Unforgettable images A multimodality pictorial review of dementia

Unforgettable images: A multimodality pictorial review of dementia Daniel Thut, DO, Alena Kreychman, MD, Susan Megas, APRN, Shan Li, MD Department of Radiology Baystate Medical Center Tufts University School of Medicine e. Ed. E-06

Disclosure The authors have nothing to disclose. 2

Dementia » What is dementia? – Dementia refers to the deterioration in memory, thinking, language, judgment and behavior. – Differentiating one type of dementia from another is a clinical challenge. » What is the role of imaging in dementia? – Structural imaging is used to rule out treatable causes for the patient’s symptoms or suggest the presence of comorbidities that may exacerbate dementia symptoms. – As new disease-modifying agents enter clinical practice, correctly diagnosing the specific type of dementia is becoming increasingly important. Currently there is no single behavioral marker that can reliably discriminate one form of dementia from another 3

Dementia » Alzheimer’s Dementia » Frontotemporal Lobe Dementia • Picks Dementia » Lewy Body Dementia » Parkinson’s Disease with Dementia » Vascular dementia • Multi-Infarct Dementia • CADASIL • Binswanger Dementia 4

Alzheimer’s Dementia » Clinically characterized by progressive memory loss, as well as change in personality and thought – Accounts for 60 -70% of dementing disorders – 4 million patients in US – 100, 000 deaths/year – $90 billion per year – Projections are for 14 million cases in 2050 » Definitive diagnosis is histopathological demonstration of beta amyloid senile plaques in the cerebral cortex and tau protein neurofibrillary tangles in the nerve cells 5

Alzheimer’s Imaging: CT » NECT is a helpful screening tool that can exclude potentially reversible or treatable causes of dementia such as subdural hematoma and normal pressure hydrocephalus. – The earliest identifiable finding on CT is medial temporal lobe atrophy. – Generalized cortical atrophy is usually a late finding. 6

Alzheimer’s Imaging: MRI » MRI: Most common changes are thinned gyri, widened sulci and enlarged lateral ventricles – There is temporal lobe predominance • particularly the hippocampal and parahippocampal gyri – Presence of deep white matter and periventricular white matter areas of high signal intensity on T 2 WI’s, in the absence of cardiovascular risk factors, are not seen with a statistical significance in patients with AD Axial FLAIR images in a patient with AD has severe bilateral hippocampal atrophy (arrows). 7

Alzheimer’s Disease: MR spectroscopy » Reduced levels of NAA (N-acetyl aspartate) and Increased levels of myoinositol especially in the frontal, temporal and occipital cortex of AD patients presumably due to neuronal loss Multivoxel MR spectroscopic imaging in (a) a 62 -year-old healthy volunteer and (b) an 80 -year-old patient with AD. Sample spectra are shown from right temporal lobe (bottom left), left insula (top right) and left thalamus (bottom right). Note the increase in myoinositol (Ino) and choline (Cho) levels and the decrease in NAA level (short arrows in b) in the right temporal lobe of the patient with AD, compared with those levels in the healthy volunteer, suggesting the presence of gliosis, increased membrane turnover, and neuronal loss in AD. (P)Cre creatine and phosphocreatine. Neuroimaging and Early Diagnosis of Alzheimer’s Disease : A Look to the Future Radiology, Petrella et al, 2003; 226: 315– 336 8

Alzheimer’s Disease: PET and SPECT – Early disease is seen as bilateral hypometabolism or hypoperfusion of the posterior cingulate and tends to involve the superior posterior parietal cortex • Early in the disease, the findings may be asymmetric. – As the disease progresses, it involves the frontal cortices, but to a much lesser extent than parietal and temporal lobe involvement – The occipital visual cortex, primary somatosensory and motor cortices, basal ganglia, thalamus, and cerebellum are spared – There is slightly higher sensitivity with F-18 FDG PET (up to 94%) than SPECT (78%-91%), with similar specificities between the 2 modalities 9

axial Alzheimer’s Disease: HMPAO SPECT sagittal coronal SPECT imaging with Tc-99 m HMPAO demonstrate subtle reduced cerebral blood flow in the temporoparietal region (arrows) 10

Alzheimer’s Disease: FDG PET axial sagittal coronal PET CT PET/CT FDG PET/CT demonstrating markedly decreased uptake in the temporal and parietal lobes, bilaterally. An enlarged sagittal image on the right highlights the hypometabolism in the temporoparietal lobes (arrows). 11

Alzheimer’s Disease: Amyloid Imaging » PET using amyloid-binding radiotracers such as 18 F Florbetapir (Amyvid) can show early AD diagnosis. – As new therapies enter clinical trials, the importance of in vivo beta amyloid (Aβ) imaging is becoming increasingly crucial. • Aβ deposition occurs well before symptom onset and likely represents preclinical AD in asymptomatic individuals and prodromal AD in patients with mild cognitive impairment (MCI). – The radiotracer crosses the blood–brain barrier and shows high-affinity binding for Aβ • Positive examinations demonstrate high levels of cortical uptake in addition to nonspecific white matter binding with loss of the normal gray-white matter differentiation 12

Alzheimer’s Imaging: Amyvid Positive Amyvid scan. 61 year old with clinical suspicion for AD. 370 MBq (10 m. Ci) of F 18 -Florbetapir (Amyvid) PET/CT showing intense cortical uptake in addition to the nonspecific binding of the radio-tracer in the white matter Negative Amyvid scan for comparison. The arrow points to normal preserved gray-white contrast (Amyvid website: http: //pi. lilly. com/us/amyvid-uspi. pdf) 13

Lewy Body Dementia » Lewy Body Dementia (LBD) accounts for approximately 25% of dementias. – On histopathology, there are Lewy body intracellular inclusions (alpha-synuclein) throughout the cortex, brainstem, and limbic system as well as loss of dopamine transporters in the striatum – Patients with LBD often demonstrate a fluctuating dementia, visual hallucinations, falls, and some parkinsonian symptoms (i. e tremors). – Lewy bodies were originally described in Parkinson disease, and it is likely that DLB and PD are related as part of a spectrum of disease. • The clinical manifestation may be similar to that of AD or the dementia associated with PD. 14

Lewy Body Dementia: CT and MRI » CT – Deep gray matter atrophy and preservation of the medial temporal lobe » MRI – T 1 WI show only mild generalized atrophy – T 2/FLAIR may demonstrate nonspecific hyperintensities in the white matter that are similar to those found in normal aging patients. – DTI may show increased mean diffusivity in the amygdala and decreased fractional anisotropy in the inferior longitudinal and inferior occipitofrontal fasciculi. – MRS shows relatively normal NAA: Cr ratios. 15

Lewy Body Dementia: SPECT and PET » SPECT or PET – Show hypoperfusion or hypometabolism changes in the posterior cortical regions. – The pattern tends to involve the occipital lobes and cerebellum • The involvement of the primary visual cortex can explain the clinical visual hallucinations. – Hippocampus is spared 16

Lewy Body Dementia: SPECT and PET FDG PET demonstrating decreased uptake in the occipital lobes in addition to posterior temporoparietal lobes, bilaterally (arrows) Silverman et al. , Semin Nucl Med 38: 251 -261, 2008 17

Parkinson’s Disease with Dementia » Parkinson disease is a multisystem neurodegenerative disorder, clinically manifested with resting tremor, bradykinesia, and rigidity. » When PD is accompanied by dementia, it is referred to as Parkinson disease dementia (PDD). 18

Parkinson’s Disease with Dementia: CT and MRI » CT and MRI – Anatomic imaging with CT and MRI is rarely useful for PDD. – CT is used primarily following deep brain stimulation (DBS) placement to evaluate for surgical complications and check electrode positioning – MRI may show midbrain volume loss with a “butterfly” configuration. • Other findings that may support the diagnosis of PD include thinning of the pars and loss of normal substantia nigra hyperintensity on T 1 WI 19

Parkinson’s Disease with Dementia: CT and MRI Axial T 2 WI at the midbrain level shows sulcal and ventricular enlargement and hypointensity and narrowing of the substantia nigra (arrows). 20

Parkinson’s Disease with Dementia: Da. Tscan » DAT Scan – Presynaptic dopamine transporter imaging with the I-123 Ioflupane (Da. T scan) will show decreased uptake in the putamen and head of the caudate nucleus – Cannot discriminate between PDD and DLB but can be very useful in the differential diagnosis between DLB and AD and can also be of some value in the differential diagnosis between DLB and vascular dementia 21

Parkinson’s Disease with Dementia: Da. Tscan Positive Da. Tscan: Axial I-123 Ioflupane (Da. T scan) SPECT and fused SPECT/CT showing absence of uptake in bilateral putamina and slightly reduced uptake in the heads of the caudate nuclei, left greater than right. 22

Frontotemporal Dementia » Frontotemporal dementia (FTD) comprises a group of dementias accounting for approximately 5– 10% of cases of dementia. » FTD is clinically characterized by behavioral changes in personality including apathy, perseverations and inappropriate social conduct and language disturbances that may precede or overshadow memory deficits. » On histopathology, there is frontal and anterior temporal neuronal degeneration. – Pick bodies, a type of protein inclusion, are sometimes found, and brain and CSF are sometimes assessed for abnormalities related to tau and ubiquitin proteins. – Amyloid and Lewy bodies are absent. » There currently is no treatment 23

Frontotemporal Dementia Imaging » CT: – Asymmetric frontal and anterior temporal atrophy is a distinctive feature of FTD that distinguishes it from AD. » MR: – T 1 WI may show generalized frontotemporal volume loss – Pick disease is associated with strongly asymmetric atrophy involving the temporal and/or frontal regions. – Gyri may be thin and “knife-like”

Frontotemporal Imaging: CT NECT showing the frontal lobes and anterior temporal poles are markedly atrophic with “knife-like” gyri (arrow), which is out of proportion to other lobes. 25

Frontotemporal Imaging: MRI Sagittal T 1 WI MRI (left) and axial T 2 BLADE (right) demonstrate marked atrophy of the frontal lobe (“knife-like” gyri ) in a patient with FTD. 26

Frontotemporal Dementia » Nuclear medicine PET or SPECT: – hypoperfusion and hypometabolism in the frontal and temporal lobes with HMPAO SPECT and FDG PET, respectively 27

Frontotemporal Dementia: SPECT » » Frontotemporal Dementia. (left) Sagittal images from SPECT, (right) axial, coronal and sagittal fused SPECT/MRI (created on a separate workstation for anatomic correlation) demonstrating marked hypometabolism in the frontotemporal lobes, bilaterally 28

Vascular Dementia » Accounts for about 15% of all dementias in the U. S. » Distinguished from AD by its more sudden or stepwise onset and association with vascular risk factors. » Vascular dementia is characterized by a stepwise course with periods of stability followed by sudden decline in cognitive function. – Patients may experience focal neurologic deficits after a sudden decline, such as slurred speech or sensorimotor dysfunction. » Vascular dementias can be thought of as a continuum of multi-infarct dementia, deep gray infarcts and white matter disease, severe white matter disease only, Binswanger and CADASIL » Control of vascular risk factors is the treatment of choice. 29

Vascular Dementia: Multi-Infarct Imaging with CT » 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 white matter 30

Vascular Dementia: Multi-Infarct Imaging with MRI » MRI: – T 1 WI often shows generalized volume loss. • Multiple hypointensities in the basal ganglia and deep WM • Focal cortical and large territorial infarcts with encephalomalacia – T 2/FLAIR scans show multifocal diffuse and confluent hyperintensities in the basal ganglia and cerebral white matter – T 2* sequences may show multiple “blooming” artifacts in the cortex and along the pial surface of the hemispheres. – DTI may demonstrate decreased fractional anisotropy and increased ADC values in otherwise normal white matter • Typically the inferior-frontal-occipital fascicles, corpus callosum, and superior longitudinal fasciculus 31

Vascular Dementia: Multi-Infarct Imaging with MRI Axial FLAIR images showing extensive hyperintensity in the periventricular and subcortical white matter) Axial T 2 BLADE images showing cystic encephalomalacia related to old infarcts in the left posterior temporal-occipital lobe and left medial occipital lobe. 32

Vascular Dementia: Multi-Infarct Imaging with FDG PET » FDG PET shows multiple diffusely distributed areas of hypometabolism, generally without specific lobar predominance PET/CT CT FDG PET/CT showing patchy areas of decreased uptake, most notably in the right frontal lobe, corresponding to an old infract on the MRI (red arrow).

Vascular Dementia: Multi-Infarct Imaging with FDG PET Arrows on this scan indicate decreased FDG uptake in the right parietal cortex (left), right prefrontal cortex, basal ganglia and thalamus (middle), and right temporal cortex (right). The decreased uptake of the left cerebellum (right) is consistent with cross-cerebellar diaschisis, caused by diminished afferent input from contralateral cortex. Silverman et al. , Semin Nucl Med 38: 251 -261, 2008

Vascular Dementia: Binswanger » Subcortical arteriosclerotic encephalopathy – Associated with hypertension, generally affects patients >55 – Slowly progressive – Involves white matter (which distinguishes it from multi-infarct dementia) and lacunar infarcts NECT scan of Binswanger's disease with diffuse hypodensity in the white matter and widening of the lateral ventricles. 35

Vascular Dementia: Binswanger on MRI (Left 2 images) Axial T 2 WI showing multiple old lacunar infarcts within bilateral basal ganglia (arrows) and the left centrum semiovale (arrowhead). (Right 2 images) Axial FLAIR images show innumerable small and patchy areas of hyperintensity in the periventricular and subcortical white matters bilaterally. 36

Vascular Dementia: CADASIL • CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most common heritable cause of stroke and vascular dementia. – Inherited arterial disease created by mutations in the Notch 3 gene on chromosome 19 – Begins in young adults with TIAs and strokes – Typical involvement of the temporal lobe white matter, internal capsule and subinsular (surrounding the basal ganglia) regions – Clinically, it presents with nonspecific symptoms including aurainitiated migraines, early-onset TIAs or stroke, mood disturbance, and progressive cognitive decline. – Imaging of patients with CADASIL commonly yields white matter hyperintensities (WMH), a nonspecific finding seen in many disorders.

Vascular Dementia: CADASIL on MRI This is a 32 years old male with a history of multiple strokes and a 1 st degree relative who died from stroke. Axial PD, T 2 and FLAIR show striking confluent deep periventricular white matter signal abnormality. The findings of such extensive white matter disease is highly unusual in a 32 year old patient. The clue to the diagnosis is seen on the FLAIR, where there is signal abnormality in both anterior temporal lobes (arrows). This is an uncommon location for typical, "small vessel vascular disease" seen in older patients. Signal abnormality in the anterior temporal lobes and external capsules, especially in a patient with a positive family history, is suggestive of CADASIL. Biopsy in this case confirmed NOTCH 3 mutation 38

Vascular Dementia: CADASIL on PET » Very few functional imaging studies have been conducted on CADASIL patients. – In a study by Tatsch et al. (2003), the mean regional metabolic rate of glucose was significantly reduced in all cortical and subcortical structures (especially thalamus and striatum) in CADASIL patients compared with healthy controls. 39

Vascular Dementia: CADASIL on PET FDG PET showing marked reduction in uptake in the frontal, temporal, and parietal cortices ( left > right ) as well as the left striatum and thalamus. Uptake is also reduced in the right cerebellar hemisphere ( arrows ), suggesting crossed cerebellar diaschisis Tatsch et al. J of Nuc Med 44. 6 (2003): 862 -869. 40

Conclusion » Often the nonspecific structural changes depicted on CT and MRI are preceded by changes in cerebral blood flow and metabolism. » Patterns of hypoperfusion and hypometabolism may be more specific for one form of dementia versus another. » New molecular imaging techniques can identify specific biomarkers, such as beta amyloid plaque deposition or dopaminergic neuron deficit, which can help differentiate between dementia types. » In summary, as there is an increasing reliance on neuroimaging as part of a comprehensive evaluation of dementia, it is important that the interpreting radiologist can recognize these common patterns and imaging characteristics to suggest the correct diagnosis.

References 1. Silverman, Daniel HS, et al. "Positron emission tomography scans obtained for the evaluation of cognitive dysfunction. " Seminars in nuclear medicine. Vol. 38. No. 4. WB Saunders, 2008. 2. Tatsch K, Koch W, Linke R et al (2003) Cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection in CADASIL: an 18 F-FDG PET study. J Nucl Med 44: 862– 869 3. Osborn, Anne G. Osborn's brain: imaging, pathology, and anatomy. Amirsys Pub. , 2013. 4. Dierckx, Rudi AJO, et al. PET and SPECT in Neurology. Springer, 2014. 5. Neuroimaging and Early Diagnosis of Alzheimer’s Disease : A Look to the Future Radiology, Petrella et al, 2003; 226: 315– 336 6. Amyvid website: pi. lilly. com/us/amyvid-uspi. pdf 42