Dopa Responsive Parkinsonism in an Early Onset Alzheimer’s Disease Patient with a Presenilin 1 Mutation (A434T)

Abstract

Alzheimer’s disease patients with presenilin 1 (PSEN1) mutations commonly show parkinsonism in addition to dementia. Yet, whether these patients show dopaminergic deficit and response to L-dopa is largely unknown. We report a 43-year-old woman with a PSEN1 mutation (A434T) who showed right side dominant parkinsonism. As disease progressed, she developed bilateral parkinsonism which was markedly relieved by L-dopa. Amyloid (Florbetaben) positron-emission tomography (PET) showed cortical florbetaben uptake, relatively sparing the striatum. Initial dopamine transporter (FP-CIT) PET showed asymmetrically decreased FP-CIT uptake in the left striatum. We suggest that in Alzheimer’s disease patients with PSEN1 mutation, parkinsonism may be relieved by L-dopa when it is associated with presynaptic dopaminergic deficit.

Keywords

Alzheimer’s disease FP-CIT PET L-dopa parkinsonism presenilin 1

INTRODUCTION

Parkinsonism1pt frequently1pt accompanies1pt Alzheimer’s disease (AD), especially when it starts at an early age [1]. In early onset AD (EOAD), autosomal dominantly inherited AD (ADAD) accounts for 5– 10% of cases [2] and commonly exhibits various motor symptoms such as parkinsonism, dystonia, cerebellar ataxia and spastic paraparesis [3].

ADAD is caused by mutations in either presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. Specifically, overt parkinsonism has been reported to be associated with several PSEN1 mutations (G217D, F105L, M146V, E280A, L286V, and L392V) [4 –10]. Several studies have explored the pathologic correlates of parkinsonism in AD. Parkinsonism in AD might be related to concomitant α-synuclein pathology, either in the presynaptic or postsynaptic dopaminergic pathway [11, 12]. Some studies have also suggested that AD pathology involving the presynaptic or postsynaptic dopaminergic pathway might explain parkinsonism in AD, in the absence of Lewy body changes [13]. Indeed, molecular positron-emission tomography (PET) studies revealed that ADAD patients typically show increased amyloid deposition in the striatum, in the early phase of the disease [14]. Other reports suggest that neuronal loss in the substantia nigra, partly due to tau lesions, is a major pathological substrate of parkinsonism in AD [15, 16]. However, whether ADAD patients show dopaminergic deficit and response to L-dopa is largely unknown [11–13 , 16].

We report an EOAD patient with a PSEN1 mutation (A434T) who showed cognitive impairment and L-dopa responsive hemiparkinsonism, which was associated with presynaptic dopaminergic deficit.

METHODS

Case description

A 43-year-old, right-handed woman visited our clinic due to progressive abnormal behavior, cognitive impairment and gait disturbance. She received 12 years of formal education and worked as a computer instructor in her early twenties. At the age of 37, she started to show depression and aggressive behaviors such as screaming or banging her head on the wall when she was angry. She also showed memory impairment and visuospatial dysfunction. At the age of 41, she developed gait disturbance along with progression of the aforementioned symptoms.

No history of dementia or neurological disease was evident in her family. Her parents were both healthy and non-demented. At initial neurological examination, she was alert but disoriented. She exhibited dysarthric speech, drooling, prominent rigidity and bradykinesia (more severe on the right side), spastic paraparesis and dystonia. She showed pathologically increased deep tendon reflexes in all four limbs with bilateral ankle clonus. After 19 months from the first visit, the parkinsonism gradually worsened and the patient developed bilateral parkinsonism. At this point, we evaluated the off- and on-medication states using the Unified Parkinson’s Disease Rating Scale (UPDRS) [17] (examined by two blinded neurologists) to determine the effect of L-dopa on her parkinsonism before starting L-dopa treatment (Table 1 and Supplementary Video).

Table 1

The Unified Parkinson’s Disease Rating Scale Part III scores during the off-medication and on-medication states

	Initial	Follow up
		(after 19 months)
	Off-medication	Off-medication	On-medication*
1. Speech	3	3	3
2. Facial expression	4	4	3
3. Tremor at Rest	0	0	0
4. Action or Postural Tremor of Hands	0	0	0
5. Rigidity
neck	2	2	1
arm (Rt/Lt)	2/2	3 / 3	1 / 1
leg (Rt/Lt)	2/1	3 / 3	1 / 1
6. Finger taps (Rt/Lt)	2/1	2 / 2	1 / 1
7. Hand movements (Rt/Lt)	2/1	3 / 3	1 / 1
8. Rapid Alternating Movements of Hands (Rt/Lt)	2/1	3 / 3	2 / 2
9. Leg Agility	4/3	3 / 3	2 / 2
10. Rising from chair	1	4	2
11. Posture	2	2	1
12. Gait	2	3	2
13. Postural stability	3	4	2
14. Body Bradykinesia and Hypokinesia	2	3	2
Total	42	59	32

^*1 h after taking Madopar (150 mg).

The patient underwent detailed neuropsychological assessment using the Seoul Neuropsychological Screening Battery (SNSB) [18, 19] and was evaluated with brain magnetic resonance imaging (MRI), ¹⁸F-florbetaben PET, and ¹⁸F FP-CIT PET. Although she had no family history of dementia or parkinsonism, because her symptoms started at a very young age, we screened for possible casual genes.

This study was approved by the Institutional Review Board. We obtained informed consent from the participant and her next of kin.

Genetic analysis

A peripheral blood specimen was collected. Genomic DNA was extracted using a Wizard Genomic DNA Purification kit according to the manufacturer’s instructions (Promega, Madison, WI). We examined the PSEN1 and PANK2 genes by Sanger sequencing methods and CAG trinucleotide repeats in the HTT gene by a PCR-based method. To identify other possible genetic variants associated with young-onset dementia or parkinsonism (LRRK2, DJ-1, PINK1, PRKN, SNCA, GBA, PSEN2, APP, FUS, MAPT, GRN, PRNP, TREM2 and SORL1), we performed whole exome sequencing using SureSelect Human All Exon V6 (Agilent Technologies, Santa Clara, CA, USA) on the Illumina NovaSeq 6000 platform (Illumina Inc., San Diego, CA, USA). We also performed apolipoprotein E (APOE) genotyping using a Real-Q ApoE genotyping kit (BioSewoom, Seoul, Korea). All variants were classified using the pathogenic criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines [20].

¹⁸F-florbetaben PET acquisition

The patient underwent ¹⁸F-florbetaben PET at the Samsung Medical Center using a Discovery STe PET/computed tomography (CT) scanner (GE Medical Systems, Milwaukee, WI, USA) in a three-dimensional scanning mode that examined 47 slices of 3.3 mm thickness spanning the entire brain. CT images were acquired using a 16-slice helical CT (140 KeV, 80 mA; 3.75 mm section width) for attenuation correction. A 20-min dynamic PET scan (consisting of 4×5-min frames) was performed 90 min after injection of 307 MBq ¹⁸F-florbetaben. Three-dimensional PET images were reconstructed in a 128×128×48 matrix with 2×2×3.27 mm voxel size, using the ordered-subsets expectation maximization (OSEM) algorithm (iteration = 4 and subset = 20). We visually assessed the ¹⁸F-florbetaben PET in accordance with the brain Aβ plaque load (BAPL) scoring system [21].

¹⁸F-FP-CIT PET acquisition

¹⁸F-FP-CIT PET was performed with a Biograph 40 TruePoint PET/CT camera (Siemens/CTI), which provides an in-plane spatial resolution of 2.0 mm, full width at half maximum, at the center of the field of view. The subject had fasted for at least 6 h, and antiparkinsonian drug administration was stopped 12 h before the scans were obtained. Image acquisition was started 3 h after intravenous injection of ¹⁸F-FP-CIT (185 MBq). Emission PET data were acquired for 10 min in the 3-dimensional mode after brain CT, which was performed in the spiral mode at 120 kVp and 380 mAs (reference standard) with the CARE Dose 4D program. ¹⁸F-FP-CIT PET images were reconstructed from CT data for attenuation correction using the TrueX algorithm and an all-pass filter with a 336×336 matrix.

RESULTS

Genetic analysis revealed a likely pathogenic variant in the PSEN1 gene (c.1300G>A, p.A434T). We did not find any other pathogenic variant, likely pathogenic variant or variant of unknown significance, in the other genes we examined, that are associated with young-onset dementia or parkinsonism: LRRK2, DJ-1, PINK1, PRKN, PANK2, SNCA, GBA, PSEN2, APP, FUS, MAPT, GRN, PRNP, TREM2, and SORL1. No expanded alleles were identified in the HTT gene. The APOE genotype was ɛ3/ɛ4.

The patient scored 20/30 on the Korean version of the Mini-Mental State Examination. At neuropsychological examination, she scored below –2.0 standard deviation of age and education matched norms in all cognitive domains (verbal and visual memory, language, visuospatial and executive functions), except attention (Supplementary Table 1) [18, 19].

Magnetic resonance imaging revealed diffuse cortical atrophy with prominent atrophy in the bilateral medial temporal areas (Fig. 1A). There were no lacunae or significant white matter changes. Gradient echo (GRE) images showed multiple lobar microbleeds in the bilateral temporo-occipital areas and a cortical superficial siderosis in the right parietal area (Fig. 1B). ¹⁸F-Florbetaben PET showed positive for amyloid deposition, scoring 3 according to the BAPL. Florbetaben uptake was prominent in the bilateral frontal, temporal, lateral parietal cortices and precuneus regions, but not in the striatal regions (Fig. 1C). Initial ¹⁸F-FP-CIT PET showed reduced dopamine transporter (DAT) binding in the left striatum and slightly reduced DAT binding in the right striatum. Follow up ¹⁸F-FP-CIT PET, at 19 months after the first evaluation, showed more severely reduced DAT binding in the bilateral striatum (Fig. 1D).

Fig.1

A) T2–fluid attenuated inversion recovery (FLAIR) images show diffuse brain atrophy. B) Gradient echo (GRE) images show microbleeds and cortical superficial siderosis suggesting cerebral amyloid angiopathy. C) ¹⁸F-Florbetaben PET shows high cortical uptake, relatively sparing the bilateral striatum. D) Initial ¹⁸F-FP-CIT PET shows asymmetrically decreased dopamine transporter (DAT) binding in the left striatum, and follow-up ¹⁸F-FP-CIT PET, taken 19 months later, shows more severely reduced DAT binding in the bilateral striatum.

The parkinsonism was markedly relieved by L-dopa. During the off-medication state, she scored 59 on the UPDRS part III, which improved to 32 one hour after taking 150 mg of Madopar (Table 1 and Supplementary Video). The patient showed functional improvement as well. During the off-medication state, she could not walk without assistance, could not swallow food, and excessively drooled. However, during the on-medication state, she could walk independently, could swallow food, and did not drool. The patient also reported subjective improvement of symptoms as she said “I feel lighter and more energetic after taking L-dopa.”

DISCUSSION

We report a case of 43-year-old woman with a likely pathogenic variant in the PSEN1 (A434T). The initial right side dominant parkinsonism matched asymmetrically reduced radioligand uptake in the left striatum, on initial ¹⁸F-FP-CIT PET. The parkinsonism was markedly improved by L-dopa. We suggest that in ADAD patients, parkinsonism may be relieved by L-dopa when it is associated with presynaptic dopaminergic deficit.

In an EOAD patient, we identified a G to A transition in exon 12 of the PSEN1 gene, which results in the substitution of alanine with threonine at codon 434 (A434T). This is the first case of the likely pathogenic variant in PSEN1 A434T to be reported in Korea. This mutation was previously detected in a Chinese EOAD family [22]. The age at onset of the proband was 38 years [22], which was similar to the onset age of our patient. However, unlike this Chinese patient, our patient showed motor symptoms such as parkinsonism, spastic paraparesis and dystonia. Her parkinsonism was asymmetric and dopa-responsive. We found asymmetrically decreased DAT binding in the left striatum, which matched her asymmetric right predominant parkinsonism at the initial examination.

Although overt parkinsonism is associated with PSEN1 mutations (G217D, F105L, M146V, E280A, L286V, L392V) [4 –9], the underlying pathomechanism of parkinsonism is unclear. In our case, based on asymmetrically reduced ¹⁸F-FP-CIT uptake matching the clinical phenotype and relatively less amyloid uptake in the bilateral striatum, we suggest that the parkinsonism in our patient might be related to presynaptic, rather than postsynaptic dopaminergic dysfunction. Presynaptic dopaminergic dysfunction in ADAD may be explained by α-synuclein or AD pathology in substantia nigra. Pathological studies have shown parkinsonism in AD to be associated with a-synuclein aggregation in the substantia nigra [12]. An autopsy study showed that an ADAD patient with a PSEN1 mutation (S170F) had widespread Lewy body pathology in the brainstem, limbic areas, and neocortex, as well as AD pathology [23]. Indeed, a preclinical study demonstrated that PSEN1 mutation was associated with increased accumulation of α-synuclein [24]. AD pathology involving the presynaptic dopaminergic pathway may also explain parkinsonism in AD. Autopsy studies have shown that AD patients with parkinsonism have more neurofibrillary tangles in the substantia nigra than those without parkinsonism [15, 16]. Other studies have suggested that postsynaptic dopaminergic dysfunction is responsible for parkinsonism in AD. Although our case showed relatively less amyloid deposition in the striatum, other molecular neuroimaging studies have shown early deposition of amyloid in the striatum of ADAD patients [14, 25].

Since ADAD has a variety of concomitant pathologies [26], the reasons for parkinsonism in each patient and the response to L-dopa may differ. L-dopa responsiveness in AD patients with parkinsonism might depend on the degree of neuronal loss in the substantia nigra [27] and studies have shown varying results. A previous study showed that three out of five AD patients with concomitant alpha-synucleinopathy responded to L-dopa [27]. Duret et al. administered L-dopa, or placebo, to 14 AD patients with rigidity. The rigidity remained unchanged in all patients regardless of treatment [28]. Merello et al. conducted apomorphine tests on 11 AD patients with parkinsonism, in which none was responsive [29]. Overall, clinical pharmacological studies are less supportive of the benefits of L-dopa replacement for treating parkinsonism in AD [28, 29]. However, since L-dopa responsiveness may vary depending on the underlying pathomechanisms, clinicians should carefully consider L-dopa when parkinsonism is associated with presynaptic dopaminergic deficits.

This study has a limitation that we do not have pathological findings of this patient. Further pathological confirmation is needed to explore the underlying pathomechanism of parkinsonism in this patient.

This case is noteworthy because it is the first ADAD case that demonstrated dopa-responsive hemiparkinsonism along with multimodal neuroimaging findings. Further studies are needed to explore biomarkers for identifying patients who will benefit from L-dopa, among AD patients with parkinsonism.

Footnotes

ACKNOWLEDGMENTS

This research was supported by grants of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI18C0335, HI18C1629, and HI14C2746); and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2018R1A1A3A04079255).

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

References

Samson

, van Duijn

, Hop

, Hofman

(1996) Clinical features and mortality in patients with early-onset Alzheimer’s disease. Eur Neurol 36, 103–106.

Cacace

, Sleegers

, Van Broeckhoven

(2016) Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement 12, 733–748.

Bateman

, Aisen

, De Strooper

, Fox

, Lemere

, Ringman

, Salloway

, Sperling

, Windisch

, Xiong

(2011) Autosomal-dominant Alzheimer’s disease: A review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res Ther 3, 1.

Kim

J.H.

, Genetics of Alzheimer’s disease, Dement Neurocogn Disord 17, 131–136.

Takao

, Ghetti

, Hayakawa

, Ikeda

, Fukuuchi

, Miravalle

, Piccardo

, Murrell

, Glazier

, Koto

(2002) A novel mutation (G217D) in the Presenilin 1 gene (PSEN1) in a Japanese family: Presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum. Acta Neuropathol 104, 155–170.

Campion

, Brice

, Hannequin

, Tardieu

, Dubois

, Calenda

, Brun

, Penet

, Tayot

, Martinez

, et al. (1995) A large pedigree with early-onset Alzheimer’s disease: Clinical, neuropathologic, and genetic characterization. Neurology 45, 80–85.

Finckh

, Muller-Thomsen

, Mann

, Eggers

, Marksteiner

, Meins

, Binetti

, Alberici

, Hock

, Nitsch

, Gal

(2000) High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet 66, 110–117.

Frommelt

, Schnabel

, Kuhne

, Nee

, Polinsky

(1991) Familial Alzheimer disease: A large, multigeneration German kindred. Alzheimer Dis Assoc Disord 5, 36–43.

Gustafson

, Brun

, Englund

, Hagnell

, Nilsson

, Stensmyr

, Ohlin

, Abrahamson

(1998) A 50-year perspective of a family with chromosome-14-linked Alzheimer’s disease. Hum Genet 102, 253–257.

10.

Lopera

, Ardilla

, Martinez

, Madrigal

, Arango-Viana

, Lemere

, Arango-Lasprilla

, Hincapie

, Arcos-Burgos

, Ossa

, Behrens

, Norton

, Lendon

, Goate

, Ruiz-Linares

, Rosselli

, Kosik

(1997) Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA 277, 793–799.

11.

Mitchell

(1999) Extrapyramidal features in Alzheimer’s disease. Age Ageing 28, 401–409.

12.

Burns

, Galvin

, Roe

, Morris

, McKeel

(2005) The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs. Neurology 64, 1397–1403.

13.

Braak

, Braak

(1990) Alzheimer’s disease: Striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol 49, 215–224.

14.

Klunk

, Price

, Mathis

, Tsopelas

, Lopresti

, Ziolko

, Bi

, Hoge

, Cohen

, Ikonomovic

, Saxton

, Snitz

, Pollen

, Moonis

, Lippa

, Swearer

, Johnson

, Rentz

, Fischman

, Aizenstein

, DeKosky

(2007) Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci 27, 6174–6184.

15.

Attems

, Quass

, Jellinger

(2007) Tau and alpha-synuclein brainstem pathology in Alzheimer disease: Relation with extrapyramidal signs. Acta Neuropathol 113, 53–62.

16.

Liu

, Stern

, Chun

, Jacobs

, Yau

, Goldman

(1997) Pathological correlates of extrapyramidal signs in Alzheimer’s disease. Ann Neurol 41, 368–374.

17.

Fahn

, Mardsen

, Jenner

, Teychenne

(1986), Recent developments in Parkinson’s disease. Raven Press, New York.

18.

Ahn

, Chin

, Park

, Lee

, Suh

, Seo

, Na

(2010) Seoul Neuropsychological Screening Battery-dementia version (SNSB-D): A useful tool for assessing and monitoring cognitive impairments in dementia patients. J Korean Med Sci 25, 1071–1076.

19.

Kang

, Na

(2003) Seoul Neuropsychological Screening Battery (SNSB). Human Brain Research & Consulting, Incheon.

20.

Richards

, Aziz

, Bale

, Bick

, Das

, Gastier-Foster

, Grody

, Hegde

, Lyon

, Spector

, Voelkerding

, Rehm

(2015) Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17, 405–423.

21.

Barthel

, Gertz

, Dresel

, Peters

, Bartenstein

, Buerger

, Hiemeyer

, Wittemer-Rump

, Seibyl

, Reininger

, Sabri

(2011) Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: A multicentre phase 2 diagnostic study. Lancet Neurol 10, 424–435.

22.

Jiao

, Tang

, Liu

, Xu

, Wang

, Zhou

, Zhang

, Yan

, Zhou

, Shen

(2014) Mutational analysis in early-onset familial Alzheimer’s disease in Mainland China. Neurobiol Aging 35, 1957.e1951–1956.

23.

Snider

, Norton

, Coats

, Chakraverty

, Hou

, Jervis

, Lendon

, Goate

, McKeel

Jr , Morris

(2005) Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol 62, 1821–1830.

24.

Winslow

, Moussaud

, Zhu

, Post

, Dickson

, Berezovska

, McLean

(2014) Convergence of pathology in dementia with Lewy bodies and Alzheimer’s disease: A role for the novel interaction of alpha-synuclein and presenilin 1 in disease. Brain 137, 1958–1970.

25.

Bateman

, Xiong

, Benzinger

, Fagan

, Goate

, Fox

, Marcus

, Cairns

, Xie

, Blazey

, Holtzman

, Santacruz

, Buckles

, Oliver

, Moulder

, Aisen

, Ghetti

, Klunk

, McDade

, Martins

, Masters

, Mayeux

, Ringman

, Rossor

, Schofield

, Sperling

, Salloway

, Morris

(2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367, 795–804.

26.

Ringman

, Monsell

, Ng

, Zhou

, Nguyen

, Coppola

, Van Berlo

, Mendez

, Tung

, Weintraub

, Mesulam

, Bigio

, Gitelman

, Fisher-Hubbard

, Albin

, Vinters

(2016) Neuropathology of autosomal dominant Alzheimer disease in the National Alzheimer Coordinating Center Database. J Neuropathol Exp Neurol 75, 284–290.

27.

Rajput

, Rozdilsky

, Rajput

, Ang

(1990) Levodopa efficacy and pathological basis of Parkinson syndrome. Clin Neuropharmacol 13, 553–558.

28.

Duret

, Goldman

, Messina

, Hildebrand

(1989) Effect of L-dopa on dementia-related rigidity. Acta Neurol Scand 80, 64–67.

29.

Merello

, Sabe

, Teson

, Migliorelli

, Petracchi

, Leiguarda

, Starkstein

(1994) Extrapyramidalism in Alzheimer’s disease: Prevalence, psychiatric, and neuropsychological correlates. J Neurol Neurosurg Psychiatry 57, 1503–1509.

Dopa Responsive Parkinsonism in an Early Onset Alzheimer’s Disease Patient with a Presenilin 1 Mutation (A434T)

Abstract

Keywords

INTRODUCTION

METHODS

Case description

Genetic analysis

18F-florbetaben PET acquisition

18F-FP-CIT PET acquisition

RESULTS

DISCUSSION

Footnotes

ACKNOWLEDGMENTS

References

¹⁸F-florbetaben PET acquisition

¹⁸F-FP-CIT PET acquisition