OBSERVATION Dementia With Lewy Bodies Studied With Positron Emission Tomography

Rebecca J. Cordery, BSc, MRCP; Philippa J. Tyrrell, MD, FRCP; Peter L. Lantos, MD, PhD, DSc, FRCPath; Martin N. Rossor, MD, FRCP

Objective: To report a case initially fulfilling the clini- Results: Oxygen 15–labeled positron emission tomo- cal criteria for probable Alzheimer disease, although later grams revealed hypometabolism in the frontal, tempo- clinical features suggested dementia with Lewy bodies. ral, and parietal lobes, more severe on the left than right. Oxygen 15–labeled positron emission tomograms re- Metabolism in the left caudate was just outside the 95% vealed a pattern of hypometabolism characteristic of Alz- reference range. Occipital metabolism was normal. heimer disease. At post mortem, there was no evidence of the pathological features of Alzheimer disease, but dif- Conclusions: Positron emission tomographic studies fuse cortical Lewy bodies were seen in the pigmented have been reported to show occipital hypometabolism brainstem nuclei and . in dementia with Lewy bodies, in addition to the char- acteristic posterior bitemporal biparietal pattern of Alz- Design: A case report. heimer disease. We suggest that although this finding may favor a diagnosis of dementia with Lewy bodies, it is not Setting: Tertiary referral center. necessary for diagnosis.

Patient: A 65-year-old white man presented with a 3-year history of memory loss and language difficulties. Arch Neurol. 2001;58:505-508

LTHOUGH CRITERIA for bonethoxy-3␤-(4-iodophenyl)-N-(3-fluo- clinical diagnosis may aid ropropyl)nortropane (a dopaminergic the distinction between presynaptic ligand) and single photon Alzheimer disease (AD) emission computed tomography can be (International Classifica- used to assess nigrostriatal pathway integ- Ation of Diseases, 10th Revision, Diagnostic rity in vivo.8 Preliminary results, though in- and Statistical Manual of Mental Disor- conclusive, suggest that it may be possible ders, Fourth Edition, and National Insti- to distinguish DLBs and AD by the ab- tute Neurological Communicative Disor- sence of nigrostiatal degeneration in the lat- ders and Stroke–Alzheimer’s Disease and ter. Positron emission tomographic stud- Related Disorders Association) and de- ies have shown occipital hypometabolism mentia with Lewy bodies (DLBs),1,2 diag- in DLBs in addition to the characteristic pos- nosis may be difficult, particularly early in terior bitemporal biparietal pattern of AD,9-12 the course of the disease. Thus, although but thus far have not contributed to estab- a parkinsonian syndrome is one distin- lishing the differential diagnosis of DLBs From the Dementia Research Group, Department of Clinical guishing feature of DLBs, a proportion of and AD. Elderly patients with late-life de- Neurology, Institute of patients with dementia of the Alzheimer pression may have a widespread, nonfocal Neurology and Division of type may also have extrapyramidal signs pattern of reduction in glucose metabo- Neurosciences, Imperial College in the absence of Lewy bodies that are at- lism similar to that seen in patients with School of Medicine tributable to extranigral factors.3,4 AD,13 a finding that may further compli- (Drs Cordery and Rossor), the Neuroimaging may contribute to the cate the diagnosis. Medical Research Council differential diagnosis. Alzheimer disease Cyclotron Unit, Hammersmith is characteristically associated with atro- REPORT OF A CASE Hospital (Dr Tyrrell), and the phy of medial structures on Department of Neuropathology, magnetic resonance images or computed A 65-year-old retired businessman pre- Institute of Psychiatry tomograms, but this atrophy is also seen sented in May 1988 with a 3-year history (Dr Lantos), London, England. 5-7 Dr Tyrrell is now with the to a lesser extent in patients with DLBs. of memory loss and language difficulties. Department of Geriatric It is therefore suggested that it is the ab- He stated that he had trouble finding both Medicine, Hope Hospital, sence of medial temporal atrophy that is spoken and written words, as well as dif- Salford, England. highly suggestive of DLBs. [123I]-2␤-car- ficulty with reading, comprehension, and

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 memory test for words.14 His speed of information pro- Regional Cerebral Metabolic Rates for Oxygen (CMRO2) cessing was impaired on a cancellation task and on a simple digit copying test. In contrast, he scored within −1 −1 CMRO2,mL·min ·dL the average range on tests of naming and object percep- Region Patient Normal* tion. Overall, the pattern was that of a generalized de- Left superior frontal 1.67 3.08 ± 0.34 cline in intellectual and memory functions. Right 2.29 3.12 ± 0.33 The results of all baseline investigations were nor- Left 1.94 2.92 ± 0.30 mal. On an electroencephalogram, the dominant rhythm Right middle frontal gyrus 2.39 2.91 ± 0.29 was slow and quite widespread, with little attenuation Left 1.83 2.98 ± 0.29 with eye opening. There were episodes of slow waves Right inferior frontal gyrus 2.51 3.04 ± 0.32 throughout, predominantly anteriorly, which were some- Left cingulate gyrus 2.69 3.42 ± 0.58 Right cingulate gyrus 2.69 3.52 ± 0.62 times independent but more often were present as a gen- Left 2.13 2.96 ± 0.25 eralized disturbance. A computed tomographic scan of Right superior temporal gyrus 3.01 3.13 ± 0.41 the brain revealed no abnormalities. Left middle temporal gyrus 1.78 3.12 ± 0.33 An oxygen 15–labeled PET scan was performed (CTI Right middle temporal gyrus 1.95 3.12 ± 0.17 931-08/12 camera; Computed Technology and Imaging Left 2.00 3.18 ± 0.21 Inc, Knoxville, Tenn) at the Medical Research Council Right inferior temporal gyrus 2.66 3.15 ± 0.37 Left 2.05 2.99 ± 0.15 Cyclotron Unit (Hammersmith Hospital, London, Right postcentral gyrus 2.33 3.07 ± 0.30 England). The performance characteristics of this scan- Left inferior 2.11 3.11 ± 0.17 ner and the practical procedure have been previously de- Right inferior parietal lobe 2.71 3.09 ± 0.25 scribed.4,15 An oxygen 15–labeled steady-state inhala- Left superior parietal lobe 1.98 3.08 ± 0.28 tional technique was used with calculation of the regional Right superior parietal lobe 2.43 3.15 ± 0.22 16,17 cerebral metabolic rate for oxygen (CMRO2 ). A se- Left thalamus 3.22 3.57 ± 0.42 ries of parametric images of CMRO were computed. Ana- Right thalamus 3.03 3.73 ± 0.52 2 Left caudate nucleus 2.96 3.77 ± 0.39 tomically correct regions of interest were placed by trans- Right caudate nucleus 3.29 3.81 ± 0.46 forming standard anatomical coordinates (from an Left putamen 3.47 4.12 ± 0.74 anatomical atlas) to functional imaging coordinates.18 The Right putamen 3.48 3.78 ± 0.68 technique involved estimating the position of the inter- Left occipital cortex 2.66 3.38 ± 0.61 commissural line (AC-PC line) directly from the PET im- Right occipital cortex 2.76 3.56 ± 0.52 age and orientating the PET image about this line.19 The Left cerebellum 3.32 3.78 ± 0.37 Right cerebellum 2.96 3.74 ± 0.60 PET slices were then directly comparable with atlas slices. Regions placed on the PET image allowed regional val- *Values are expressed as mean ± SD. ues of CMRO2 to be obtained. The results were com- pared with those from a group of 9 normal subjects (wom- en older than childbearing age and men older than 30 arithmetic. He denied having any problems with mobil- years [mean age, 59.9 years]). These subjects were asymp- ity or stiffness. His wife had noticed that his behavior was tomatic, with normal results on clinical examinations, becoming more obsessive and that he was more verbally scoring at least 29/30 on the Mini-Mental State Exami- aggressive than he used to be. nation. The mean±SD CMRO2 value for each cortical re- There was no significant medical history. He was gion (left and right hemispheres) is shown in the Table. married, smoked 10 cigarettes per day, and had mild al- Individual values are given for each region, and those out- cohol intake. There was a family history of depression side the 95% reference range of the normal data differ in both his father and his brother. He was not taking any significantly from normal at a level of PϽ.05. regular medications. The findings of his general exami- Statistically significant areas of hypometabolism in- nation were normal, and his blood pressure was 100/70 cluded the frontal, temporal (predominantly left and pos- mm Hg. He had mildly reduced movement of his right teriorly), and parietal lobes (predominantly left). Me- arm on walking and on examination had a mildly in- tabolism in the left caudate was just below the 95% creased tone of his upper limbs, more marked on the right, reference range. The occipital and cerebellar rates of me- with cogwheeling rigidity. His limb power was normal, tabolism were normal. A diagnosis of probable AD with with symmetrical reflexes and flexor plantar responses. extrapyramidal features was made. On sensory examination, he had mildly reduced vibra- Over the following year, there was a progressive de- tion and joint position sense in his lower limbs. He had terioration in the patient’s mental status: his verbal and a positive pout reflex. He was mildly dyspraxic, being un- performance IQ scores had declined to 73 and 71, re- able to copy complex . spectively. There was a further decline in his memory In July 1988, he was assessed on the Wechsler Adult functions. Naming and perceptual skills remained rela- Intelligence Scale-Revised and obtained a verbal IQ of 80 tively preserved. He was gradually slowing up; his walk- and a performance IQ of 79. His reading IQ equivalent ing had become very stiff; and he tended to fall. He was score was 104, indicating a moderate degree of intellec- experiencing some and described seeing tual deterioration from a previously average level. His a cloaked, hooded figure in the bedroom. On examina- memory functions were globally impaired. He scored be- tion, there was no bradykinesia but postural reflexes were low the fifth percentile on a recognition memory test for impaired. Both plantar responses were now extensor. A faces and below the first percentile on a recognition final diagnosis of AD with cortical Lewy bodies was made,

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 A B

C D

A, Cortical Lewy bodies in the temporal lobe (␣-synuclein, original magnification ϫ480). B, Abnormal Lewy neurites in the CA2 and CA3 region of the hippocampus (␣-synuclein, original magnification ϫ280). C, Positively stained inclusions and neurites in the nucleus basalis of Meynert (␣-synuclein, original magnification ϫ480). D, Lewy bodies, neuronal loss, extraneuronal pigment, and astrocytosis in the substantia nigra (ubiquitin, original magnification ϫ280). All parts of the figure were stained using the avidin-biotin complex method.

and a trial of carbidopa-levodopa therapy was initiated. demonstrated in the CA2-CA3 area of the hippocampus, There was minimal improvement, and as the dosage was by both ␣-synuclein and ubiquitin. Alzheimer-type changes increased, adverse effects were experienced. The therapy of neuritic plaques and neurofibrillary tangles were ex- was discontinued, without clinical deterioration. The pa- tremely rare in the neocortex and hippocampus (Figure). tient died 5 years after his initial presentation. Immunohistochemical studies for ␤-amyloid showed no The brain weighed 1323 g, and the brainstem, with significant deposits in the cerebral parenchyma. Apply- the cerebellum, 162 g. There was mild cerebral atrophy ing the Newcastle Consensus Criteria, the diagnosis of DLBs affecting mainly the frontoparietal region, while the tem- (neocortical type) was made. poral lobes, with the hippocampi, were preserved. The pigmented nuclei of the brainstem were paler than usual. COMMENT Blocks of tissue were taken from the frontal, tem- poral (with the hippocampus), parietal, and occipital The hypometabolic pattern associated with AD using both lobes; basal ganglia (to include the caudate nucleus, len- oxygen 15– and fludeoxyglucose 18–labeled PET (FDG- tiform nucleus, and nucleus basalis of Meynert); amyg- PET) is characterized by posterior biparietal and bitempo- dala; midbrain; pons; medulla oblongata; and cerebellar ral hypometabolism with a variable reduction in metabo- vermis and hemisphere. Sections were stained with he- lism in the frontal association cortices.20 However, metabolic matoxylin-eosin and the modified Bielshowsky tech- patterns in individual patients are heterogeneous and can nique and immunostained for ␣-synuclein, ␶-protein, be related to cognitive and behavioral profiles and to the ␤-amyloid, and ubiquitin. regional severity of histopathological changes.21,22 This pat- Histologically, the substantia nigra and the locus ce- tern of hypometabolism is in contrast to that of the cau- ruleus showed neuronal loss, extraneuronal pigment, many date and thalamus, for example, which have been shown Lewy bodies, several pale bodies, Marinesco bodies, an oc- to be relatively preserved in AD. Thus, these areas are now casional neurofibrillary tangle, and astrocytosis. Immu- used as reference tissues in image analysis.23,24 nostaining for ␣-synuclein revealed additional abnormal Albin et al9 described FDG-PET studies in 6 pa- positively stained neurites. Lewy bodies were also seen in tients: 3 with a pathological diagnosis of DLBs and 3 with the cerebral cortex, including the transentorhinal, cingu- both AD and DLBs. All cases showed a marked reduc- lar, insular, temporal, frontal, and parietal cortices. Many tion in parietal, temporal, and frontal association cortex Lewy bodies were also noted in the nucleus basalis of Mey- and posterior metabolism, similar to that nert and . A network of abnormal neurites was seen in patients with AD. In addition, however, both

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 groups of patients showed marked hypometabolism in of the Medical Research Council Cyclotron Unit, Hammer- the occipital association and primary visual cortices. These smith Hospital, and Elizabeth Warrington, DSc, of the De- areas of hypometabolism did not correlate pathologi- mentia Research Group, National Hospital for Neurology cally with areas of high density of Lewy bodies. and Neurosurgery, London. A similar pattern was reported by Imamura et al,10 Corresponding author and reprints: Martin N. Rossor, who studied 19 patients with probable DLBs and 19 with MD, FRCP, Dementia Research Group, National Hospital for probable AD using FDG-PET. When the regional cere- Neurology and Neurosurgery, Queen Square, London WC1N bral metabolic rate for glucose in the DLB disease group 3BG, England (e-mail [email protected]). was compared with that in the AD group, significant de- creases were seen bilaterally in the temporo-parieto- occipital association cortices (including the occipital lobes, REFERENCES except medially) and the cerebellar hemispheres. The pa- 1. McKeith IG, Galasko D, Kosaka K, et al, for the Consortium on Dementia with tients with AD, in contrast, showed more marked de- Lewy Bodies. Consensus guidelines for the clinical and pathologic diagnosis of creases in the middle cingulate gyrus and the medial tem- dementia with Lewy bodies (DLB). Neurology. 1996;47:1113-1124. poral areas. The recurrent visual hallucinations of DLBs 2. McKeith IG, Perry EK, Perry RH, for the Consortium on Dementia with Lewy Bod- ies. 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Glucose hypometabolism and neuropatho- whereby regional CMRO2 values are directly compared with logical correlates in brains of dementia with Lewy bodies. Exp Neurol. 2000;162: mean regional control levels. However, both clinical and 247-256. 13. Kumar A, Newberg A, Alavi A, Berlin J, Smith R, Reivich M. Regional cerebral glu- PET features are clearly moderately atypical in this case. cose metabolism in late-life depression and Alzheimer disease: a preliminary posi- The predominantly left temporal lobe, left parietal lobe, tron emission tomography study. Proc Natl Acad SciUSA.1993;90:7019-7023. and frontal hypometabolism that were seen in our patient 14. Warrington EK. Recognition Memory Tests. Windsor, England: NFER-Nelson Pub- lications Ltd; 1984. are consistent with his progressive memory problems, lan- 15. Spinks T, Guzzardi R, Bellina CR. Performance characteristics of a whole body guage difficulties, aggressive outbursts, and obsessional positron tomograph. 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Friston KJ, Passingham RE, Nutt JG, Heather JD, Sawle GV, Frackowiak RS. Lo- confusional state provoked by an intercurrent illness. calisation in PET images. J Cerebl Blood Flow Metab. 1989;9:690-695. This case provides further information on PET in 20. Frackowiak RS, Pozzilli C, Legg NJ, et al. Regional cerebral oxygen supply and autopsy-confirmed DLBs. It emphasizes the clinical het- utilization in dementia. Brain. 1981;104:753-778. 21. Rapoport SI. Positron emission tomography in Alzheimer’s disease in relation erogeneity that can be observed within the degenerative to disease pathogenesis. Cerebrovasc Brain Metab Rev. 1991;3:297-335. dementias and demonstrates that although occipital hy- 22. Desgranges B, Baron J-C, de la Sayette V, et al. The neural substrates of memory systems impairment in Alzheimer’s disease. Brain. 1998;121:611-631. pometabolism on functional imaging may favor a diag- 23. Kuhl DE, Metter EJ, Riege WH. Patterns of cerebral glucose utilisation in depres- nosis of DLBs, it is not necessary for diagnosis. sion, multiple infarct dementia and Alzheimer’s disease. Res Publ Assoc Res Nerv Ment Dis. 1985;63:211-226. 24. Minoshima S, Frey KA, Foster NL, Kuhl DE. Preserved pontine glucose metabo- Accepted for publication November 17, 2000. lism in Alzheimer’s disease. J Comput Assist Tomogr. 1995;19:541-547. This case was seen as part of a study supported by a project 25. Hansen L, Salmon D, Galasko D, et al. The Lewy body variant of Alzheimer’s dis- ease: a clinical and pathologic entity. Neurology. 1990;40:1-8. grant from the Medical Research Council, London, England. 26. Sahgal A, Galloway PH, McKeith IG, et al. Matching-to-sample deficits in pa- We would like to acknowledge the London Neurode- tients with senile dementias of the Alzheimer and Lewy body types. Arch Neurol. gerative Diseases Brain Bank, London, and Heidi Barnes, 1992;49,1043-1046. 27. Lennox G. Dementia with Lewy bodies. In: Growden J, Rossor M, eds. Blue Books BSc, for her skillful technical assistance. We would also like of Practical Neurology: The Dementias. Woburn, Mass: Butterworth- to acknowledge the assistance of Richard Frackowiak, MD, Heinemann; 1998:67-79.

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