. Iron deposition in the GP and SN plateaus in early adulthood, but iron storage in the putamen continues well past 80 years of age.

Ferric iron deposition is best demonstrated on T2* sequences. Susceptibility-weighted images (SWI) are more sensitive than gradient-refocused (GRE) images. As field heterogeneity and magnetic susceptibility effects are proportional to field strength, hypointensity increases on 3.0-T images.

Hypointensity on T2* scans is normal in the medial GP (33-5). 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 years and one-third of patients aged 80 years 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.

DTI. The deleterious effect of WM changes on cognition depends on lesion burden, volume loss, and characteristics such as WM integrity that may not be apparent on standard imaging sequences. Even "normal-appearing white matter" may demonstrate loss of fractional anisotropy on DTI.

MRS. MRS shows a gradual decrease in NAA in the cortex, cerebral WM, and temporal lobes with concomitant increases in both Cho and Cr.

FDG PET/pMR

FDG PET studies show a gradual decrease in rCBF with aging, particularly in the frontal lobes. Patients with low total brain perfusion on pMR studies have more WMHs, but the precise relationship to cognitive performance is unclear.

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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 and early "preclinical" AD. WMHs are markers of microvascular disease, so there is considerable overlap between normal brains and those with subcortical arteriosclerotic encephalopathy.

Dementias

Dementia is an acquired impairment in intellectual abilities that affects multiple cognitive domains including memory, language, and visuospatial skills. Emotional ability changes, behavioral alterations, and deteriorating ability to execute the activities of daily living are common. Dementia is one of the greatest fears people have about aging.

The three most common dementias are Alzheimer disease, 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 (formerly known as Pick disease) and corticobasal degeneration. It can be difficult to distinguish between the various dementia syndromes because clinical features frequently overlap and so-called mixed dementias are common.

As new disease-modifying agents enter clinical practice, correctly diagnosing dementia type is becoming increasingly important. Assessment of patients with a potential dementing illness requires a detailed clinical history and careful physical examination as well as evaluation of cognition, behavior, and functional and social capacity.

Currently there is no single behavioral marker that can reliably discriminate Alzheimer disease—by far the most common dementing disorder—from other major dementia syndromes. As imaging plays a growing role in the diagnosis of dementias, we discuss each major type. Where possible, we point out features and new advanced imaging modalities that help distinguish the different types from potentially reversible nondementing disorders.

Alzheimer Disease

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

Three ongoing longitudinal studies, namely the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, and the ADCS Prevention Initiation, have recently been joined by a new study, the Harvard Aging Brain Study (HABS). These and other important initiatives aim to predict the emergence of clinical symptoms and elucidate the molecular, functional, and structural imaging markers that signal the transition from

(33-6) Autopsy specimen from a patient with histologically proven early Alzheimer disease shows enlarged lateral ventricles. Temporal horns are proportionally enlarged, and hippocampi appear mildly atrophic. (R. Hewlett, MD.)

normal cognition to preclinical AD that characterizes the earliest stages along the trajectory of this devastating disorder.

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.

AD is also known as senile dementia of Alzheimer type. There is increasing evidence that AD is not a single, all-encompassing disorder but instead a continuum of severity. The pathogenic process of AD 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 mild cognitive impairment (MCI) develops.

Etiology

General Concepts. AD is characterized by an "amyloid cascade." Amyloidosis is one of the earliest events in the neuropathologic cascade leading to AD. Reduced clearance of the protein aggregate amyloid-β (Aβ) results in its aggregation in neurons. The Aβ42 residue is both insoluble and highly neurotoxic. Aβ42 clumps form senile plaques in the cortical gray matter. Aβ42 deposits also thicken the walls of cortical and leptomeningeal arterioles, causing amyloid angiopathy.

The majority of Aβ accumulation occurs before the progressive structural neurodegeneration and cognitive decline occur. One-third of clinically normal patients with elevated Aβ are in the preclinical stage of AD.

(33-7) Axial NECT scan in a 54y woman with severe early-onset Alzheimer disease shows markedly enlarged temporal horns and sulci .

Another key feature of AD is tauopathy. Abnormal phosphorylation of a microtubule-associated protein known as "tau" eventually leads to the development of neurofibrillary tangles and neuronal death. CSF tau levels are almost tripled in patients with AD.

Genetics. 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 below).

Approximately 10% of AD cases have a strong family history of the disorder. Three autosomal-dominant gene mutations are associated with early-onset AD: amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2).

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 (33-6). The frontal lobes are commonly involved, whereas the occipital lobes and motor cortex are relatively spared.

The hippocampus is severely affected in 75% of cases. Relative hippocampal sparing is seen in 10%, and limbic-predominance accounts for 15% of AD cases.

Microscopic Features. The three characteristic histologic hallmarks of AD are senile plaques, neurofibrillary tangles, and

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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 over 90% of AD cases. Vascular and AD pathology are additive; patients with both have clinically more severe dementia.

Staging, Grading, and Classification. There are several scales for the histologic staging of Alzheimer pathology. One of the most widely used—the Braak and Braak system—is based on the topographic distribution of neurofibrillary tangles and neuropil threads, with grades from 1 to 6. The Consortium to Establish a Registry for Alzheimer Disease (CERAD) scale is based on the quantity of neocortical neuritic plaques in relation to age.

A third system (the Poly Pathology AD Assessment 9 or PPAD9) is based not just on neurofibrillary tangles and neuritic plaques, but also a combination of other factors, including the extent of neuronal degeneration, microvacuolization, cytoarchitectural disorder, and gliosis. Each finding is calculated for nine different regions of the brain.

To date, correlation between these major staging systems is suboptimal. Choice of staging system affects the evaluation of AD pathology and therefore the final diagnosis.

Clinical Issues

Epidemiology and Demographics. AD is the most common cause of dementia, accounting for approximately 50-60% of all cases and affecting more than 35 million people worldwide. The World Alzheimer Report predicts that this number will almost double by 2030 and will exceed 100 million by 2050.

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 (more than 90 years), with mixed pathologies—typically AD plus 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) on the ADCS-PACC to frank AD.

Historically, the definitive diagnosis of AD was made only by biopsy or autopsy. The clinical diagnosis of AD using the National Institute of Neurological Disorders and StrokeAlzheimer Disease and Related Disorders (NINDS-ADRA) criteria 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.

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The Alzheimer Disease Neuroimaging Initiative (ADNI) is an ongoing longitudinal, multicenter study designed to identify clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of AD. The ADNI standardized datasets are currently the most commonly used references for the computer-aided diagnosis of dementia.

Presentation. Minimal cognitive impairment causes a slight but noticeable (and measurable) decline in cognitive abilities. The mildest MCI is a single cognitive domain (amnestic) form that is characterized by memory loss beyond that expected for age and education. Here global cognitive function is maintained, and the capacity to perform activities of daily living is preserved.

Individuals with MCI do not meet the diagnostic guidelines for dementia but are nevertheless at increased risk of eventually developing AD or another type of dementia.

Patients with very early AD show impaired short-term memory. As the disease progresses, memory deficits increase and are associated with neuropsychiatric changes, difficulties in finding words and spatial cognition, and reduced executive functioning. Motor, sensory, and gait disturbances are uncommon until relatively late in the disease.

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

There are no established treatments to prevent or reverse AD. Many current disease-modifying drugs focus on reducing Aβ amyloidosis. Treating MCI patients with cholinesterase inhibitors or NMDA receptor antagonists may transiently improve cognitive functioning but does not delay conversion from MCI to AD.

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" (see below).

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 a helpful screening procedure that may exclude potentially reversible or treatable causes of dementia, such as subdural hematoma and normal pressure hydrocephalus. Otherwise, CT scans are generally uninformative, especially in the early stages of AD.

Medial temporal lobe atrophy is generally the earliest identifiable finding on CT (33-7). Late findings include generalized cortical atrophy.

MR Findings. The current role of conventional 1.5- and 3.0-T MR in the evaluation of patients with dementing disorders is to (1) exclude other causes of dementia, (2) identify regionspecific patterns of brain volume loss (e.g., "lobarpredominant" 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 (33- 8) (33-10) as are the posterior cingulate gyri (33-9).

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 (33-11). 7-T MR can identify abnormalities in the hippocampal subfields. The most consistent finding is reduction in CA1 volume (specifically CA1-SRLM) (33-12).

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

MRS shows decreased NAA and increased myoinositol in patients with AD, even during the early stages of the disease (33-13). The NAA:myoinositol ratio is relatively sensitive and highly specific in differentiating AD patients from the normal elderly. NAA:Cr ratio in the posterior cingulate gyri and left occipital cortex predicts conversion from MCI to probable AD with relatively high sensitivity and good specificity.

DTI in patients with AD shows decreased FA in multiple regions, especially the superior longitudinal fasciculus and corpus callosum splenium. Reduced FA reflects early microstructural WM changes.

Functional Neuroimaging. fMR shows decrease in intensity and/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. 18F FDG PET demonstrates areas of regional hypometabolism (33-14) and helps distinguish AD from other lobar-predominant dementias (e.g., frontotemporal lobar degeneration).

PET using amyloid-binding radiotracers such as 11[C] PiB (Pittsburgh compound B) 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.

Differential Diagnosis

The most difficult distinction is differentiating normal agerelated degenerative processes and early "preclinical" AD.

"Mixed dementias" are common, especially in patients over the age of 90 years. 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. Lewy bodies are sometimes found in AD patients ("Lewy body variant of AD").

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(33-13) MRS in AD shows elevated myoinositol (mI) peak . The NAA -to-mI ratio is decreased; creatine (Cr) peak is decreased.

(33-14A) 18F FDG PET in AD shows markedly reduced metabolism in both temporal lobes with comparatively normal frontal lobes .

(33-14B) Parietal hypometabolism on cephalad PET shows temporal/parietal hypometabolism; preserved frontal activity common.

Frontotemporal lobar degeneration shows frontal and/or anterior temporal atrophy and hypometabolism; the parietal lobes are generally spared. Dementia with Lewy bodies typically demonstrates generalized, nonfocal hypometabolism. Patients with corticobasal degeneration 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.

ALZHEIMER DISEASE

Pathoetiology

•Neurotoxic "amyloid cascade"

○Aβ42 accumulation → senile plaques, amyloid angiopathy

•Tauopathy → neurofibrillary tangles, neuronal death

Clinical Issues

•Most common dementia (50-60% of all cases)

•Prevalence increases 15-25% per decade after 65 years

•Pathology begins at least a decade before clinical symptoms emerge

○"Clinically normal" on preclinical Alzheimer cognitive composite

○Aβ in clinically normal predicts significant longitudinal decline

Imaging

•Frontoparietal dominant lobar atrophy

○Hippocampus, entorhinal cortex

○FDG PET shows hypometabolism

○Amyloid-binding markers, such as 11[C] PiB

•Amyloid angiopathy

○Present in > 95% of cases

○T2* cortical "blooming black dots""

○With or without cortical siderosis

Differential Diagnosis

•Exclude reversible dementias!

○Subdural hematoma

○Normal pressure hydrocephalus

•DDx

○Normal aging

○Vascular dementia

○Frontotemporal lobar degeneration

○AD often mixed with other dementias (especially vascular)

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 is becoming increasingly well recognized, as is its link with AD as a significant comorbidity.

Terminology

Vascular dementia (VaD) is sometimes also called multiinfarct dementia, vascular cognitive disorder, vascular cognitive impairment, subcortical ischemic vascular dementia, and poststroke dementia. All are broadly encompassing terms for cognitive dysfunction associated with—and presumed to be caused by—vascular brain damage.

Etiology

Inherited Vascular Dementias. Monogenic disorders are estimated to cause approximately 5% of all strokes and 10% of vascular dementias.

Known monogenic disorders that can cause VaD are (1) cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, caused by NOTCH3 mutations on chromosome 19) and cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL, caused by mutations in the HTRA1 gene); (2) Fabry disease (an X-linked lysosomal disease caused by a mutation of the GLA gene); (3) pontine autosomal-dominant microangiopathy and leukoencephalopathy (PADMAL, i.e., COL4A1-A2 gene-related arteriopathies); (4) retinal vasculopathy with cerebral leukodystrophy (RCVL, associated with TREX1 mutation); and (5) the recently-described Forkhead Box C1 mutations (FOXC1).

Sporadic Vascular Dementias. Most cases of VaD are sporadic and are 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 both with AD and vasculogenic cognitive impairment.

VASCULAR DEMENTIA: ETIOLOGY

Inherited ( ≈ 10%)

•CADASIL

○Most common inherited cerebral small vessel disease

○Autosomal-dominant; NOTCH3 mutation

○MR after 35 years of age always abnormal!

○WM lesions, lacunae

○Especially anterior temporal, external capsule; corpus callosum

•CARASIL

○Autosomal-recessive; HTRA1 mutation

•Fabry disease

○X-linked recessive; α-GAL A (GLA) mutation

○WM lesions, lacunae; T1 hyperintense pulvinar

Sporadic or Mixed ( ≈ 90%)

•VaD = 2nd most common dementia

•Multiple etiologies

○Systemic hyperlipidemia, cardiovascular risk factors

○MTHFR mutations (increased plasma homocysteine)

○Amyloid angiopathy

Pathology

Gross Pathology. The most common readily identifiable gross finding in VaD is multiple infarcts with focal atrophy (33-15) (33-17). Multiple subcortical lacunar infarcts (33-16) and/or widespread white matter ischemia are more common than cortical branch occlusions or large territorial infarcts (33-17).

Microscopic Features. Vessel wall modifications are the most common and presumably the earliest identifiable changes associated with VaD.

Arteriolosclerosis and amyloid angiopathy are the major underlying pathologies in small vessel vascular disease. Myelin loss and modifications in perivascular spaces are the next most common vascular findings in dementia.

So-called microinfarcts—minute foci of neuronal loss, gliosis, pallor, or frank cystic degeneration—and other cerebrovascular lesions are seen at autopsy in nearly two-thirds of patients with VaD and more than half 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.

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(33-15) Graphic of VaD shows multiple chronic infarcts , acute left occipital lobe infarct , and small basal ganglia lacunar infarcts .

(33-16) VaD shows multiple WM , cortical lacunae at the level of the lateral ventricle (L), corona radiata (R). (Courtesy R. Hewlett, MD.)

(33-17) Autopsied multiinfarct dementia shows territorial , cortical infarcts, WM lesions in the left hemisphere. (Courtesy R. Hewlett, MD.)

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Clinical Issues

Epidemiology and Demographics. VaD is the second most common cause of dementia (after AD) and accounts for approximately 10% of all dementia cases in developed 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.

Recently proposed definitions of major VaD subtypes include

(1) poststroke dementia, (2) mixed dementias (i.e., with AD, diffuse Lewy disease), (3) subcortical ischemic VaD (mostly small vessel disease with lacunar infarcts and subcortical ischemic white matter lesions) that incorporates the overlapping clinical entities of Binswanger disease and lacunar state, and (4) multiinfarct dementia (multiple large cortical infarcts).

VASCULAR DEMENTIA: PATHOLOGY AND CLINICAL ISSUES

Pathology

•Small > large vessel

•Atherosclerosis, arteriolosclerosis, amyloid angiopathy

Clinical Issues

•2nd most common dementia (10%)

•Multiple strokes; episodic step-like deterioration

•Subtypes

○Poststroke dementia

○Mixed dementias

○Subcortical ischemic VaD

○Multiinfarct dementia

Presentation. A history of multiple stroke-like episodes with focal neurologic deficits is characteristic of patients with VaD.

Mood and behavioral changes are more typical than memory loss.

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.

MR Findings. T1WI often shows greater than expected generalized volume loss. Multiple hypointensities in the basal

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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 (33-18). T2* sequences may demonstrate multiple "blooming" hypointensities in the cortex and along the pial surface of the hemispheres (33-19) (33-20).

DTI may demonstrate decreased FA and increased ADC values in otherwise normal-appearing or minimally abnormal WM. Multiple regions are affected, especially the inferior-frontal- occipital fascicles, corpus callosum, and superior longitudinal fasciculus.

Nuclear Medicine. FDG PET shows multiple diffusely distributed areas of hypometabolism, generally without specific lobar predominance (33-18D) (33-19D).

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Differential Diagnosis

The major differential diagnosis of VaD is Alzheimer disease. 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.

Frontotemporal lobar degeneration (FTLD) is characterized by early onset of behavior changes, whereas visuospatial skills remain relatively unaffected. Frontotemporal atrophy with knife-like gyri is typical.

VASCULAR DEMENTIA: IMAGING AND DIFFERENTIAL DIAGNOSIS

Imaging

•Varies with subtype

○Often mixed

•General features

○Multifocal infarcts (lacunae, cortical > large territorial)

○WM ischemia (patchy and/or confluent T2/FLAIR hyperintensities)

○T2* "blooming black dots" (amyloid or HTN)

Differential Diagnosis

•Alzheimer disease

•CADASIL (most common inherited VaD)

•FTLD

•Lewy body disease

•Cerebral amyloid angiopathy 7

Dementia with Lewy bodies (DLB) may be difficult to distinguish from VaD without biopsy. The entire brain is hypometabolic, and atrophy is generally minimal or absent. DLB typically occurs without infarcts.

Cerebral amyloid angiopathy commonly coexists with both AD and VaD and may be indistinguishable without biopsy.

Frontotemporal Lobar Degeneration

Terminology

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders—sometimes called frontotemporal dementias (FTDs)—that principally affect the frontal and temporal lobes.

FTLD is a "disorder of threes." There are three main genetic mutations, three principal histologies, and three major associated clinical syndromes. All three can exist separately or in combination with amyotrophic lateral sclerosis (ALS, see below). The FTLD spectrum also includes Parkinson disease with dementia.

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(33-21) Graphic shows frontal atrophy in latestage FTLD with "knife-like" gyri. Parietooccipital lobes are spared.

Etiology

Genetics. Mutations in three major genes, MAPT, GRN, and C9orf72, along with several other less common gene mutations account for most cases of FTLD. Approximately 10% of cases are caused by mutations in the microtubule-associated protein tau gene (MAPT), whereas another 10% have mutations in the progranulin gene (GRN).

Tau protein—the product of MAPT—is responsible for the assembly/disassembly of microtubules, vital for intracellular transport. Mutations in MAPT drive FTLD-tau pathology. These mutations lead to abnormal tau accumulations in neurons and/or glia known as Pick bodies.

FTLD-TDP pathology is associated with either mutations in GRN or expansions in C9orf72. The semantic dementia variant of FTLD and ALS are both TDP-43 proteinopathies. A key characteristic of both is the presence of TDP-43 or the protein fused in sarcoma (FUS) immunoreactive cytoplasmic inclusions in neuronal and glial cells. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of reactive nitrogen species metabolism.

Pathology

Gross Pathology. FTLDs are characterized by severe frontotemporal atrophy with neuronal loss, gliosis, and spongiosis of the superficial cortical layers (33-21). The affected gyri are thinned and narrowed, causing the typical appearance of knife-like gyri. The posterior brain regions, especially the occipital poles, are relatively spared until very late in the disease process

(33-22).

Microscopic Features. The three principal FTLD histologies are characterized by abnormal neuronal (and sometimes glial) accumulations of aggregated proteins. These are (1) tau, (2) TDP-43, and (3) FUS proteins.

In approximately 45% of cases, the neuronal intracytoplasmic inclusions are composed of the microtubule-associated protein, tau, and termed FTLD-tau. In most cases the neuronal tau occurs as either Pick bodies (round or oval silver-staining inclusions) or neurofibrillary tangle-like structures. Pick bodies are most commonly found in the dentate gyrus, amygdala, and frontal and temporal neocortex.

In about 50% of FTLD cases, the RNAand DNA-binding protein TDP-43 is present in dystrophic neurites. These cases are termed FTLD-TDP.

(33-22A) Autopsy of FTLD shows striking atrophy of the frontal gyri and normal-appearing parietal and occipital lobes.

(33-22B) Submentovertex view in the same case shows striking frontal and temporal lobe atrophy . (Courtesy R. Hewlett, MD.)

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The remaining 5% of cases show inclusions composed of the protein FUS. These cases are described as FTLD-FUS. In a very small minority of cases no inclusions are seen.

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 occurs between the third and ninth decades, but the average age at disease onset is typically around 60 years, younger than seen in AD and other neurodegenerative disorders.

Excluding alcoholic encephalopathy, FTLD is the third most common overall cause of dementia (after AD and VaD), constituting 10-25% of all dementia cases. The estimated prevalence varies between 5 and 15 cases/100,000. Up to 40% of patients have a history of a similar disorder within their families. An autosomal-dominant pattern of inheritance is seen in 10% of cases.

Presentation. Three different clinical subtypes of FTLD are recognized. The most common is behavioral-variant frontotemporal dementia (bvFTD), which accounts for more than half of all cases. Core behavioral features of bvFTD are personality changes and social disinhibition. In contrast to AD, visuospatial functions are initially well preserved.

A second, less common syndrome is semantic dementia (SD), a disorder of conceptual knowledge. Patients with SD exhibit behavioral changes and difficulties with language comprehension while speech itself remains relatively fluent.

The third clinical syndrome is termed progressive nonfluent aphasia (PNFA). PNFA is a disorder of expressive language associated with asymmetric atrophy of the left hemisphere.

There is a clinical overlap between bvFTD and progressive supranuclear palsy and corticobasal syndrome.

The correlation between histopathology and clinical syndromes varies. bvFTD is histopathologically heterogeneous, whereas SD is usually associated with TDP pathology and PNFA with tau pathology.

Natural History. Median survival for patients with FTLD is 6-11 years following symptom onset.

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 versus right) is most severely affected.

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

(33-23).

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MR Findings. Whereas standard T1 scans may show generalized frontotemporal volume loss, voxel-based morphometry can discriminate between various pathologic subtypes. FTLD-tau is associated with strongly asymmetric atrophy involving the temporal and/or extratemporal (i.e., frontal) regions. FTLD-TDP disease shows asymmetric, relatively localized temporal lobe atrophy.

Clinical FTLD subtypes also correlate with frontal-versus- temporal and left-versus-right atrophy predominance. The SD subtype shows bilateral temporal volume loss but little or no frontal atrophy (33-24). bvFTD and PNFA both demonstrate bilateral frontal and temporal volume loss, but the right hemisphere is most affected in bvFTD, whereas left-sided volume loss dominates in PNFA.

WM damage also occurs in FTLD and is probably secondary to damage in the overlying cortex. DWI shows elevated mean diffusivity in the superior frontal gyri, orbitofrontal gyri, and anterior temporal lobes.

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(33-25A) Coronal T2WI in a 64y woman with FTLD shows severe volume loss, especially in the frontal and temporal lobes .

(33-25B) Coronal FDG PET-CT shows severe hypometabolism in both temporal lobes .

DTI with reduced FA in the superior longitudinal fasciculus is common in bvFTD and correlates with behavior disturbances, whereas the inferior longitudinal fasciculus is more affected in the SD variant. MRS shows decreased NAA and elevated myoinositol in the frontal lobes.

Nuclear Medicine Findings. FDG PET scans show hypoperfusion and hypometabolism in the frontal and temporal lobes (33-25).

Differential Diagnosis. The major differential diagnoses of FTLD are AD (parietal lobe, hippocampi more than frontal) and VaD (WM, basal ganglia lacunae).

FRONTOTEMPORAL LOBAR DEGENERATION

Etiology

•Three major mutations

○MAPT

○GRN

○C9orf72

Pathology

•Three major types

○FTLD-tau (45%)

○FTLD-TDP (50%)

○FTLD-FUS (5%)

Clinical Issues

•Second most common cause of "presenile" dementia

•Accounts for 20% of all cases < 65 years of age

•Three major subtypes

○Behavioral variant (bvFTD)

○Semantic dementia (SD)

○Progressive nonfluent aphasia (PNFA)

Imaging

•Classify atrophy (volumetric MR best)

○Temporal vs. extratemporal (frontal) predominance

○Symmetric or asymmetric

•18F FDG PET

○Frontotemporal hypometabolism

Differential Diagnosis

•Alzheimer disease

○Parietal, temporal > frontotemporal

•Vascular dementia

○Multifocal infarcts

○WM ischemic changes

Lewy Body Dementias

Lewy body dementias include dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and the Lewy body variant (LBV) of Alzheimer disease (LBAD). All three diseases have significant clinicopathologic overlap.

Terminology

Lewy body dementias are characterized by the presence of Lewy bodies (see below).

Etiology

(33-25C) Axial FDG PET-CT shows hypometabolism in both frontal and temporal lobes characteristic of FTLD.

Lewy bodies are spherical intraneuronal protein aggregates that consist primarily of α-synuclein (α-syn), a presynaptic microtubule-associated misfolded protein similar to tau. DLB is therefore considered a synucleinopathy and belongs to a group of disorders with α-synuclein gene

mutations that also includes Parkinson disease, PDD, multisystem atrophy, pure autonomic failure, and REM sleep behavior disorder.

Pathology

Gross Pathology. The gross appearance of DLB resembles early AD. Frontotemporal and parietal atrophy is generally mild to moderate, whereas the hippocampi and occipital lobes are typically spared (33-26). There is marked depigmentation of the substantia nigra and locus ceruleus.

Microscopic Features. The histopathologic hallmark of DLB is the presence of Lewy body inclusions in the cortex and brainstem, especially the substantia nigra and dorsal mesopontine GM. Loss of tegmental dopamine and basal forebrain cholinergic cell populations is typical.

Some pathologic hallmarks of AD, namely amyloid plaques and neurofibrillary tangles, can be found in many patients with DLB. In turn, Lewy body inclusions have also been identified in some Alzheimer patients (LBAD).

Clinical Issues

Epidemiology and Demographics. DLB is now recognized as the second most common neurodegenerative dementia, accounting for approximately 15-20% of all cases.

Presentation and Diagnosis. Because DLB symptoms can resemble other more commonly recognized dementias (AD, PDD), it is widely underrecognized as a cause of progressive cognitive decline and is often diagnosed only at autopsy.

Three core diagnostic features of DLB have been defined: (1) recurrent visual hallucinations and visuospatial disturbances, (2) spontaneous parkinsonism, and (3) fluctuating cognition with variations in attention, executive function, and alertness. The presence of two of these three features is considered evidence of probable DLB.

Natural History. Patients with pure DLB have annual rates of atrophy and ventricular enlargement that are comparable to those of age-matched controls and less marked than those of patients with AD.

Imaging

General Features. The most commonly used neuroimaging technique for the diagnosis of LBD is dopaminergic imaging of the basal ganglia with a sensitivity of 87% and specificity of 94% for differentiating between LBD and other dementia types such as PDD.

Despite the prominent visual symptoms that often characterize DLB, major occipital volume loss is not a typical finding. Standard anatomic imaging studies are often normal or show only mild generalized volume loss.

MR Findings. T1 scans show only mild generalized atrophy without lobar predominance (33-27). T2/FLAIR may demonstrate nonspecific WM hyperintensities that are similar to those found in cognitively normal aging patients.

Manual and automated volumetric studies generally show relatively little cortical atrophy. Reduced volume in the hypothalamus, basal forebrain, and midbrain may be seen in some severe cases. There is usually more putaminal and relatively less medial temporal lobe atrophy in DLB compared with AD.

DTI demonstrates increased mean diffusivity in the amygdala and decreased FA in the inferior longitudinal and inferior occipitofrontal fasciculi. MRS shows relatively normal NAA:Cr ratios.

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(33-26A) Autopsy case of dementia with diffuse Lewy bodies shows mild generalized volume loss without specific lobar predominance.

(33-26B) Submentovertex view in the same case shows mild frontal volume loss . The temporal lobes appear normal.

(33-26C) Axial section shows mildly enlarged lateral ventricles, normal occipital lobes; diffuse Lewy body disease. (Courtesy R. Hewlett, MD.)

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(33-27A) T2WI in a patient with cognitive decline and visual hallucinations shows mild diffuse atrophy. Occipital lobes appear relatively normal.

(33-27B) More cephalad scan in the same patient shows mild symmetric and diffuse volume loss. Clinical diagnosis was probable DLB.

(33-28) FDG PET scan in another patient with DLB shows occipital hypometabolism . (Courtesy N. Foster, MD.)

Nuclear Medicine. Occipital hypometabolism on FDG PET and reduced cerebral blood flow on SPECT-HMPAO or pMR are typical of DLB (33-28). The primary visual cortex is especially affected.

Presynaptic dopamine transporter (DaT) imaging with the FP-CIT ligand shows almost absent uptake in the putamen and markedly reduced uptake in the caudate. Cholinergic radioligands may help identify the profound cholinergic neuronal loss that occurs in DLB and PDD.

Differential Diagnosis

The major differential diagnosis of DLB is Parkinson disease with dementia (PDD). The second most important differential diagnosis is Alzheimer disease (AD). Hippocampal hypometabolism and volume loss are more common in AD. Multiple system atrophy and the parkinsonian tauopathies progressive supranuclear palsy and corticobasal degeneration can be difficult to distinguish from DLB. Posterior cortical atrophy (see below) can mimic DLB clinically but generally occurs in younger patients.

LEWY BODY DEMENTIAS

Etiology

•α-synuclein mutation

•Others = Parkinson disease dementia, AD (variant with Lewy bodies), multisystem atrophy

Pathology

•Lewy bodies with α-synuclein inclusions

•Striatonigral degeneration

•Tegmental dopamine, basal forebrain cholinergic cells seriously reduced

○Substantia nigra depigmented

Clinical Issues

•2nd most common neurodegenerative dementia

•Visual symptoms, spontaneous parkinsonism, cognition reduced

Imaging

•MR nonspecific (mild generalized atrophy)

•SPECT dopaminergic imaging best

○DaT scan shows sharply reduced uptake putamen, caudate

Differential Diagnosis

•Other dementias with parkinsonism (e.g., PDD, multisystem atrophy)

•Alzheimer disease (Lewy body variant)

Miscellaneous Dementias

Creutzfeldt-Jakob Disease

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of neurodegenerative disorders that includes

Creutzfeldt-Jakob disease (CJD), kuru, Gerstmann-Sträussler-Schenker syndrome, and fatal familial insomnia. Animal TSEs include scrapie (from sheep and goats), chronic wasting disease (from mule deer and elk), bovine spongiform encephalopathy ("mad cow disease"), and feline encephalopathy (from domestic cats).

Kuru was the first recognized human TSE, occurring in the Fore population of Papua New Guinea. Kuru is a uniformly fatal cerebellar ataxic syndrome; it has now almost disappeared with the discontinuation of cannibalism, the only source of human-to-human transmission.

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 and is detailed in the following discussion.

Etiology. CJD is a rapidly progressive neurodegenerative disorder caused by proteinaceous infectious particles ("prions") that are devoid of DNA and RNA. The abnormal prion protein, PrP(Sc), is a misfolded isoform (a β-pleated sheet) of the normal host prion protein, PrP(C). The abnormal form propagates itself by recruiting the 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, cadaveric corneal transplants, and pituitary-derived human growth hormone). vCJD typically results from the transmission of bovine spongiform encephalopathy from cattle to humans. vCJD is also known as "new variant" CJD.

Pathology. Gross pathology shows ventricular enlargement, caudate atrophy, and cortical volume loss that varies from minimal to striking (3329). The white matter is relatively spared.

The classic triad of histopathologic findings in CJD is marked neuronal loss, spongiform change, and striking astrogliosis. The cerebral and cerebellar cortex are often most severely affected although the basal ganglia and thalami are also frequently involved. Amyloid plaques can be identified in 10% of cases.

Various deposits of PrP(Sc) are present, and PrP(Sc) immunoreactivity is the gold standard for the neuropathologic diagnosis of human prion diseases.

HUMAN PRION DISEASES

Sporadic (Idiopathic) Prion Diseases (85%)

•sCJD

•Sporadic fatal insomnia, variably protease-sensitive prionopathy

Acquired (Infectious) Prion Diseases (2-5%)

•iCJD (due to medical interventions)

•Kuru

•vCJD

Familial (Inherited/Genetic) Prion Diseases (5-15%)

•iCJD

•Gerstmann-Sträussler-Scheinker syndrome

•Fatal familial insomnia

Epidemiology and Demographics. CJD now accounts for more than 90% of all human prion diseases. Approximately 85% of CJD cases are sporadic (sCJD) with an annual worldwide incidence of one to two cases per million. Peak age of onset is 55-75 years. There is no sex predilection. gCJD causes most of the remaining cases (5-15%). vCJD and iCJD together now account for less than 5%.

vCJD typically presents in younger patients between 15 and 40 years. Psychiatric symptoms predominate. Approximately 220 vCJD cases have been reported with most—but not all—occurring in the United Kingdom. The incidence of vCJD has declined in recent years, but small numbers of new cases are still identified.

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(33-29) sCJD shows caudate , anterior basal ganglia atrophy , cortical thinning especially in the occipital lobes . (Courtesy R. Hewlett, MD.)

(33-30A) Axial FLAIR shows classic findings of sCJD with hyperintense caudate nuclei , anterior putamina , and thalami .

(33-30B) More cephalad FLAIR shows subtle hyperintensity in the left frontal cortex . This is autopsy-proven sCJD.

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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 approximately 4 months, although vCJD progresses more slowly.

The diagnosis of CJD is complex and is often based on the exclusion of other, more frequent causes of rapidly progressive dementia. The definitive diagnosis of sCJD requires autopsy or brain biopsy.

The current WHO guidelines for the antemortem diagnosis of sCJD use a combination of clinical manifestations, EEG, and a laboratory measure of CSF 14-3-3. More recent criteria such as the European MRI-CJD Consortium include imaging manifestations in the diagnosis of probable CJD.

Five clinicopathologic subtypes of sCJD have been identified. Three subtypes prominently affect cognitive functions, and the other two impair cerebellar motor activities. In the most common subtype, rapidly worsening dementia is followed by

myoclonic jerks and akinetic mutism. In two-thirds of sCJD cases, EEG shows a characteristic pattern of periodic bior triphasic complexes.

Two less common but important presentations of sCJD are the so-called Brownell-Oppenheimer variant (a pure cerebellar syndrome) and the Heidenhain variant (pure visual impairment leading to cortical blindness).

Imaging. CJD primarily involves the gray matter structures of the brain. The cerebral cortex, hippocampus, basal ganglia, thalami, and the cerebellum are the most frequently affected areas. WM disease is much less common and is usually a late finding.

CT scans are typically normal although serial studies may show progressive ventricular dilatation and sulcal enlargement.

MR with DWI is the imaging procedure of choice. T1 scans are often normal but may show faint hyperintensities in the

posterior thalami (33-33). 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 (33-30). Occipital lobe involvement predominates in the Heidenhain variant (33-31), whereas the cerebellum is primarily affected in the Brownell-Oppenheimer 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 (33-32). 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 the recently characterized autoimmune-mediated inflammatory disorders, such as voltage-gated K-channel, NMDAR, or GABA

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encephalopathies. These CJD "mimics" can usually be excluded with appropriate serologic examination.

Common disorders with rare presentations that can mimic CJD include hypoxic-ischemic encephalopathy, liver failure with hepatic encephalopathy, Wernicke encephalopathy, hypoglycemia, and thyroid dysfunction (Hashimoto encephalopathy).

Other dementias such as Alzheimer disease and frontotemporal lobar degeneration 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.