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Apakah frekuensi tremor umumnya meningkat seiring perkembangan penyakit Parkinson?

Apakah frekuensi tremor umumnya meningkat seiring perkembangan penyakit Parkinson?


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Saya telah mencoba untuk meneliti pertanyaan ini, tetapi sebagian besar jika tidak semua jurnal online memerlukan langganan yang mahal, dan penelitian yang diposting melihat frekuensi getaran sehubungan dengan faktor-faktor lain.

Pertanyaan saya berkaitan dengan frekuensi tremor, mulai dari onset dini hingga stadium lanjut penyakit Parkinson - selama perjalanan penyakit, dan tanpa perawatan obat (seperti L-dopa), apakah frekuensi tremor umumnya meningkat?


Frekuensi tremor biasanya tetap konstan untuk orang tersebut. Levadopa (sinemet) tidak mengubah frekuensi.

Biasanya frekuensi getaran akan berada dalam kisaran dari 3Hz hingga 7Hz. Ada ungkapan umum ketika berhadapan dengan PWP (Orang Dengan Penyakit Parkinson). Jika Anda telah melihat satu PWP, Anda telah melihat satu PWP.

Saat ini saya adalah bagian dari studi oleh Yayasan Michael J Fox menggunakan Jam Tangan Pebble dan Ponsel pintar untuk memantau PD.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1014720/ Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Akurasi diagnosis klinis penyakit Parkinson: studi klinis-patologis dari 100 kasus . J Neurol Bedah Saraf Psikiatri 55: 181-184.

https://blog.getpebble.com/2014/08/25/mjff-intel-parkinsons/


Hasil yang menjanjikan dari uji klinis percontohan baru-baru ini menunjukkan bahwa stimulasi otak dalam mungkin efektif dalam mengobati penyakit tahap awal.

Penyakit Parkinson adalah penyakit neurodegeneratif progresif, yang berarti sel-sel otak akan terus mati saat penyakit berlanjut. Sel-sel otak yang paling terpengaruh pada penyakit Parkinson adalah sel-sel yang memproduksi dopamin, zat kimia di otak yang diketahui penting dalam mengontrol gerakan tubuh. Apa yang diterjemahkan dalam hal gejala adalah perkembangan penyakit di mana kemampuan pasien untuk mengontrol gerakan memburuk dari waktu ke waktu . Pasien mulai merasakan sedikit tremor saat istirahat, yang berkembang menjadi kekakuan, dan kehilangan keseimbangan. Pada stadium lanjut penyakit, pasien kehilangan kemampuan untuk berjalan atau berdiri.

Perawatan garis depan saat ini untuk pasien penyakit Parkinson tetap sama selama 60 tahun terakhir. Levodopa, bahan kimia yang diubah menjadi dopamin di otak, digunakan sebagai terapi pengganti. Tujuannya adalah untuk mengisi kembali dopamin yang terus hilang untuk pasien penyakit Parkinson. Sementara pengobatan levodopa efektif dalam mengelola gejala yang terlihat pada penyakit Parkinson, manfaatnya umumnya menjadi kurang konsisten dari waktu ke waktu. Obat tersebut pada akhirnya tidak mampu memperlambat perkembangan penyakit. Umumnya, seiring perkembangan penyakit Parkinson, pasien biasanya akan menerima kombinasi obat lain selain levodopa. Ini termasuk COMT, yang meniru dopamin, atau obat yang dikenal sebagai: Penghambat MAO-B yang memperlambat pemecahan alami dopamin.

Untuk pasien yang tidak merespons, atau berhenti merespons pengobatan, ada prosedur pembedahan yang tersedia. Perawatan ini, yang disebut DBS atau stimulasi otak dalam, seperti memasukkan "alat pacu jantung" ke dalam otak. Ahli bedah menanamkan elektroda ke dalam otak yang akan mengirimkan pulsa listrik untuk merangsang penembakan sel-sel otak. Para ilmuwan memiliki bukti bahwa denyut listrik ini berfungsi untuk mengatur kembali aktivasi normal sel-sel otak yang tidak diatur sebagai akibat dari penyakit Parkinson, dan ini pada akhirnya membantu mengendalikan gejala penyakit. Sementara jenis prosedur ini umumnya diperuntukkan bagi pasien dengan penyakit Parkinson lanjut, para peneliti baru-baru ini menyelidiki apakah DBS dapat bermanfaat bagi pasien penyakit Parkinson tahap awal juga.

Ini adalah lokasi di otak tempat elektroda ditempatkan untuk perawatan DBS. Andreashorn / CC BY-SA

Di Vanderbilt University Medical Center, para ilmuwan telah menyelesaikan studi lanjutan untuk uji klinis percontohan di mana pasien penyakit Parkinson tahap awal diberi DBS sebagai tambahan untuk pengobatan mereka. Pasien-pasien ini dibandingkan dengan pasien stadium awal lainnya yang hanya menerima pengobatan. Para peneliti melihat hasil pasien lima tahun kemudian, dan menemukan bahwa pasien yang menerima pengobatan dan DBS bernasib jauh lebih baik pada berbagai ukuran hasil penyakit Parkinson.

Misalnya, pasien yang menerima DBS dan obat-obatan ternyata membutuhkan dosis levodopa yang jauh lebih rendah daripada pasien tahap awal yang tidak menjalani DBS. Rata-rata, pasien yang menerima DBS dan pengobatan mengalami peningkatan dosis obat yang kira-kira setengah dari pasien yang tidak menjalani DBS. Mereka juga lima kali lebih kecil kemungkinannya mengalami tremor istirahat yang memburuk dan lima belas kali lebih kecil kemungkinannya membutuhkan beberapa jenis obat penyakit Parkinson.

Secara keseluruhan, para peneliti menyimpulkan bahwa implementasi awal DBS dapat mengurangi risiko perkembangan penyakit Parkinson. Jika hasil uji coba di masa depan mendukung hasil awal ini, penambahan DBS ke pengobatan tahap awal penyakit Parkinson dapat berarti hasil yang lebih baik dan perkembangan penyakit yang lebih lambat untuk pasien. Para peneliti sekarang pindah ke percobaan skala yang lebih besar untuk menyelidiki lebih lengkap potensi DBS untuk memperlambat perkembangan penyakit Parkinson. Jika berhasil, pengobatan baru ini bisa menjadi penemuan penting untuk perawatan penyakit Parkinson.

Posting terkait:


Demensia dengan Badan Lewy

  • Demensia dengan badan Lewy (DLB) adalah gangguan neurodegeneratif progresif di mana deposit abnormal protein yang disebut alpha-synuclein menumpuk di beberapa area otak.
  • DLB pertama menyebabkan masalah progresif dengan memori dan fluktuasi dalam berpikir, serta halusinasi. Gejala-gejala ini bergabung kemudian dalam perjalanan penyakit oleh parkinsonisme dengan kelambatan, kekakuan dan gejala lain yang mirip dengan PD.
  • Sementara protein abnormal yang sama (alpha synuclein) ditemukan di otak mereka yang menderita PD, ketika individu dengan PD mengalami masalah memori dan berpikir, hal itu cenderung terjadi kemudian dalam perjalanan penyakit mereka.
  • Tidak ada pengobatan khusus untuk DLB. Perawatan berfokus pada gejala.

Memahami Patologi

Sistem saraf terdiri dari unit individu yang disebut sel saraf atau neuron. Neuron berfungsi sebagai "jaringan komunikasi" di dalam otak dan di seluruh tubuh seseorang. Penyakit Parkinson berkembang ketika neuron di otak dan di tempat lain di sistem saraf gagal berfungsi secara normal atau mati. Gejala khas PD & mdash bradikinesia, tremor, ketidakstabilan postural, dan kekakuan & mdash hasil terutama dari kematian neuron di substansia nigra, sebuah wilayah di otak tengah yang penting untuk kontrol motorik.

Untuk berkomunikasi, neuron menggunakan pembawa pesan kimia yang disebut neurotransmiter. Neurotransmitter mengirim informasi antar neuron dengan melintasi ruang di antara mereka, yang disebut sinaps. Biasanya, neuron di substansia nigra menghasilkan neurotransmitter yang dikenal sebagai dopamin. Dopamin sangat penting untuk gerakan dan membantu mengirimkan pesan di dalam otak untuk memastikan otot menghasilkan gerakan yang mulus dan terarah. Hilangnya hasil dopamin dalam pola penembakan saraf abnormal yang mengganggu gerakan. Pada saat Parkinson didiagnosis, kebanyakan orang telah kehilangan sekitar 60 hingga 80 persen sel penghasil dopamin di substansia nigra.

Sementara hilangnya dopamin menyumbang ciri khas penyakit ini, penelitian terbaru mengungkapkan bahwa sejumlah sistem otak lainnya juga rusak. Ini termasuk struktur otak yang mengatur jalur kimia yang bergantung pada norepinefrin, serotonin, dan asetilkolin. Perubahan neurotransmiter dan sirkuit ini dapat menjelaskan banyak fitur non-motorik PD.

Faktor yang diyakini memainkan peran mendasar dalam perkembangan PD melibatkan kelainan protein yang disebut alpha-synuclein. Di otak normal, alpha-synuclein terletak di sel saraf dalam struktur khusus yang disebut terminal presinaptik. Terminal ini melepaskan neurotransmiter yang membawa sinyal antar neuron. Sistem pensinyalan ini sangat penting untuk fungsi otak normal.

Sementara fungsi alpha-synuclein normal terkait dengan penyimpanan dan pelepasan neurotransmitter, bukti menunjukkan penumpukan alpha-synuclein yang berlebihan dan abnormal memainkan peran kunci dalam perkembangan PD. Ada contoh langka dari keluarga di mana mutasi genetik tertentu pada alpha-synuclein telah terbukti menyebabkan protein alpha-synuclein salah lipat menjadi konfigurasi abnormal. Kebanyakan individu dengan PD tidak memiliki mutasi pada alpha-synuclein, tetapi bahkan ketika tidak ada mutasi, hampir setiap kasus PD dikaitkan dengan penumpukan alpha-synuclein yang abnormal dan salah lipatan. Saat protein yang salah melipat terakumulasi, ia menggumpal menjadi agregat, atau kumpulan, yang bergabung bersama untuk membentuk benang protein kecil yang disebut fibril. Fibril adalah blok bangunan untuk badan Lewy, struktur abnormal yang terbentuk di dalam sel saraf di substansia nigra dan di tempat lain di otak. Badan Lewy adalah ciri patologis PD. Penelitian menunjukkan bahwa penumpukan alpha-synuclein yang berbahaya dapat mempengaruhi fungsi normal dan memicu kematian sel saraf.

Tubuh Lewy ditemukan lebih dari 100 tahun yang lalu, dan masih ada pertanyaan yang belum terjawab tentang peran mereka dalam penyakit. Mereka ditemukan di otak hampir setiap pasien yang terkena PD, tetapi apakah tubuh Lewy sendiri berkontribusi pada kematian neuron masih belum jelas. Atau, akumulasi protein dalam badan Lewy mungkin menjadi bagian dari upaya yang gagal untuk melindungi sel dari toksisitas agregat alpha-synuclein.

Tujuan utama bagi para peneliti yang bergerak maju adalah untuk lebih memahami fungsi normal dan abnormal dari alpha-synuclein dan hubungannya dengan mutasi genetik yang berdampak pada PD.

Dalam dekade terakhir, peneliti yang didanai NINDS telah menemukan banyak tentang faktor genetik yang berkontribusi terhadap PD. Dalam kebanyakan kasus penyebab PD tidak diketahui, namun sebagian kecil kasus dapat dikaitkan dengan faktor genetik. Diperkirakan 15 hingga 25 persen orang dengan penyakit Parkinson memiliki riwayat keluarga dengan gangguan tersebut. Relatif jarang PD disebabkan oleh mutasi tunggal dari salah satu dari beberapa gen tertentu. Ini hanya menyumbang sekitar 30 persen kasus di mana ada riwayat keluarga PD dan hanya 3 sampai 5 persen kasus sporadis & kasus mdash tanpa riwayat keluarga yang diketahui.

Para peneliti semakin percaya bahwa sebagian besar, jika tidak semua, kasus PD mungkin melibatkan komponen genetik dan lingkungan. Penyakit Parkinson onset dini relatif jarang dan lebih mungkin dipengaruhi oleh faktor genetik daripada bentuk penyakit yang berkembang di kemudian hari.

Beberapa proyek NIH membantu membangun infrastruktur untuk penelitian genetika PD. Proyek Genom Manusia dan Proyek HapMap Internasional meletakkan dasar untuk penelitian ini, menghasilkan alat untuk membantu peneliti menemukan kontribusi genetik untuk penyakit umum. Dengan menggunakan alat ini, para peneliti mendukung Studi Asosiasi Genom Luas Penyakit Parkinson (PD-GWAS). Didanai oleh NINDS dan National Institute on Aging (NIA), upaya ini bertujuan untuk mendeteksi faktor risiko genetik untuk PD dari kelompok di seluruh dunia. Termasuk dalam PD-GWAS adalah data dari hampir 14.000 orang dengan PD dan lebih dari 95.000 orang tanpa PD. Dengan membandingkan kedua kelompok ini, peneliti dapat mengidentifikasi pola di daerah tertentu, atau lokus, genom manusia di mana gen yang menyebabkan atau meningkatkan risiko PD cenderung berada. Sama seperti kode pos, lokus genetik menggambarkan lingkungan umum gen.

Berdasarkan analisis data PD-GWAS dan sumber lain, para ilmuwan yang didanai NIH telah mengidentifikasi 28 lokus yang diyakini terkait secara independen dengan risiko PD dan lebih banyak lokus yang secara tentatif dikaitkan dengan gangguan tersebut.

Teknologi genetik generasi berikutnya telah menghasilkan sejumlah penemuan baru dan memungkinkan para ilmuwan mempelajari lebih lanjut tentang faktor genetik apa yang berkontribusi terhadap risiko pengembangan PD. Keberhasilan pertama adalah hasil dari genotipe konten tinggi, sebuah metode untuk mengidentifikasi varian umum dalam genom manusia. Saat ini, ada banyak kegembiraan mengenai sekuensing generasi berikutnya & metode sekuensing genetik yang memungkinkan pengurutan cepat pasangan basa DNA di lokus tertentu genom. Metode ini telah secara signifikan memangkas waktu dan biaya yang diperlukan untuk mengidentifikasi gen yang terlibat dengan PD dan akan terus memfasilitasi identifikasi gen terkait PD di masa depan.

Terobosan lain dalam pengurutan genetik adalah NeuroX, chip DNA pertama yang mampu mengidentifikasi varian genetik dalam genom seseorang untuk menentukan risiko pengembangan sejumlah penyakit neurodegeneratif onset lambat, termasuk PD. Sebuah usaha patungan antara NINDS dan penyelidik di NIA , chip NeuroX dikembangkan sebagai hasil dari lokakarya NINDS 2011. Lokakarya ini menghasilkan analisis data dari investigasi PD-GWAS di seluruh dunia. Studi tersebut membantu mengkorelasikan varian genetik dan sifat umum di antara orang-orang dengan PD, yang memungkinkan chip NeuroX.

Terlepas dari inovasi ini, diperlukan lebih banyak penelitian untuk mengidentifikasi gen terkait PD dan proses seluler yang didukungnya untuk memahami bagaimana fungsi ini berkontribusi pada timbulnya dan perkembangan PD. Variasi genetik umum saja tidak dapat sepenuhnya menjelaskan bagaimana genetika berkontribusi pada risiko pengembangan PD. Sebaliknya, para peneliti berhipotesis harus ada kontribusi genetik tambahan dari varian yang tidak cukup umum untuk dideteksi oleh investigasi PD-GWAS.

Mutasi Genetik yang Diketahui

PD yang diwariskan telah ditemukan terkait dengan mutasi pada sejumlah gen termasuk: SNCA, LRRK2, TAMAN2,TAMAN7, dan PINK1. Masih banyak lagi gen yang dapat diidentifikasi. Studi asosiasi genom telah menunjukkan bahwa varian umum dalam gen ini juga berperan dalam mengubah risiko kasus sporadis.

Mutasi pada jenis gen lain, termasuk GBA, gen di mana mutasi menyebabkan penyakit Gaucher's, tidak menyebabkan PD, tetapi tampaknya mengubah risiko berkembangnya kondisi tersebut pada beberapa keluarga. Mungkin juga ada variasi gen lain yang belum diidentifikasi yang berkontribusi pada risiko penyakit.

Pada tahun 1997, para ilmuwan mengidentifikasi mutasi genetik pertama (SNCA) terkait dengan PD di antara tiga keluarga yang tidak terkait dengan beberapa anggota yang terkena PD. NS SNCA gen memberikan instruksi untuk membuat protein alpha-synuclein, yang biasanya ditemukan di otak serta jaringan lain dalam tubuh. Menemukan mutasi ini mengarah pada penemuan bahwa agregat alpha-synuclein adalah komponen utama dari tubuh Lewy. Ini adalah contoh bagaimana mutasi langka penyebab penyakit dapat menjelaskan keseluruhan proses penyakit.

PD terkait dengan SNCA mutasi gen bersifat autosomal dominan, artinya hanya satu salinan gen yang bermutasi di setiap sel sudah cukup untuk mempengaruhi seseorang. Orang dengan mutasi ini biasanya memiliki orang tua dengan penyakit ini.

Meskipun lebih dari selusin mutasi di SNCA gen telah dikaitkan dengan PD, mutasi ini dianggap sebagai penyebab penyakit yang relatif jarang. Dalam beberapa kasus, SNCA mutasi gen diyakini menyebabkan protein alpha-synuclein gagal melipat. Lainnya SNCA mutasi membuat salinan tambahan gen, yang menyebabkan produksi protein alfa-synuclein yang berlebihan. Bahkan ketika tidak ada mutasi, penumpukan synuclein abnormal merupakan ciri khas PD. NINDS mendanai beberapa penelitian yang bertujuan untuk menentukan bagaimana tingkat alpha-synuclein yang salah lipat dan berlebihan dapat berkontribusi untuk mengembangkan PD.

Mutasi dari LRRK2 gen adalah penyebab genetik paling umum dari PD autosomal dominan. Mutasi ini berperan dalam sekitar 10 persen bentuk PD yang diturunkan dan sekitar 4 persen orang yang tidak memiliki riwayat penyakit dalam keluarga. Studi menunjukkan bahwa satu LRRK2 mutasi, G2019S, menyumbang hingga 20 persen PD dalam kelompok tertentu, seperti populasi Yahudi Ashkenazi.

Para peneliti masih mempelajari bagaimana tepatnya LRRK2 mutasi gen menyebabkan PD, tetapi tampaknya mutasi ini memengaruhi pembuatan dan pembuangan protein yang tidak diinginkan dalam berbagai cara. PD terkait dengan LRRK2 mutasi melibatkan bentuk awal dan akhir penyakit. NS LRRK2 gen adalah enzim kinase, sejenis protein yang menandai molekul di dalam sel dengan bahan kimia yang disebut gugus fosfat. Proses penandaan ini, yang disebut fosforilasi, mengatur enzim protein dengan mengubahnya menjadi &ldquoon&rdquo atau &ldquooff&rdquo dan ini sangat mendasar bagi fungsi dan kesehatan sel saraf dasar.

Penyelidik yang didukung NINDS di Pusat Udall di Universitas Johns Hopkins (JHU) telah menemukan bahwa: LRRK2 mutasi meningkatkan tingkat di mana protein gen menandai protein ribosom, komponen kunci dari mesin pembuat protein di dalam sel. Hal ini dapat menyebabkan mesin memproduksi terlalu banyak protein, yang menyebabkan kematian sel.

LRRK2 mutasi gen juga diyakini menghambat metode pembuangan limbah yang disebut autophagy, proses di mana sel memecah nutrisi, mendaur ulang komponen seluler, dan membuang limbah yang tidak dapat digunakan. Autophagy adalah sarana penting untuk kontrol kualitas dengan memungkinkan sel untuk menghilangkan organel yang rusak dan protein abnormal.

LRRK2 mutasi gen menghambat jenis autophagy yang disebut chaperone-mediated autophagy. Selama jenis autophagy ini, protein &ldquochaperone&rdquo mengawal protein yang rusak ke lisosom, vesikel bulat di dalam sel yang mengandung asam yang membantu memecah molekul yang tidak diinginkan. Akibatnya, LRRK2 mutasi gen dapat menyebabkan penumpukan alpha-synuclein menjadi agregat beracun di dalam sel. Para peneliti sedang mengeksplorasi apakah senyawa tertentu mungkin mampu menggantikan LRRK2 efek mutasi gen dengan me-reboot sistem pembuangan yang dimediasi pendamping.

  • Gen untuk parkin (TAMAN2)/ Gen untuk PTEN menginduksi putative kinase 1, atau PINK1 (TAMAN6)

TAMAN2 mutasi adalah mutasi genetik paling umum yang terkait dengan PD awitan dini, yang pertama kali muncul pada usia 50 tahun atau lebih muda. TAMAN6 mutasi gen juga dikaitkan dengan PD awitan dini, tetapi jauh lebih jarang. Kedua jenis mutasi dikaitkan dengan PD resesif autosomal, yang berarti bahwa dua salinan gen yang bermutasi hadir di setiap sel dan bahwa siapa pun yang terpengaruh mungkin memiliki orang tua yang tidak terpengaruh yang masing-masing membawa satu salinan gen yang bermutasi.

Temuan dari studi yang didanai NINDS menunjukkan bahwa orang dengan TAMAN2 mutasi cenderung memiliki perkembangan penyakit yang lebih lambat dibandingkan dengan mereka yang tidak membawa TAMAN2 mutasi.

Gen-gennya TAMAN2, TAMAN6, PINK1, bersama dengan protein parkin, semuanya terlibat di berbagai titik di sepanjang jalur yang mengontrol integritas mitokondria, pembangkit tenaga di dalam sel yang menghasilkan energi dengan mengatur proses kontrol kualitas. Sel-sel otak sangat energik dan bergantung pada suplai energi mitokondria. Secara khusus, parkin danPINK1 mengatur autophagy mitokondria & mdash proses yang dikenal sebagai mitofag. Proses ini sangat penting untuk menjaga kumpulan mitokondria yang sehat dengan menyediakan sarana untuk menghilangkan mitokondria yang tidak lagi berfungsi dengan baik.

Masih banyak pekerjaan yang harus dilakukan untuk memahami asosiasi TAMAN2 dan TAMAN6 mutasi dan disfungsi mitokondria, serta untuk menyelidiki apakah dan bagaimana disfungsi mitokondria menyebabkan PD. Bukti menunjukkan bahwa parkin dan PINK1 berfungsi bersama. Kapan PINK1 (yang terletak di mitokondria) merasakan kerusakan mitokondria, ia merekrut parkin untuk memulai proses mitofag.

Peneliti NINDS sedang mencari cara untuk merangsang PINK1/parkin jalur untuk mendorong mitofag. Para ilmuwan berharap ini akan membantu mereka mengembangkan perawatan untuk orang-orang dengan penyakit mitokondria, termasuk bentuk-bentuk PD tertentu. Selain itu, peneliti NINDS menyaring bahan kimia untuk mengidentifikasi agen yang mungkin dapat merangsang ekspresi PINK1, dan mencari gen lain yang dapat mempengaruhi fungsi PINK1 dan parkin.

Bukti menunjukkan bahwa parkin merupakan faktor dalam beberapa jalur tambahan yang mengarah ke PD, termasuk bentuk sporadis penyakit yang terkait dengan toksisitas alpha-synuclein.

NS TAMAN7 gen mengkode untuk protein DJ-1. Beberapa mutasi pada gen untuk DJ-1 dikaitkan dengan beberapa bentuk PD dini yang langka. Fungsi gen DJ-1 tetap menjadi misteri. Namun, satu teori adalah dapat membantu melindungi sel dari stres oksidatif. Stres oksidatif terjadi ketika molekul tidak stabil yang disebut radikal bebas terakumulasi ke tingkat yang dapat merusak atau membunuh sel. Beberapa penelitian menunjukkan bahwa gen DJ-1 memperkuat kemampuan sel untuk melindungi terhadap toksisitas logam dan bahwa fungsi pelindung ini hilang dalam beberapa mutasi DJ-1. Penelitian pada hewan menunjukkan DJ-1 berperan dalam fungsi motorik dan membantu melindungi sel dari stres oksidatif.

Mutasi pada gen yang mengkode enzim lisosom beta-glucocerebrosidase (GBA) berhubungan dengan gangguan penyimpanan lisosom, penyakit Gaucher. Orang dengan penyakit Gaucher juga lebih mungkin mengalami parkinsonisme, sekelompok gangguan saraf dengan gejala yang mirip dengan penyakit Parkinson. Hal ini mendorong para peneliti untuk mencari kemungkinan hubungan antara kedua penyakit tersebut. Peneliti yang didanai NIH telah melakukan penelitian terhadap individu dengan kedua gangguan untuk menilai perubahan otak mereka, riwayat keluarga, dan untuk menyaring jaringan dan sampel DNA, yang telah membantu mengkonfirmasi hubungan ini.

Sebuah studi multicenter yang dipimpin NIH yang melibatkan lebih dari 10.000 orang dengan dan tanpa PD menunjukkan bahwa orang dengan PD lebih dari 5 kali lebih mungkin untuk membawa GBA mutasi dibandingkan mereka yang tidak menderita penyakit. Pembawa mutasi juga lebih mungkin didiagnosis dengan PD lebih awal dalam hidup mereka dan memiliki riwayat keluarga dengan penyakit tersebut. Para ilmuwan telah mengamati bahwa penipisan beta-glucocerebrosidase menghasilkan akumulasi alpha-synuclein dan neurodegenerasi.

Penelitian lebih lanjut diperlukan untuk memahami hubungan antara GBA mutasi gen dan PD. NINDS mendukung banyak jalur penelitian yang menyelidiki peran GBA mutasi gen. Proyek ditujukan untuk memperkirakan risiko PD yang terkait dengan GBA pembawa dan mengidentifikasi sifat-sifat fenotipik.

Mempelajari gen yang bertanggung jawab atas kasus PD yang diturunkan dapat membantu menjelaskan kasus PD yang diwariskan dan sporadis. Gen dan protein yang sama yang diubah pada kasus PD yang diturunkan mungkin berperan dalam kasus penyakit yang sporadis. Dalam beberapa kasus, mutasi genetik mungkin tidak secara langsung menyebabkan PD tetapi dapat meningkatkan kerentanan berkembangnya penyakit, terutama jika ada racun lingkungan atau faktor lain.

Jalur Seluler dan Molekul ke PD

Apa yang terjadi di otak seseorang yang menyebabkan dia mengembangkan PD? Untuk menjawab pertanyaan ini para ilmuwan bekerja untuk memahami jalur seluler dan molekuler yang mengarah ke PD.

Disfungsi Mitokondria

Penelitian menunjukkan bahwa kerusakan mitokondria memainkan peran utama dalam perkembangan PD. Mitokondria adalah bagian unik dari sel yang memiliki DNA sendiri yang sepenuhnya terpisah dari gen yang ditemukan di inti setiap sel.

Disfungsi mitokondria adalah sumber utama radikal bebas & molekul mdash yang merusak membran, protein, DNA, dan bagian sel lainnya. Stres oksidatif adalah penyebab utama kerusakan oleh radikal bebas. Perubahan terkait stres oksidatif, termasuk kerusakan radikal bebas pada DNA, protein, mitokondria, dan lemak telah terdeteksi di otak individu dengan PD. Sejumlah gen yang ditemukan menyebabkan PD mengganggu proses pembuangan mitokondria yang rusak di dalam neuron (mitofag).

Untuk mempelajari lebih lanjut tentang bagaimana proses mitofag berhubungan dengan PD, para ilmuwan telah beralih ke interferensi RNA (RNAi), sebuah proses alami yang terjadi dalam sel yang membantu mengatur gen. Para ilmuwan dapat menggunakan RNAi sebagai alat untuk mematikan gen yang menarik untuk menyelidiki fungsinya dalam sel kultur atau model hewan PD. Sebuah teknik yang dikenal sebagai teknologi RNAi throughput tinggi memungkinkan para ilmuwan NIH untuk mematikan hampir 22.000 gen satu per satu. Proses ini membantu para ilmuwan mengidentifikasi lusinan gen yang mungkin mengatur pembersihan mitokondria yang rusak. Para peneliti terus mempelajari bagaimana gen ini mengatur penghapusan mitokondria yang rusak dari sel dan gen yang diidentifikasi dalam penelitian ini dapat mewakili target terapi baru untuk PD.

Salah satu mekanisme yang membantu mengatur kesehatan mitokondria adalah autophagy, yang memungkinkan pemecahan dan daur ulang komponen seluler. Para ilmuwan telah lama mengamati bahwa gangguan dalam proses autophagy dikaitkan dengan kematian sel di substansia nigra dan akumulasi protein di otak orang dengan PD serta penyakit neurodegeneratif lainnya.

Sistem Ubiquitin-proteasome

Area lain dari penelitian PD berfokus pada sistem ubiquitin-proteasome (UPS), yang membantu sel tetap sehat dengan menyingkirkan protein abnormal. Bahan kimia yang disebut ubiquitin bertindak sebagai &ldquotag&rdquo&rdquo yang menandai protein tertentu dalam sel untuk degradasi oleh proteasom, struktur di dalam sel yang meluncurkan reaksi kimia yang memutuskan ikatan peptida. Para peneliti percaya bahwa jika gejala pembuangan ini gagal bekerja dengan benar, racun dan zat lain dapat terakumulasi ke tingkat yang berbahaya, yang menyebabkan kematian sel. Penurunan UPS diyakini memainkan peran kunci dalam beberapa gangguan neurodegeneratif, termasuk penyakit Alzheimer, Parkinson, dan Huntington.

Kontribusi UPS terhadap perkembangan PD tampaknya multifaktorial, artinya UPS mempengaruhi interaksi beberapa gen. Peneliti yang didanai NINDS telah menemukan bahwa UPS sangat penting untuk degradasi alpha-synuclein yang salah lipatan dalam sel. Sebaliknya, bukti menunjukkan bahwa alpha-synuclein yang abnormal atau salah lipatan juga dapat menghambat berfungsinya UPS. Sebuah loop umpan balik mungkin ada dimana alpha-synuclein abnormal menghambat fungsi UPS, menyebabkan lebih banyak alpha-synuclein abnormal menumpuk dan penekanan tambahan aktivitas UPS. Peneliti yang didanai NINDS juga telah mengidentifikasi protein yang terakumulasi tanpa adanya parkin yang berkontribusi pada hilangnya neuron dopaminergik.

Beberapa peneliti yang didanai NINDS sedang menjajaki cara untuk meningkatkan fungsi UPS sebagai strategi terapi potensial.

Transmisi Sel ke Sel dari Protein yang Terlipat Secara Tidak Normal

Para peneliti telah belajar lebih banyak tentang bagaimana kerusakan terkait PD menyebar ke berbagai bagian otak dan sistem saraf. Sebuah pola karakteristik telah muncul di mana tubuh Lewy didistribusikan di berbagai wilayah otak. Perubahan otak paling awal tampaknya melibatkan badan Lewy di daerah batang otak (medulla oblongata dan pontine tegmentum, serta bulbus olfaktorius).

Pementasan braak adalah metode klasifikasi enam tingkat yang digunakan untuk mengidentifikasi derajat patologi postmortem akibat PD. Menurut klasifikasi ini, orang-orang di Braak tahap 1 dan 2 umumnya dianggap presimptomatik. Saat penyakit berkembang ke tahap Braak 3 dan 4, badan Lewy menyebar ke substansia nigra, area otak tengah, otak depan basal, dan neokorteks.

Bukti yang lebih baru menunjukkan bahwa bahkan sebelum perubahan otak seperti itu terjadi, agregat alfa-synuclein dan badan Lewy dapat ditemukan di sistem saraf saluran pencernaan dan di kelenjar ludah, sebuah temuan yang mendukung teori bahwa banyak PD tidak berasal dari otak tetapi dalam sistem saraf otonom. Gejala non-motorik seperti sembelit sebenarnya bisa menjadi tanda penyakit yang mempengaruhi saraf di luar otak sebelum penyakit itu pindah ke otak yang kemudian mempengaruhi daerah yang mengontrol gerakan.

Para peneliti di Udall Center di Perelman School of Medicine dari University of Pennsylvania menyuntikkan tikus dengan bentuk sintetis dari alpha-synuclein abnormal dan menemukan bahwa alpha-synuclein yang salah lipatan tampaknya menyebar ke seluruh otak. Para peneliti berhipotesis bahwa alpha-synuclein abnormal yang disuntikkan dapat bertindak seperti benih yang memicu alpha-synuclein tikus itu sendiri untuk salah lipat, yang mengarah ke transmisi sel ke sel perubahan otak seperti PD, terutama di daerah otak yang penting untuk fungsi motorik. Tikus juga menunjukkan gejala motorik seperti PD.

Memahami lebih lanjut tentang bagaimana protein abnormal menyebar melalui sistem saraf dapat memberikan jendela potensial untuk strategi terapeutik yang mengganggu proses transmisi protein dan memperlambat atau menghentikan perkembangan penyakit. Misalnya, peneliti yang didanai NINDS sedang melihat terapi kekebalan dan antibodi atau imunisasi terhadap alpha-synuclein, untuk memblokir transmisi PD di otak tikus.

Pengaruh lingkungan
Keadaan lingkungan diperkirakan mempengaruhi perkembangan PD. Paparan racun tertentu mungkin memiliki hubungan langsung dengan perkembangan PD. Ini adalah kasus di antara orang-orang yang terpapar MPTP, produk sampingan yang secara tidak sengaja diproduksi dalam pembuatan opioid sintetis dengan efek yang mirip dengan morfin. Selama tahun 1980-an, obat jalanan yang terkontaminasi zat ini menyebabkan sindrom yang mirip dengan PD. MPTP juga secara struktural mirip dengan beberapa pestisida. Otak mengubah MPTP menjadi MPP+, yang beracun bagi neuron substansia nigra. Paparan MPP+ menghasilkan parkinsonisme permanen yang parah dan telah digunakan untuk membuat model hewan PD.

Dalam kasus lain, paparan logam mangan di antara mereka yang bekerja di industri pertambangan, pengelasan, dan baja telah dikaitkan dengan peningkatan risiko parkinsonisme. Beberapa bukti menunjukkan bahwa paparan herbisida tertentu seperti paraquat dan maneb meningkatkan risiko PD. Para ilmuwan percaya bahwa ada faktor lingkungan lain yang belum diidentifikasi yang berperan dalam PD di antara orang-orang yang secara genetik rentan untuk mengembangkan penyakit ini.

Institut Nasional Ilmu Kesehatan Lingkungan (NIEHS) adalah lembaga utama di NIH yang menyelidiki hubungan antara PD dan pengaruh lingkungan seperti pestisida dan pelarut serta faktor-faktor lain seperti cedera otak traumatis. Misalnya, NIEHS mendanai sebuah proyek di University of Washington yang bertujuan mengembangkan dan memvalidasi biomarker untuk mengidentifikasi proses penyakit neurologis tahap awal yang terkait dengan agen beracun seperti bahan kimia, logam, dan pestisida. Model hewan sedang dikembangkan untuk mempelajari dampak pestisida pada pekerja pertanian dan logam pada tukang las profesional.

NIEHS juga mendanai studi Parkinson&rsquos, Genes & Environment. Studi ini dirancang untuk menentukan peran gen serta faktor makanan, gaya hidup, dan lingkungan terhadap risiko pengembangan PD dan potensinya untuk menyebabkan penyakit. Lebih dari 500.000 peserta studi awalnya direkrut pada tahun 1995 sebagai bagian dari National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. Peneliti akan terus mengikuti peserta dari waktu ke waktu untuk membahas beberapa teori paling menarik tentang penyebab PD. Already they have found, for example, that people who consume low levels of healthy dietary fats, such as those from fish, or high levels of saturated fats are more vulnerable to developing PD after being exposed to neurotoxins such as pesticides. The findings need to be confirmed, however, they suggest the possibility that diets rich in healthy fats and low in saturated fats may reduce the risk of PD.

The development of PD is a complex interplay between environmental, genetic, and lifestyle factors. Scientists are increasingly aware that in any given individual, there may be multiple factors that cause the disease.

In some cases, environmental factors may also have a protective effect. Population-based studies have suggested, for example, that people with high levels of vitamin D in their blood have a much lower risk of developing PD compared with people with very low concentrations of vitamin D. Further research is need to determine if vitamin D deficiency puts people at higher risk for PD, but such findings suggest the possibility that vitamin D supplements may have a beneficial effect. However, there may be genetic factors that cause people with low vitamin D levels to have higher rates of PD in which case vitamin D supplements would not be helpful.

To answer to this question, researchers at the Udall Center at the University of Miami are examining the pharmacogenetics of vitamin D. The investigators are studying a large dataset to confirm the finding that low levels of vitamin D is a risk factor for PD. At the same time, they are trying to identify any potential genetic modifiers of vitamin D&rsquos effect on PD risk.

Certain drugs and chemicals available as a supplement or in a person&rsquos diet also have been shown to have a neuroprotective effect for PD and other disorders. For example, regular use of caffeine (coffee, tea) was found to reduce the loss of dopamine-producing neurons. Studies hope to define the optimal caffeine dose in treating movement disorders like PD while gaining a better understanding of the mechanisms involving caffeine&rsquos benefit. Uric acid, because of its antioxidative effect, may lower the risk for multiple neurodegenerative disorders, in particular, PD. A preliminary clinical trial funded by the Michael J. Fox Foundation examined the effectiveness of the drug inosine to safely raise uric acid levels and possibly slow the progression of Parkinson&rsquos disease.

Neuroinflammation
Neuroinflammation is a protective biological response designed to eliminate damaged cells and other harmful agents in nervous system tissue. Mounting evidence suggests that neuroinflammation plays a role in PD. Several lines of research funded by the NINDS are investigating this connection.

Compared to people without PD, those with PD tend to have higher levels of pro-inflammatory substances known as cytokines in their cerebrospinal fluid. Immune cells in the brain called microglia also are more likely to be activated in the brains of individuals with PD. Epidemiological studies suggest that rates of PD among people who frequently use non-steroidal anti-inflammatory drugs (NSAIDS) are lower than in those who do not use NSAIDS.

Evidence from animal studies also suggests that elevated levels of the protein alpha-synuclein may trigger microglia to become activated in the brains of people with PD.

Currently, scientists are investigating whether inflammation itself is a cause of brain cell death or if it is a response to an already occurring process that contributes to the development of a disease. If researchers can interrupt the neuroinflammatory processes, they may be able to develop neuroprotective treatments for people with PD that prevent or slow the progression of the disease by halting, or at least reducing, the loss of neurons.

Models for Studying PD
Much of the research advancing our understanding and treatment of PD would not be possible without research models &mdash yeast, fruit flies, worms, fish, rodents, and non-human primates &mdash that have specific characteristics that mimic PD biology in humans. Scientists depend on these models to investigate questions about what goes wrong in PD, how cellular processes fit into the context of neuronal circuits, and how potential new treatments affect these disease processes.

The NINDS supports ongoing studies at the Udall Centers and elsewhere to refine existing research models and develop new ones. Better models are needed to more accurately mimic human disease in animals and to study PD&rsquos mechanisms and potential treatments. Currently, none of the models express all the key pathologic features of PD or reflect the complement of clinical motor and non-motor features of the disease in humans.

In addition to creating new animal models, NINDS-funded researchers also look for ways of combining different types of models (i.e., genetic and toxin-induced) to better understand the interplay between genetic and environmental factors that contribute to the development of PD.

Genetic Models
The identification of genetic mutations among some families with hereditary forms of PD led to the development of animal models (rodent, non-human primate, worm, and fly) engineered to have mutations or deletions of PD genes. Each model has its strengths and shortcomings in helping researchers study the disease.

For example, mice with SNCA mutations develop an adult-onset degenerative disease characterized by movement dysfunction and aggregation of alpha-synuclein, but these mice have no loss of dopaminergic neurons. Other mice have been engineered to express LRRK2 mutations, but show little evidence of PD symptoms. Fruit flies and worms engineered to overexpress LRRK2 exhibit reductions in motor abilities and loss of dopamine neurons, but they do not adequately reflect the disease as it occurs in humans.

Scientists have developed numerous models aimed at interrupting key cellular functions known to play a role in PD. For example, the MitoPark mouse model disrupts the functioning of the mitochondria, leading to some PD-like motor symptoms that respond to levodopa treatment.

Toxin-induced Models
For decades, the most widely used models for studying PD involved those in which toxins were used to induce PD-like motor symptoms. Such models were used to evaluate potential therapies. The first toxin-induced models relied on MPTP or the neurotoxin 6-hydroxydopamine to kill dopamine-producing neurons in the substantia nigra, causing PD-like motor symptoms. Later, researchers developed another type of model that examined how toxins interfered with the activities of mitochondria. Toxins for this purpose included the pesticide rotenone and the herbicides paraquat and maneb. Rats exposed to such toxins develop large inclusions in substantia nigra neurons that resemble Lewy bodies and contain alpha-synuclein and ubiquitin. The animals also developed bradykinesia, rigidity, and gait problems. Such toxin models are helpful for studying the consequences of dopamine depletion. However, they are limited in their ability to model the all the factors that cause PD in humans.

Induced Pluripotent Stem Cells
Genetic engineering is another mechanism for modeling some of the processes that go wrong in PD. Recently scientists developed a breakthrough modeling mechanism using induced pluripotent stem cells (iPSCs), which are cells that can become any type of cell in the body. Researchers take samples of skin, blood, hair follicles, or other types of tissue from a person with PD and then manipulate those cells to become iPSCs. These cells are then programmed to become dopaminergic neurons, making it possible for scientists to study the molecular and cellular mechanisms that lead to PD as well as potential treatments. NIH-funded researchers have also coaxed iPSCs to become tissue from other parts of the body such as the gastrointestinal tract and the heart, allowing them to study the mechanisms of PD in other regions of the body.

NINDS-funded researchers at the Udall Center at Johns Hopkins University have used iPSCs from people with PD as well as presymptomatic people who carry PARK6 atau LRRK2 genetic mutations to develop brain cells to study specific aspects of mitochondrial functioning. They also are testing potential ways of intervening to reverse mitochondrial dysfunction.

The ability to create neurons or other cell types from an individual with PD presents the possibility of providing a personalized treatment approach. iPSC-derived neurons may prove useful for testing the effectiveness of a drug before giving it to people with PD.

The NINDS created and supports an open-access repository of iPSCs from people who have genetic mutations associated with PD. Specimens in the repository are collected and characterized by a team of collaborating researchers at seven major institutions participating in the Parkinson&rsquos iPSC Consortium. The iPSCs are available through the NINDS Repository for researchers to study the causes of PD, as well as to screen potential drug therapies.


Hasil

Cohort demographics

Table 1 describes the demographics of the EMR and Claims based cohorts, stratified by the PD case status. The EMR dataset contained records from 22,102 individuals, while the Claims dataset contained records from 28,216 individuals. Age of first diagnosis was slightly higher in the Claims cohort but was over 70 in both datasets. Our cohorts align with accepted estimates of PD incidence in the population [26]. Population statistics between cases and matched controls largely align between the EMR and Claims data though the latter population is slightly younger (owing to the transfer of individuals above 65 to Medicare) and has more extended terms of coverage due to the nature of the data sources. EMR records only capture an individual’s interactions with that particular hospital system, while claims records capture all of an individual’s paid interactions while they were insured.

Parkinson’s disease trajectory is characterized by a prodromal period

We began by constructing two prediction algorithms, one linear and one non-linear, for future PD diagnosis utilizing 2 years of observations prior to the PD diagnosis in cases and matched controls. In contrast to prior models, we sequentially compared different time periods before the PD diagnosis date. We found a significant spike in prediction accuracy as the size of this window was reduced, which reached a maximum immediately prior to the PD diagnosis (Fig. 1a, b). We found that the accuracy of the deep neural network and a logistic regression model trained on identical claims data converged as the diagnosis date approached, implying that the most relevant signal for that time period was additive, with linear relationships between clinical events (diagnoses and procedures) driving predictions of PD status. In contrast, prediction accuracy at earlier time points appeared to be driven by non-linear, complex relationships between factors that only neural networks could resolve. The increase in performance closer to PD diagnosis date by both prediction models indicated the existence of a pre-diagnostic window during which motor symptoms were present but the diagnosis had not yet been made. Clinicians have described a time period immediately prior to diagnosis ranging between 3 months to 1 year [19] where PD is suspected and the patient is referred to neurologists or subjected to more rigorous clinical evaluation before a formal PD diagnosis is rendered. Consequently, the strong performance of classifiers that include this period may be illusory: the models draw signal from the actions of clinicians who already suspect PD. We find that the dominant features of this window include diagnoses of abnormality of gait, as well as diagnoses corresponding to tremor disorders (abnormal involuntary movements, essential tremor) (Table 2), which likely represent proxy diagnoses for PD prior to a neurologist or specialist confirming the diagnosis. Other features represent traditional, well-known, prodromal features of PD such as depression and constipation while others are less traditional such as malaise and fatigue, pain, and type 2 diabetes. To take advantage of these observations, we sought to construct models using diagnoses represented in Table 2 as new engagement points for deploying prediction models to then enable accelerated diagnosis of PD. We specifically selected gait and tremor disorders for the first set of engagement or index points for future analysis due to their comparatively extreme odds ratios. However, the remaining diagnoses, either alone or in combination, represent alternative points that could have been chosen.

Area under the ROC Curve predicting PD onset at various points prior to PD diagnosis. A Logistic Regression vs. Neural Network in Claims B EMR vs. Claims Logistic Regression

Gait and tremor disorders highlight PD differential diagnostic window

In order to better characterize the predictive implications and utility of this pre-diagnostic window, we examined the rates of different diagnoses relative to the PD diagnosis date corresponding to select phenotypes (Fig. 2): gait disorders, tremor disorders, constipation (a known prodromal symptom of PD), as well as a clinical event with little if any known physiological connection to PD: breast cancer screening (Supplementary Table 2). It was hypothesized that, after controlling for gender, the frequency of this clinical event among PD and non-PD patients would be roughly equivalent. Gait and tremor diagnoses were chosen based on their strength of association and the presence of sufficient patients to create PD classifiers indexed to their first diagnosis point. In the case of constipation, we found elevated rates of diagnosis prior to the PD diagnosis date, that steadily rise prior to and post PD diagnosis. A small spike at PD diagnosis is likely due to increased documentation at this critical inflection point in care. In contrast, constipation among PD controls increases more gradually over the whole window but is agnostic to the baseline date itself. This behavior is consistent with constipation’s role as a symptom of PD. Breast cancer testing, a test performed as a part of the standard of care, showed little variance between PD cases and controls throughout the entire window, consistent with the lack of evidence for a physiological association to PD. We find that gait and tremor disorders among PD cases slowly diverge from controls until a large spike approximately 1 year prior to the PD diagnosis and fall off in the years post diagnosis, likely due to their replacement with a PD code. This suggests that gait and tremor diagnoses are being used as proxy diagnoses in the runup to the PD diagnosis, consistent with the presence of a pre-diagnostic window.

Frequency of phenotypes relative to PD diagnosis date (cases)/matched baseline date (controls). Each point represents the frequency of the phenotype among the population in the year defined at the point: a tremor frequency of 0.08 at day 730 implies that 8.0% of PD cases had a tremor diagnosis between 730 and 365 days prior to their PD diagnosis. The data in subfigures represent the population diagnosed with a (A) gait disorder, B tremor disorders, C constipation, or D breast cancer testing. Details of the ICD/CPT codes associated with each subfigure are presented in Supplementary Table 2

Predicting Parkinson’s disease progression from first gait/tremor diagnosis

Based on the importance of gait and tremor diagnoses in the prediagnostic models and the above finding that they are widely used as proxies for a PD diagnosis, we constructed three new cohorts where baseline classification dates were defined as i) the diagnosis of first gait or tremor disorder, ii) the first diagnosis of gait disorder only, and iii) the first diagnosis of tremor disorder only. In all three cases, all subjects were gait/tremor naive prior to their baseline. Two years of features for each subject prior to the baseline were collected. The shift from a predictor based on a case-control study to a cohort study is useful in several ways. Not only are cohort studies considered a higher level of evidence [21], but the presence of a well-defined entry date allows for deployment of a predictor in clinical workflow. We used identical model architectures/parameters (both neural network and penalized logistic regression) for gait and tremor indexed models as for prediagnostic models (Fig. 1). The primary difference was the selection of the baseline point: a point in the future for the prediagnostic models, compared to a point at present for the gait/tremor models. We find that as the models are directed to focus on more specific cohorts, accuracy declines, in both claims and EMR, as well as between both logistic regression and deep neural network-based models (Table 4). The feature importance of both models trained on both data sources showed strong correlation (Pearson correlation of 0.71) between individual feature odds ratios. Furthermore, the logistic regression model trained over EMR generalized to the external Claims population with an AUC of 0.701 (95% CI: 0.698–0.704). The strongest predictor for future PD diagnosis for all three (gait or tremor, gait only, tremor only) cohorts was bipolar disorder (Table 4A, Supplementary Tables 3–4), an association that has been highlighted by other epidemiologic studies [27]. It is important to note that many Bipolar treatments (antipsychotic medications, valproic acid) are known to cause secondary Parkinsonism, which may be a reason underlying the high observed odds ratio. However, overall, the impact of bipolar on the accuracy of the model is low given the small affected population, with 2.6% of those eventually being diagnosed with PD. Other identified features align with what has previously been documented as potential risk factors for PD including major depressive disorder [28] and voice disturbance [29]. Progression into PD from gait disorders only was uniquely defined by a history of features such as urinary tract infection and chronic laryngitis, while progression from tremor disorders only was uniquely defined by parasomnia. While both gait and tremor are known to be early symptoms of PD, the distinction that the presence of these additional diagnoses may contribute towards risk in these cohorts and may indicate differences between two subsets of disease.

We examined the strongest performing model (Table 3A), the neural network predicting PD progression from either first gait or tremor in more depth (Tables 3B and 4). For this model, we examined the average days-in-advance that the model predicted PD for individuals who truly went on to experience a PD diagnosis on record at various false positive rate (FPR) thresholds. While the mean days saved declined slightly as the FPR threshold was increased, the average was still in excess of 300 days with an FPR rate of 0.01. This indicates that model performance is not dominated by individuals who immediately go on to develop PD after a gait or tremor diagnosis, and that among this selective cohort, early diagnosis is feasible.

Upon review of the results, we highlighted sets of diagnoses that were significantly different between the first prediagnostic model and the gait and tremor cohort model (Table 4B). In particular, the odds ratio directionality of anemia and hypotension reversed when evaluated in the presence of first gait/tremor, meaning that these diagnoses were no longer predictive of future PD. Similarly, while constipation is a known symptom of prediagnostic PD [26], it is less useful at predicting who will progress to PD from gait/tremor than in the original cohorts. These results suggest that distinct trajectories into PD may be present, including trajectories characterized by gait or tremor disorders. Further analysis motivated by these findings, outside the scope of this article, may be warranted to evaluate differential subtypes prior to a PD diagnosis. These findings also suggest that the controls defined in gait/tremor indexed cohorts represent a distinct population from traditionally defined PD controls, and that the true real-world PD progression prediction task is sensitive to the particular comparisons that a clinician is making.


ETIOLOGY

PD is a multifactorial disease, with both genetic and environmental factors playing a role. Age is the biggest risk factor for PD, with the median age of onset being 60 years of age (15). The incidence of the disease rises with age to 93.1 (per 100,000 person-years) in age groups between 70 and 79 years (16, 17). Additionally, there are cross-cultural variations, with higher prevalence reported in Europe, North America, and South America compared with African, Asian and Arabic countries (1).

Cigarette smoking

Cigarette smoking has been extensively studied with respect to PD, with mostly consistent results. Most of the epidemiological reports are case-control studies showing a reduced risk of developing PD, with larger cohort studies also in agreement (18�). A large meta-analysis including 44 case-control studies and 8 cohort studies from 20 countries showed an inverse correlation between smoking and PD, with a pooled relative risk of 0.39 for current smokers (21). Two other meta-analyses also reported an inverse correlation between smoking and PD, with a pooled odds ratio ranging from 0.23 to 0.70, indicating a protective mechanism against PD (22, 23). They also reported an inverse correlation between the number of pack years, the number of years smoking and the risk of PD, with the risk of developing PD being significantly reduced in heavy or long-term smokers compared with nonsmokers (23).

The reasons underlying this associated reduced risk are not fully understood. Activation of nicotinic acetylcholine receptors on dopaminergic neurons by nicotine or selective agonists has been shown to be neuroprotective in experimental models of PD (24, 25). Nevertheless, nicotine can also stimulate the release of dopamine, which is involved in the reward mechanisms it is therefore difficult to confirm whether smoking prevents PD or whether PD helps prevent the habitual use of cigarettes. As a result of a reduction in dopamine in patients with PD, patients may be less prone to addictive behaviours, and thus less likely to smoke. This hypothesis is supported by the fact that patients with prodromal PD and PD were able to give up smoking much easier than controls, suggesting this association could be due to the decreased responsiveness to nicotine (26).

Kafein

Several studies have investigated the effect of caffeine on the development of PD and reported a reduced risk of developing PD among coffee drinkers. Caffeine is an adenosine A2A receptor antagonist, which is believed to be protective in PD (27) and has been shown to be neuroprotective in a mouse model of PD (28). It has been previously reported that there is a 25% risk reduction in developing PD among coffee drinkers (14). Two large prospective epidemiological studies (27, 29), as well as multiple retrospective studies (30), have also shown a reduced risk of developing PD with a relative risk ranging from 0.45 to 0.80 in coffee drinkers versus non-coffee drinkers. A meta-analysis including eight case-control studies and five cohort studies also showed a significantly reduced risk of developing PD in coffee drinkers (RR 0.69) (21). Regular tea drinkers also have been reported to have a lower risk of developing PD (29).

As with smoking, the causative role of caffeine in preventing PD remains to be established. Furthermore, there were differences noted between studies with respect to gender. In two cohort studies (27, 29), there was a strong inverse correlation between coffee and the development of PD in men, whereas in women this association was weaker. Additionally, in post-menopausal women, the effect of caffeine depended on whether the females were taking hormone replacement therapy including estrogens. As estrogen competitively inhibits caffeine metabolism, interactions between estrogen and caffeine may explain in part why PD risk is dependent on hormone replacement therapy in post-menopausal women (31, 32).

Pesticides, herbicides, and heavy metals

In 1983, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was first discovered to be associated with nigrostriatal degeneration when several people developed typical PD signs after injecting themselves with a drug contaminated with MPTP. MPTP is metabolized into the neurotoxin, MPP+ (1-methyl-4-phenylpyridinium), which is a mitochondrial complex-I inhibitor that selectively damages dopaminergic cells in the substantia nigra (32, 33). The identification of MPTP as a cause of nigral degeneration led to the idea that PD could be caused by an environmental toxin. Since then, several studies have shown an association between pesticides and PD, with one case-control study showing an increased association with professional pesticide exposure in men and late-onset PD (odds ratio [OR] 2.2) (34). Paraquat (a herbicide which is structurally very similar to MPP+) (35) and rotenone (a pesticide) are also selective complex-I inhibitors and induce dopaminergic depletion in animal models of PD (36). The relationship between exposure to these chemicals and the risk of developing PD has been investigated in other epidemiological studies (37). It has also led to the study of surrogate markers, including the association of farming, drinking well water, and living in rural areas with PD risk. Welding and heavy metal exposure (e.g., iron, copper, lead, aluminum, and zinc) have also been investigated, but the relationship between these and PD remains inconclusive.

Genetika

Although PD is generally an idiopathic disorder, there is a minority of cases (10�%) that report a family history, and about 5% have Mendelian inheritance (38). Furthermore, an individual’s risk of PD is partially the product of as-yet poorly defined polygenic risk factors. The genes that have been found to potentially cause PD are assigned a “PARK” name in the order they were identified. To date, 23 PARK genes have been linked to PD. Mutations in the PARK genes demonstrate either autosomal dominant (e.g., SCNA, LRRK2, dan VPS32) or autosomal recessive inheritance (e.g., PRKN, PINK1, dan DJ-1) and are summarized in Table 1. The involvement of some of these genes has not been conclusively confirmed (PARK5, PARK11, PARK13, PARK18, PARK21, and PARK23), while others are considered risk factors (PARK3, PARK10, PARK12, PARK16, and PARK22) (39).

Table 1

PARK-designated genes involved in familial Parkinson’s disease.

The numerically most important genetic risk factors predisposing to PD are mutations in GBA1, a gene encoding β-glucocerebrosidase𠅊 lysosomal enzyme responsible for the hydrolysis of glucocerebrosides (see Chapter 3) (40). GBA1 mutations are known to cause Gaucher disease, which is the most common lysosomal storage disorder (41). Other genetic risk factors include the major histocompatibility complex, class II (HLA-DQB1) (42) and the gene encoding the protein tau, peta (43), among others.

Autosomal dominant PD

The first type of familial PD caused by a point mutation in the α-synuclein gene (SNCA) was discovered in 1997 (44). Four additional point mutations, as well as gene duplication or triplication, have now been linked to autosomal dominant PD (45�). However, these mutations are relatively rare. The most frequent autosomal dominant monogenic PD is caused by mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2). Enam LRRK2 mutations have been confirmed as pathogenic (51), the most common of which is p.G2019S, estimated to account for 1% of sporadic and 4% of familial PD worldwide (51). More recent genetic studies have led to the discovery of additional mutations in other genes responsible for autosomal dominant PD, including VPS35 (Tabel 1).

Autosomal recessive PD

Autosomal recessive forms of PD typically present with an earlier onset than classical PD. Three of the PARK-designated genes causing autosomal recessive PD have been linked to mitochondrial homeostasis (PRKN, PINK1, dan DJ-1). Specifically, the proteins PINK1 and parkin (encoded by the PRKN gene) are both involved in the same mitochondrial quality control pathway, with PINK1 recruiting parkin to dysfunctional mitochondria and thus initiating mitophagy (52). Mutasi di PRKN are the most common cause of autosomal recessive familial PD, occurring in up to 50% of all early-onset cases (39). Finally, several of the autosomal recessive genes have been linked to atypical parkinsonism with variable features (Table 1), including ATP13A2 (PARK9), PLA2G6 (PARK14), FBX07 (PARK17), and SYNJ1 (PARK20) (53�).


Klasifikasi

Tremors are classified as either resting or action (Table 1) .8 A rest tremor occurs in a body part that is relaxed and completely supported against gravity (e.g., when resting an arm on a chair). It is typically enhanced by mental stress (e.g., counting backward) or movement of another body part (e.g., walking), and diminished by voluntary movement of the affected body part.3 , 9 , 10 Most tremors are action tremors, which occur with voluntary contraction of a muscle. Action tremors can be further subdivided into postural, isometric, and kinetic tremors.8 , 9 A postural tremor is present while maintaining a position against gravity. An isometric tremor occurs with muscle contraction against a rigid stationary object (e.g., when making a fist). A kinetic tremor is associated with any voluntary movement and includes intention tremor, which is produced with target-directed movement.2

Broad Classification of Tremor

Occurs with voluntary contraction of muscle

Includes postural, isometric, and kinetic tremors

Occurs when the body part is voluntarily maintained against gravity

Includes essential, physiologic, cerebellar, dystonic, and drug-induced tremors

Occurs with any form of voluntary movement

Includes classic essential, cerebellar, dystonic, and drug-induced tremors

Subtype of kinetic tremor amplified as the target is reached

Presence of this type of tremor implies that there is a disturbance of the cerebellum or its pathways

Occurs in a body part that is relaxed and completely supported against gravity

Most commonly caused by parkinsonism, but may also occur in severe essential tremor

Adapted with permission from Leehey MA. Tremor: diagnosis and treatment . Primary Care Case Rev . 20014:34 .

Broad Classification of Tremor

Occurs with voluntary contraction of muscle

Includes postural, isometric, and kinetic tremors

Occurs when the body part is voluntarily maintained against gravity

Includes essential, physiologic, cerebellar, dystonic, and drug-induced tremors

Occurs with any form of voluntary movement

Includes classic essential, cerebellar, dystonic, and drug-induced tremors

Subtype of kinetic tremor amplified as the target is reached

Presence of this type of tremor implies that there is a disturbance of the cerebellum or its pathways

Occurs in a body part that is relaxed and completely supported against gravity

Most commonly caused by parkinsonism, but may also occur in severe essential tremor

Adapted with permission from Leehey MA. Tremor: diagnosis and treatment . Primary Care Case Rev . 20014:34 .

ESSENTIAL TREMOR

The most common pathologic tremor is essential tremor. In one-half of cases, it is transmitted in an autosomal dominant fashion, and it affects 0.4 to 6 percent of the population.4 , 8 Careful history reveals that patients with essential tremor have it in early adulthood (or sooner), but most patients do not seek help for it until 70 years of age because of its progressive nature. Despite being sometimes called �nign essential tremor,” essential tremor often causes severe social embarrassment, and up to 25 percent of those afflicted retire early or modify their career path.8

Essential tremor is an action tremor, usually postural, but kinetic and even sporadic rest tremors have also been described.3 , 11 It is most obvious in the wrists and hands when patients hold their arms in front of themselves (resisting gravity) however, essential tremor can also affect the head, lower extremities, and voice.12 It is generally bilateral, is present with a variety of tasks, and interferes with activities of daily living.1 , 5 In a series of 200 Italian patients referred to a neurologist for evaluation of tremor, 15 percent had uncommon clinical features that included postural, action, rest, orthostatic, and writing tremors, and 10 percent had tongue or facial dyskinesia.13

Diagnostic criteria have been proposed, but none have been accepted universally. Persons with essential tremor typically have no other neurologic findings therefore, it is often considered a diagnosis of exclusion.12 If the tremor responds to a therapeutic trial of alcohol consumption (two drinks per day), the diagnosis of essential tremor is assured.

PARKINSONISM

Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia, rigidity, and postural instability. Many patients will also have micrographia, shuffling gait, masked facies, and an abnormal heel-to-toe test.10 , 14 – 16 Causes of parkinsonism include brainstem infarction, multiple system atrophy, and medications that block or deplete dopamine, such as methyldopa, metoclopramide (Reglan), haloperidol, and risperidone (Risperdal).9 , 10 Idiopathic Parkinson disease is a chronic neurodegenerative disorder its prevalence increases with age. It is the most common cause of parkinsonism.17

More than 70 percent of patients with Parkinson disease have tremor as the presenting feature. The classic parkinsonian tremor begins as a low-frequency, pill-rolling motion of the fingers, progressing to forearm pronation/supination and elbow flexion/extension. It is typically asymmetric, occurs at rest, and becomes less prominent with voluntary movement. Although rest tremor is one of the diagnostic criteria for Parkinson disease, most patients exhibit a combination of action and rest tremors.3 , 11

ENHANCED PHYSIOLOGIC TREMOR

A physiologic tremor is present in all persons. It is a low-amplitude, high-frequency tremor at rest and during action that is not reported as symptomatic. This tremor can be enhanced by anxiety, stress, and certain medications and metabolic conditions. Patients with a tremor that comes and goes with anxiety, medication use, caffeine intake, or fatigue do not need further testing.1 , 8


Drug Treatment of Tremor

PARKINSONIAN TREMOR

Treatment of Parkinson's disease includes both medical and surgical intervention. Dopamine replacement therapy by means of levodopa clearly revolutionized the treatment of Parkinson's disease. Levodopa is almost exclusively given in combination with the peripheral decarboxylase inhibitor carbidopa (Sinemet). Carbidopa blocks the peripheral metabolism of levodopa to dopamine, decreasing the peripheral adverse effects of levodopa, such as nausea and vomiting, while increasing levodopa's availability in the brain.15 , 16 In addition to modulating the tremor associated with Parkinson's disease, levodopa improves bradykinesia, rigidity and other commonly associated symptoms. Carbidopa–levodopa is available in formulations of 10/100 mg, 25/100 mg and 25/250 mg. It is advantageous to begin treatment of mild disease with the 25/100-mg dosage, one tablet three times a day, and then increase the dosage as symptoms become less manageable.

When tremor is the predominant presenting symptom of Parkinson's disease or when tremor persists despite adequate control of other parkinsonian symptoms with low dosages of levodopa, an anticholinergic agent such as trihexyphenidyl (Artane) or benztropine (Cogentin) may be the treatment of choice. In most patients, however, anticholinergics do not significantly improve bradykinesia and rigidity. Trihexyphenidyl dosages necessary to improve tremor are between 4 and 10 mg per day (maximum: 32 mg), and useful benztropine dosages range from 1 to 4 mg per day. The side effects of these agents are their limiting factor, particularly in the elderly. Side effects include memory impairment, hallucinations, dry mouth, urinary difficulties and blurred vision.15

Other antiparkinsonian drugs𠅏or example, amantadine (Symmetrel), tolcapone (Tasmar) and dopamine agonists such as pergolide (Permax), bromocriptine (Parlodel), ropinirole (Requip) and pramipexole (Mirapex)𠅊re most helpful in patients whose tremor responds poorly to levodopa alone.

ESSENTIAL TREMOR

As with other tremors, effective treatment of essential tremor is not found in a single, universal agent. Some therapies may be satisfactory in some patients and ineffective in others. The most widely used drugs for essential tremor are the beta-adrenergic blocker propranolol (Inderal) and the anticonvulsant primidone (Mysoline). The typical dosage range for propranolol is 80 to 320 mg per day and for primidone, 25 to 750 mg per day.3 Other beta-adrenergic receptor antagonists used in the treatment of essential tremor include metoprolol (Lopressor) and nadolol (Corgard).2 Alcohol is also effective in relieving essential tremor, but abuse may be an adverse consequence.3

In our experience, propranolol and primidone are equally effective in the treatment of essential tremor. Patients who do not respond to one medication after a few weeks of therapy should be tried on the other one. Primidone may be preferred, because of the exercise intolerance associated with high-dose beta blockade. Patients who have a very-low-amplitude rapid tremor are generally more responsive to these agents than those who have a slower tremor with greater amplitude. Patients who have tremor of the head and voice may also be more resistant to treatment than patients with essential tremor of the hands.

OTHER TREMORS

There is no established treatment for cerebellar tremor.2 In patients with multiple sclerosis, severe cerebellar tremor may be improved with isoniazid, in a dosage of 600 to 1,200 mg per day, given together with pyridoxine.4

Propranolol in a dosage of 160 mg per day is very effective in reducing the tremor associated with alcohol withdrawal.10

Treatment of orthostatic tremor should first be attempted with clonazepam (Klonopin). In one small study,14 eight of nine patients responded to clonazepam in dosages ranging from 0.5 to 2.0 mg per day. The patient who did not respond to clonazepam responded to chlordiazepoxide (Librium), in a dosage of 30 mg twice a day. In another study,12 10 of 18 patients had sustained improvement with clonazepam, and valproic acid was effective in the remaining eight patients. However, propranolol in daily dosages of up to 320 mg had no effect on controlling orthostatic tremor.

Tremor due to peripheral neuropathy may be ameliorated with propranolol, primidone, benzodiazepines or baclofen (Lioresal), but the underlying cause of the neuropathy itself should be treated as well.2

Other medications have been shown to be helpful in the management of tremor but should probably only be tried in consultation with a neurologist, when the previously mentioned drugs have failed to control the tremor.


Motor symptoms in Parkinson's disease

This chapter reviews the pathophysiological mechanisms and the clinical features of motor manifestations of Parkinson's disease (PD). The most typical and easily recognized symptom of PD is unilateral, 4–6 Hz, rest tremor. This is differentiated from the typical 5–8 Hz postural tremor of essential tremor (ET), enhanced physiologic tremor (8–12 Hz), and cerebellar outflow tremor (2–5 Hz). The rest tremor characteristically disappears with action (a feature differentiating it from ET) and during sleep. Stimulation of the subthalamic nucleus (STN), which is typically hyperactive in PD, can also normalize the amplitude and frequency of PD tremor towards physiologic ranges. In PD, the rigidity is usually accompanied by a “cogwheel” phenomenon, probably a manifestation of underlying tremor. Rigidity often increases with reinforcing maneuvers such as voluntary movements of the contralateral limb. This examination technique can greatly assist in the diagnosis of early PD, as the rigidity is ipsilateral to the rest tremor, if present.


Ringkasan

Parkinson's disease is a recognisable clinical syndrome with a range of causes and clinical presentations. Parkinson's disease represents a fast-growing neurodegenerative condition the rising prevalence worldwide resembles the many characteristics typically observed during a pandemic, except for an infectious cause. In most populations, 3–5% of Parkinson's disease is explained by genetic causes linked to known Parkinson's disease genes, thus representing monogenic Parkinson's disease, whereas 90 genetic risk variants collectively explain 16–36% of the heritable risk of non-monogenic Parkinson's disease. Additional causal associations include having a relative with Parkinson's disease or tremor, constipation, and being a non-smoker, each at least doubling the risk of Parkinson's disease. The diagnosis is clinically based ancillary testing is reserved for people with an atypical presentation. Current criteria define Parkinson's disease as the presence of bradykinesia combined with either rest tremor, rigidity, or both. However, the clinical presentation is multifaceted and includes many non-motor symptoms. Prognostic counselling is guided by awareness of disease subtypes. Clinically manifest Parkinson's disease is preceded by a potentially long prodromal period. Presently, establishment of prodromal symptoms has no clinical implications other than symptom suppression, although recognition of prodromal parkinsonism will probably have consequences when disease-modifying treatments become available. Treatment goals vary from person to person, emphasising the need for personalised management. There is no reason to postpone symptomatic treatment in people developing disability due to Parkinson's disease. Levodopa is the most common medication used as first-line therapy. Optimal management should start at diagnosis and requires a multidisciplinary team approach, including a growing repertoire of non-pharmacological interventions. At present, no therapy can slow down or arrest the progression of Parkinson's disease, but informed by new insights in genetic causes and mechanisms of neuronal death, several promising strategies are being tested for disease-modifying potential. With the perspective of people with Parkinson's disease as a so-called red thread throughout this Seminar, we will show how personalised management of Parkinson's disease can be optimised.


Tonton videonya: What are Motor symptoms in Parkinsons Disease? Neuroaholics (Oktober 2022).