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Ž .Psychiatry Research: Neuroimaging Section 108 2001 133�140

PET findings and neuropsychological deficits in a caseof Fahr’s disease

Albrecht Hempela,�, Marcus Henzeb, Christopher Berghoff a,Nohazarahit Garciaa, Reinhard Ody c, Johannes Schrodera¨

aDepartment of Psychiatry, Uni�ersity of Heidelberg, Voßstr. 2, D-69115 Heidelberg, GermanybClinical Cooperation Unit, Nuclear Medicine, German Cancer Research Center and Uni�ersity of Heidelberg, Germany

cDepartment of Psychiatry, Marien-Hospital, Euskirchen, Germany

Received 25 September 2000; received in revised form 7 August 2001; accepted 19 August 2001

Abstract

In a case of Fahr’s disease with frontal lobe type dementia and hyperkinetic-hypotone syndrome, functionalŽ . 18 Ž .changes were investigated using positron emission tomography PET with F-fluorodeoxyglucose FDG as a tracer.

Computed tomography showed bilateral calcifications in the putamen and globus pallidus consistent with thediagnosis of Fahr’s disease and a frontally pronounced brain atrophy. In contrast, reduced glucose uptake in PET wasnot only confined to the areas mentioned above, but extended to the temporal and parietal cortices, bilaterally. Thesefunctional changes corresponded to the neuropsychological deficits observed, i.e. disturbed selective attention andcognitive flexibility, verbal perseverations, and declarative memory deficits. It is suggested that functional changesmay precede cerebral atrophy in Fahr’s disease and may reflect deficits in functional circuits, which involve both thebasal ganglia and the frontal, parietal, and temporal lobes. � 2001 Elsevier Science Ireland Ltd. All rights reserved.

Ž .Keywords: Positron emission tomography PET ; Idiopathic basal ganglia calcification; Frontal lobe

1. Introduction

Idiopathic basal ganglia calcification or Fahr’sŽ .disease Fahr, 1930 is a rare neurodegenerative

disorder characterized by extrapyramidal motorŽsigns, dementia and organic psychosis Konig and¨

.Haller, 1984; Trautner et al., 1988 . Clinical diag-

� Corresponding author. Fax: �49-56-5477.E-mail address: albrecht [email protected]�

Ž .A. Hempel .

nosis is facilitated by the presence of bilateralcalcifications in the basal ganglia in computed

Ž .tomography CT . These calcifications cannot beexplained by any particular disorder of the cal-cium�phosphorus metabolism or other diseasesinvolving the basal ganglia like toxoplasmosis, tu-berous sclerosis, myotonic muscular dystrophy,idiopathic hemochromatosis, or mitochondrial en-cephalopathies. In a post-mortem histopathologi-

Žcal and electron microscopic study Kobayashi et.al., 1987 , calcifications were found bilaterally in

0165-1781�01�$ - see front matter � 2001 Elsevier Science Ireland Ltd. All rights reserved.Ž .PII: S 0 1 6 5 - 1 7 8 1 0 1 0 0 3 0 8 - 0

( )A. Hempel et al. � Psychiatry Research: Neuroimaging 108 2001 133�140134

the basal ganglia, cerebral cortex, and cerebel-lum. Calcium deposits were also described in theadventitial cells of blood vessels. Apart from thecalcareous deposition of Fahr’s type in the basalganglia, an atrophy of the temporal and frontal

Ž .lobes was observed Shibayama et al., 1992 .Numerous patients present a familiar trait with

autosomal dominant transmission. Recently, a lo-cus on chromosome 14q was identified in a familywith dominant transmission of Fahr’s diseaseŽ .Geschwind et al., 1999 .

In a CT study involving 62 patients, Taxer et al.Ž .1986 found the extent of basal ganglia calcifica-tion to be associated with more pronounced neu-

Ž .ropsychiatric deficits Taxer et al., 1986 . Theinitial phase of the disorder is often characterizedby obsessive�compulsive states and by affectiveand schizophrenic symptoms; later stages, by or-ganic brain syndromes of variable severity. Thesesyndromes cannot be explained entirely by basalganglia changes alone, but suggest the involve-ment of other cerebral sites, in particular, thefrontal lobes. The basal ganglia are heavily inter-connected with the frontal cortices via a number

Ž .of frontostriatal pathways Alexander et al., 1986 .Hence, one can hypothesize that functional cere-bral changes in Fahr’s disease are not restrictedto the basal ganglia, but may also involve thefrontal and temporal lobes. This assumption is

Ž .supported by Smith et al. 1988 , who examinedregional cerebral blood flow changes in sixpatients with non-specified basal ganglia diseasesusing single photon emission computed tomogra-phy with hexamethylpropyleneamine as a tracer.Four of the patients examined showed a promi-nently decreased regional cerebral blood flow inthe basal ganglia matching the distribution ofcalcifications observed in CT. Moreover, Uygur et

Ž .al. 1995 reported regional cerebral blood flowdecreases not only in the basal ganglia, but also inthe frontal lobes and the right parietal lobe in apatient with Fahr’s disease.

In the present study, we examined regionalglucose uptake using positron emission tomogra-

Ž . 18 Ž .phy PET with F-fluorodeoxyglucose FDG asa tracer in a patient with Fahr’s disease. We wereable to combine the better local resolution capac-ity of PET with neuropsychological testing reveal-

ing defined performance deficits in addition tothe mere determination of clinical symptoms.

2. Methods

2.1. Patient

2.1.1. Present medical historyThe 25-year-old male patient was admitted to

the Department of Psychiatry of the University ofHeidelberg with organic psychosis of unknownetiology. Born in Sri Lanka as the seventh of 10children, the patient attended primary school upto 5th grade. In 1988, he asked for asylum inGermany after having lost his mother and five ofhis siblings in the civil war during the 1980s. Onebrother died in a car accident in 1989. Starting in1994, the patient showed behavioral changes in-cluding leaving stores without paying for his shop-ping or driving without having a license. In addi-tion, loss of distance in contact, deterioration ofspeech and general restlessness of motion weredescribed. Since 1996, the patient presented re-duced initiative, indifference and an increasedsuspicion. Two years later he was committed to aresidential home.

After admission, the patient was treated withPipamperon, a fluorbutyrophenone, resulting in amild improvement of motor symptoms and perse-verations.

A 15-year-older sister was hospitalized in 1995and 1997, and diagnosed with Fahr’s disease. Asevere dementia had developed within 7 years.Beginning in 1989, she showed ‘childlike’ behav-ioral changes, loss of distance and a cheerful andfearful affect. She was unable to care for her sonand daughter and developed intermittent para-noid symptoms as well as severe mnestic deficits.In 1997, the patient was unable to care for herself

Ž .and computed tomography CT revealed aprominent basal ganglia calcification bilaterallyŽ .Figs. 1 and 2 . Her 9-year-old son and 14-year-olddaughter showed normal mental and psychomotordevelopment.

2.1.2. Mental status examinationOn admission, the patient was co-operative,

( )A. Hempel et al. � Psychiatry Research: Neuroimaging 108 2001 133�140 135

Fig. 1. CT of the patient with three consecutive slices through the basal ganglia showing markedly bilateral calcification of thestriatum and globus pallidus.

alert and fully oriented. He displayed a friendlybut partly inappropriate ‘chummy’ attitude. Hismovements were awkward with signs of hyperac-tivity, i.e. he suddenly, and without being able togive a reason, walked across the room in a slouchyand desultory gait. During the examination thepatient constantly smiled, even when describingsad or negative events. This inappropriate emo-tional display made it difficult for the examiner toassess his true affective state. The speech was ofsimple vocabulary and non-fluent, spoken in asoft and monotonous voice. It was often inter-

rupted by word-finding difficulties, echolalia andverbal perseverations. The patient was easily dis-tractible and did not believe himself to be ill. Hismemory for commonly known facts and historicalevents was intact, but he had difficulties in long-term recall. No signs of psychosis such as delu-sions or hallucinations were observed.

Neurologically, the patient showed intermittentmild dystonic movements of both hands, a milddysarthria and facial grimacing. The musculartonus of the extremities was reduced with nosigns of circumscribed pareses. Sensibility was

Fig. 2. CT of the patient’s sister 6 years ago; three consecutive slices through the basal ganglia show markedly bilateral calcificationof the striatum and globus pallidus.


found to be normal for all qualities on standardneurological testing.

2.1.3. Laboratory testsBlood analysis including copper, coerulo-

plasmin, ferritin, calcium, phosphorus andparathormon, and analysis of cerebrospinal fluid

Žincluding Tau protein concentration for method-.ological details, see Schonknecht et al., 2000 ,¨

Ž .were normal 168 pg�ml . The ophthalmologicalexamination did not reveal any changes of thecornea. Electroencephalography showed an occip-ital alpha rhythm with bilateral frontotemporaldeceleration.

Ž .Computed tomography CT revealed a gener-alized brain atrophy with accentuation of thefrontal lobes as well as bilateral basal gangliacalcification in the putamen and in the internal

Ž .segment of the globus pallidus Fig. 1 .

2.1.4. Neuropsychological e�aluationDue to the patient’s difficulty in speaking and

language, non-verbal tests were used for neu-Ž .ropsychological examination Table 1 . The d-2Ž .Attention Performance Test Brickenkamp, 1994

revealed disturbed selective attention and con-centration. On the reduced Wechsler Intelligence

Ž .Test Dahl, 1986 , the patient exhibited severeimpairment regarding abstract reasoning and spa-tial imagination with numerous verbal persevera-

Ž .tions. On the Benton test Benton, 1996 , bothfigural memory and constructive praxis were

Žequally affected. The Trail-Making Test Reitan,.1979 revealed severe deceleration in information

processing and an inability to execute part II atall, indicating severe deficits in cognitive flexibil-ity. The Clock Drawing Test, which is generallyadministered as non-verbal screening for demen-

Ž .tia Shulman and Gold, 1993 , revealed a severegeneral cognitive impairment.

2.2. PET data acquisition and analysis

ŽFDG with a high activity concentration 500

Table 1aNeuropsychological test results

Function Test Score Performance

General intelligence WIP General Knowledge: RS 2; PR 2 Far below averageFinding commons: RS 0; PR 0Completing pictures: RS 2; PR 0Mosaic Test: RS 0; PR 0

Concentration� d-2 Total number of processed signs: Far below averageselective attention 99; PR 0

Percentage of errors: 26,3; PR 0

Visual memory Benton test Total number correct: RS 1; PR 0 Far below averageŽ .instruction A Total number of errors: RS 22; PR 0

Information processing TMT-A 142 s; PR 0 Far below average

Cognitive flexibility TMT-B �600 s; PR 0 Far below average

Constructive praxis� Clock RS 4 Impairedabstract thinking Drawing Test

Degree of cognitive deficits GDS RS 6 Severely impaired

aAbbre�iations: WIP, reduced Wechsler Intelligence Test; d-2, Attention Performance Test; TMT-A�B, Trail Making Test; GDS,Global Deterioration Scale; RS, raw score; and PR, percentile range.


.MBq�ml was produced as described by Oberdor-Ž .fer et al. 1986 . Achieved radiochemical purity

was higher than 98%. Scans were taken 45 minafter intravenous injection of 160-MBq FDG on

Ž .the fasted patient blood glucose�81 mg�dl in aquiet environment with eyes closed.

Brain measurements were performed using thelatest generation whole-body PET system ECAT

� ŽEXACT HR Siemens�CTI, Knoxville, TN,.USA . The scanner consists of four rings with 72

bismuth germanate block detectors, each covering155 mm as the axial field of view. Data were in a3D mode without inter-slice tungsten septa. Forthe standard acquisition parameters, the total trueevent sensitivity in the 3D mode is higher by afactor of approximately 4.9 than in the 2D modeŽ .Brix et al., 1997 . In the 3D mode, the transaxialresolution is in the range between 4.8 and 4.1mm. The scanner is equipped with three 68 Geline sources with an activity of approximately 100MBq each for the acquisition of a transmissionand blank scan. Starting a static scan 45 min afterinjection, emission and transmission data wereacquired over 20 and 10 min, respectively. Thediscretization of the image matrix was 256�256pixels. Iterative reconstruction of the data wasperformed using the OSEM algorithm.

For semiquantitative analysis, regions of inter-Ž .est ROIs were manually placed on all transaxial

slices, covering the normal and hypometabolicbrain areas given in Table 2. After correction for

Ž .radioactive decay T �109.7 min , FDG uptake1�2was expressed as the standardized uptake valueŽ .SUV :

Ž .SUV�C� D�m .

where C is the tissue activity concentrationŽ . Ž .kBq�g , D the injected dose kBq and m the

Ž .body weight grams . Because CT showed apronounced frontal atrophy, SUVs were cor-rected for partial volume effect, using recoverycoefficients which were previously published for

Ž .our PET scanner Adam et al., 1997 . Semiquanti-tative measurements of tracer uptake were ob-tained by calculating relative SUVs normalized tothe global brain metabolism. The respective meanvalues and S.D.s are based on values obtained in

Table 2ŽRegional glucose metabolism relative SUV normalized to the

.global brain metabolism

Patient Mean Mean�S.D.�2 S.D.

Frontal cortex 1.10 1.20 1.33�0.06Motor cortex 1.43 1.18 1.32�0.07Temporal cortex 1.04 1.06 1.18�0.06Parietal cortex 1.06 1.16 1.31�0.08Occipital cortex 1.45 1.38 1.50�0.06Insula 1.18 1.05 1.23�0.09Thalamic area 1.10 0.97 1.21�0.12Hippocampal area 0.92 0.94 1.06�0.06Striatal area 1.14 1.15 1.37�0.11Cerebellum 1.13 0.79 1.01�0.11

Ž .Thresholds, mean values and standard deviations S.D.are based on the glucose metabolism in 12 normal controls

Ž .measured by Volkow et al. 2000 .

Ž12 normal controls 11 males, one female, 30�8. �years of age also using a Siemens�CTI HR PET

Ž .scanner Volkow et al., 2000 .At the time of PET examination, the patient

had been treated with 320 mg�day Pipamperonfor 5 weeks.

3. PET results

Glucose uptake was moderately reduced in thestriatum bilaterally; the respective standardizeduptake values were at least 15% lower than mean

Ž .values obtained in controls Fig. 3 . Marked bilat-eral reductions were found in the frontal andtemporo-parietal cortices and the hippocampal

Ž .area Fig. 3 , while glucose uptake was preservedin other cortical regions such as the sensorimotorand occipital cortices and in the cerebellum. Theresults of the semiquantitative analysis are givenin Table 2.

4. Discussion

We report the case of a 25-year-old patientwith Fahr’s disease, who presented with frontallobe syndrome and dementia, both of which hadbeen worsening steadily over the past 5 years. CT


Ž . Ž .Fig. 3. FDG PET transaxial slices demonstrating areas of reduced glucose metabolism arrows in the parietal and frontal cortexŽ . Ž . Ž .a, b , the striatum c and the temporal cortices d bilaterally.

showed a bilateral calcification of the putamenand globus pallidus consistent with Fahr’s diseaseand a frontally pronounced brain atrophy. In con-trast, reduced glucose uptake in PET was notrestricted to the basal ganglia, but also involvedthe frontal, temporal and parietal cortices corre-sponding to the impaired cognitive flexibility, fig-

ural memory and constructive praxis revealed byneuropsychological testing. Secondary causes ofthe calcifications were excluded by laboratorytesting.

In the present case, a hereditary variant offrontotemporal dementia with concomitant basalganglia calcifications had to be considered as a


differential diagnosis, since clinical symptomsclearly fulfilled the criteria for this disorder sug-

Žgested by the Lund and Manchester Group Neary.et al., 1998 . Basal ganglia changes are not con-

sidered to be a common feature of frontotem-Ž .poral dementia Jauss et al., 2001 . In the present

case, the coincidence of dementia with basal gan-glia calcification afflicting two siblings, thepatient’s young age and the hyperkinetic-hypo-tone syndrome render the diagnosis of frontotem-poral dementia rather unlikely.

ŽRecent anatomical studies in animals Smeets.et al., 2000, for review have demonstrated that

vertebrates share a common pattern of basal gan-glia organization. The corpus striatum receivesnumerous fibers from the cerebral cortex and issupposed to represent the entrance to the basalganglia circuit, whereas the internal segment ofthe globus pallidus and the substantia nigra con-stitute the exit with an inhibitory effect on thepremotor neurons of the ventral thalamus.Between these structures, a direct monosynapti-cal and indirect polysynaptical pathway with con-nections to the external segment of the globuspallidus and the subthalamic nucleus form abalance, which controls movements and musculartonus.

According to these findings, the hyperkinetic-hypotone syndrome observed in the present casemay reflect a reduced activity in the internalsegment of the globus pallidus. This assumption is

Žsubstantiated by animal studies Cromwell and.Berridge, 1994 demonstrating that damage af-

fecting at least 60% of the ventromedial globuspallidus results in a hyperkinetic syndrome; more-over, in the CT study cited above, Taxer et al.Ž .1986 described a close association between basalganglia changes and both motor and cognitivedeficits.

Functional abnormalities did not entirely paral-lel morphological changes, but were also found inthe temporal and parietal lobes which appearedto be rather unaffected in CT. Hence, one mayconclude that functional abnormalities may pre-cede morphological changes in the diseaseprocess. Alternatively, one may argue that thebasal ganglia are heavily interconnected withparietal, temporal, and in particular, the frontal

Ž .lobes Alexander et al., 1986; Buchsbaum, 1995 .The reduced glucose uptake observed in the re-spective regions may therefore also reflect sec-ondary deficits due to diminished functions ofcircuits involving the basal ganglia.

Acknowledgements

The authors are grateful to Ch. Bottmer forher suggestions on the manuscript.

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