The amyloid plaque found in Alzheimer's disease (AD) are made of beta amyloid, a protein fragment snipped from a larger protein called amyloid precursor protein. These fragments clump together and are mixed with other molecules, neurons, and non-nerve cells. In AD, plaques develop in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are used in thinking and making decisions. 

Beta amyloid plays a central role in the development of AD. Its insights let us understand the effects of cholesterol and apolipoprotein E on AD. The early-onset familial AD that occurs between the ages of 30 and 60 has also been demonstrated to result from mutations of the genes involved in the production of beta amyloid. For this reason, beta amyloid is an important target in the development of new drugs against AD.

From APP to Beta Amyloid (A)

The amyloid precursor protein (APP) appears to be important in helping neurons grow and survive. APP may help damaged neurons repair themselves and may help parts of neurons grow after brain injury. After it is made, APP sticks through the neuron's membrane, partly inside and partly outside the cell.

The beta amyloid (A) is generated by two enzymes which cut APP at two different positions:  -secretase cuts APP at a position outside the cell and  -secretase cuts APP at a position inside the cell membrane. The resulting Apeptide contains about 40 amino acids.

The -secretase lacks sequence specificity. Its cleavage site may shift slightly, depending on the molecular structure of the enzyme and its environment. As a result, the length of A ranges from 39 to 43 amino acids. It has been found that the longer one is more likely to form plaques than the shorter one. Researchers usually use two A peptides to compare their toxicities: A with 40 amino acids (represented as A40) and A with 42 amino acids (represented as A42). A42 is more toxic than A40.

The Toxicity of A

Individual Apeptides can be cleared away by degradative enzymes such as  insulin-degrading enzyme, neprilysin, and plasmin. After they aggregate to form plagues, they are difficult to be removed. The plagues may induce inflammatory responses, creating oxygen free radicals. In addition, they may promote the formation of neurofibrillary tangles, resulting in cell death (more info).

In a normal brain, A40 is produced at higher level than A42. However, the amyloid plaque in Alzheimer's disease is composed primarily of A42. Experiments have also

shown that A42 aggregates more rapidly than A40, consistent with other observations that A42 is more toxic than A40.

AD Genetics and A

Four genes have been conclusively shown to affect the development of Alzheimer's disease: the APP gene on chromosome 21, the PS1 gene on chromosome 14, the PS2 gene on chromosome 1, and the apoE gene on chromosome 19. Mutations of APP, PS1 and PS2 genes are linked to the rare early-onset form of familial AD. Many people with Down's syndrome also develop AD-like dementia by the age of 40. They have three copies of chromosome 21 (where the APP gene is located), instead of two for normal people.

The APP gene encodes the precursor protein to beta amyloid. One more copy of the APP gene in people with Down's syndrome should make more precursor proteins, thereby producing more A peptides. Mutations of the APP gene in the early-onset AD either increase the total level of A peptides or favor the production of A42 (more info). Both cases increase the chance of forming amyloid plaques.

PS1 and PS2 genes encode presenilin 1 and presenilin 2, respectively. They are the components of the -secretase, which cleaves APP to generate A. Their mutations favor the production of A42.

The apoE gene enclodes apolipoprotein E (apoE) which helps carry cholesterol in the blood. The effects of apoE and cholesterol on beta amyloid are discussed in a separate page.

 

F00 DEMENSIA PADA PENYAKIT ALZHEIMER

Pedoman Dianostik• Terdapatnya gejal demesia.• Onset bertahap(insidious onset) dengan deteriorasi lambat.Onset biasanya sulit ditentukan waktunya yang persis, tiba-tiba orang lain sudah menyadari adanya kelainan tersebut. Dalam perjalanan penyakitnya dapat terjadi suatu taraf stabil (plateu) secara nyata.• Tidak adanya bukti klinis, atau temuan dari pemeriksaan khusus, yang menyatakan bahwa kondisi mental itu dapat disebabkan oleh penyakit otak atau sistemik lain yang dapat menimbulkan demensia (misalnya hipotiroidisme, hiperkalsemia, defisiensi vitamin B12, defisiensi niasin, neurosifilis, hidrosefalus bertekanan normal, atau hematoma subdural).• Tidak adanya serangan apoleptik mendadak, atau gejal neurologic kerusakan otak fokal seperti hemiparesis, hi;angnya daya sensorik, defek lapangan pandang mata, dan inkoordinasi yang terjadi pada masa dini dari gangguan itu (walaupun fenomena ini kemudian hari dapat tumpang tindih).

Diagnosis banding• Gangguan depresif (F30-F39): (+)/(-) gejala somatik, terdapat perubahan aktivitas (↑ pada manic, ↓ pada hipomanik)• Delirium (F05): terdapat gangguan kesadaran(berkabut-koma), gangguan psikomotor(kadang ↑, kadang ↓), gangguan siklus tidur bangun (nightmare-insomnia)• Sindroma amnestik organic (F04): ↓ daya ingat short term memory, amnesia (antegrad/retrograd), atesia dan kesadaran masih baik, terdapat cedera pada otak.• Demensia primer pada penyakit lain YDK (F02.-): gangguan perilaku terlebih dahulu lalui diikuti gangguan daya ingat & terdapat atrofi pada lobus frontalis• Demensia sekunder penyakit lain YDK (F02.8): terdapat gejala somatic dan gangguan serebral lainnya.• Retardasi mental (F70-F72): ↓ IQ (ringan 50-69 atau sedang 35-45), gangguan bahasa, sangat jarang diakibatkan oleh gangguan organik, autistic thingking & terdapat gangguan perilaku• Demensia Alzheimer + Vaskuler (F00.2)

Multiaksial:AKSIS I : F00.0 Demensia pada penyakit Alzheimer onset diniF00.1 Demensia pada penyakit Alzheimer onset lambatF00.2 Demensia pada penyakit Alzheimer, Tipe tak khas atau Tipe Campuran (atypical or mixed type)F00.9 Demensia pada penyakit Alzheimer YTT (unspecified)

KONDISI LAIN YANG MENJADI FOKUS PERHATIAN KLINISR41.8 Penurunan fungsi kognitif berkaitan dengan usiaAKSIS II :AKSIS III : Tidak ada (none)AKSIS IV : Masalah dengan “primary support group” (keluarga)AKSIS V : Awal→ 40-31, beberapa disabilitas dalam hubugan dgn realita & komunikasi, disbilitas berat dalam beberapa fungsiAkhir → 30-21, disabilitas berat dalam komunikasi & daya nilai, tidak mampu berfungsi hampir semua bidang

F00.0 Demensia pada penyakit Alzheimer onset diniPedoman diagnostik• Dimensia yang onsetnya sebelum usia 65 tahun• Perkembangn gejala cepat dan progresif (deteriorasi)• Adanya riwayat keluarga yang berpenyakit Alzheimer merupakan faktor yang menyokong diagnosis etapi tidak harus dipenuhi

F00.1 Demensia pada penyakit Alzheimer onset lambatSama tersebut di atas, hanya onsetnya sesudah usia 65 tahun dan perjalanan penyakit yang lamban dan biasanya dengan gangguan daya ingat sebagai gamabran utamanya.

F00.2 Demensia pada penyakit Alzheimer, Tipe tak khas atau Tipe Campuran (atypical or mixed type)Yang tidak cocok dengan pedoman untuk F00.0 atau F00.1, tipe campuran adalah dementia Alzheimer + vaskular

Diagnosis

Alzheimer

a. DefinisiDementia progresif yang terjadi pada usia dewasa menengah atau lansia ditandai dengan ↓daya ingat jangka pendek, deteriorasi intelektul & perilaku, dan lambat berpikir.

b. Epidemiologi• Lansia• Perempuan > pria

c. Etiologi• Genetik: autosomal dominan, early onset kromosom 21q & late onset kromosom19, sporadic pada kromosom6• gangguan fungsi imunitas• infeksi virus: terdapat antibodi reaktif & neurofibrillary tangles (NFT) (x: penyakit Creutzfeldt-Jacob & Kuru)→ plak amiloid SSP→ gagangguan fungsi luhur• lingkungan:o polusi udara/industryo intoksikasi logamx: alanin, aluminium, silikon, merkuri, zinc,asam amino glutamat• trauma: ditemukan banyak neurofibrillary tangles• defisit formasi sel-sel• filament• imunologis: (+) kelainan serum protein →albumin ↓, α-protein↑, anti trypsin alphamarcoglobuli dan haptoglobuli• neurotransmitter:1. asetilkolin2. noradrenalin

3. dopamin masih kontroversial4. serotonin5. MAO (monoamino oxidase)

d. Manifestasi klinisGejala umum:1. Kehilangan daya ingat/memori, terutama memori jangka pendek. Pada orang tua normal, dia tidak ingat nama tetangganya, tetapi dia tahu orang itu adalah tetangganya. Pada penderita Alzheimer, dia bukan saja lupa nama tetangganya tetapi juga lupa bahwa orang itu adalah tetangganya.2. Kesulitan melakukan aktivitas rutin yang biasa, seperti tidak tahu bagaimana cara membuka baju atau tidak tahu urutan-urutan menyiapkan makanan.3. Kesulitan berbahasa.Umumnya pada usia lanjut didapat kesulitan untuk menemukan kata yang tepat, tetapi penderita Alzheimer lupa akan kata-kata yang sederhana atau menggantikan suatu kata dengan kata yang tidak biasa.4. Disorientasi waktu dan tempat.Kita terkadang lupa kemana kita akan pergi atau hari apa saat ini, tetapi penderita Alzheimer dapat tersesat pada tempat yang sudah familiar untuknya, lupa di mana dia saat ini, tidak tahu bagaimana cara dia sampai di tempat ini, termasuk juga apakah saat

ini malam atau siang.5. Penurunan dalam memutuskan sesuatu atau fungsi eksekutif, misalnya tidak dapat memutuskan menggunakan baju hangat untuk cuaca dingin atau sebaliknya.6. Salah menempatkan barang.Seseorang secara temporer dapat salah menempatkan dompet atau kunci. Penderita Alzheimer dapat meletakkan sesuatu pada tempat yang tidak biasa, misal jam tangan pada kotak gula.7. Perubahan tingkah laku.Seseorang dapat menjadi sedih atau senang dari waktu ke waktu. Penderita Alzheimer dapat berubah mood atau emosi secara tidak biasa tanpa alasan yang dapat diterima.8. Perubahan perilakuPenderita Alzheimer akan terlihat berbeda dari biasanya, ia akan menjadi mudah curiga, mudah tersinggung, depresi, apatis atau mudah mengamuk, terutama saat problem memori menyebabkan dia kesulitan melakukan sesuatu.9. Kehilangan inisiatifDuduk di depan TV berjam-jam, tidur lebih lama dari biasanya atau tidak menunjukan minat pada hobi yang selama ini ditekuninya.

Karakteristik dementia pada Alzheimer1. Predementia:• Gangguan kognitif ringan -8 tahun sebelum diagnosis ditegakkan• Defisit memori• apatis

2. Demensia onset awal• ↑ gangguan learning & memori• Gangguan bahasa, ↓ kosakata & kata, ↓ kemampuan bahasa oral & tulisan• Gangguan persepsi (agnosia)• Gangguan gerakan (apraxia)• Terlihat bodoh• Kurang inisiasi untuk melakukan aktivitas

3. Dementia moderat• Deteriorasi progresif• Tidak mampu membaca & menulis• Gangguan long-term memory• Subtitusi penggunaan kata (parafasia)• Misidentifikasi• Labil• Mudah marah• Delusi• Inkontinen system urinaria

4. Dementia tahap lanjut (advanced)• Tidak dapat mengurus diri secara• Kehilangan kemampuan verbal total

• Agresif• Apatis ekstrim• Deteriorasi massa otot & mobilitas• Kehilangan kemampuan untuk makan

Berdasarkan stadium:Stadium I (lama penyakit 1-3 tahun)• Memori : defek daya ingat baru (leaning), gangguan recall ringan• Kemampuan Visuospatial : disorientasi topografi, tidak mampu membentuk komplex• Bahasa : sulit membentuk kata baru, anomia• Personalitas : indiferens,kadang-kadang mudah marah• Manifestasi psikiatri: sedih atau beberapa delusi• Sistem motorik : normal• EEG : normal• CT/MRI : normal• PET/SPECT : bilateral posterior hypometabolism/hyperfusion

Stadium II (lama penyakit 3-10 tahun)• Memori : daya ingat baru (leaning) & gangguan recall berat• Kemampuan Visuospatial: disorientasi spasial, poor contructions• Bahasa : fluent aphasia• kalkulasi : akalkulation• Personality : indiferens & mudah marah• Manifestasi psikiatri: delusi• Sistem motorik: restlessness, pacing• EEG : slow background rhythm• CT/MRI : normal or ventricular and sulcal enlargeent• PET/SPECT : bilateral parietal and frontal hypometabolism/hyperfusion

Stadium III (lama penyakit 8-12 tahun)• Intelectual function : severely deteriorated• Motor system : limb rigidity and flexion poeture• Sphincter control : urinary and fecal• EEG : diffusely slow• CT/MRI : ventricular and sulcal enlargeent• PET/SPECT : bilateral parietal and frontal hypometabolism/hyperfusion

e. Patofisiologi

f. Cara menegakkan diagnosisTerdapat beberapa kriteria untukdiagnosa klinis penyakit alzheimer yaitu:1. Kriteria diagnosis tersangka penyakit alzheimer terdiri dari:• Demensia ditegakkan dengan pemeriksaan klinik dan pemeriksaan status mini mental atau beberapa pemeriksaan serupa, serta dikonfirmasikan dengan test neuropsikologik• Didapatkan gangguan defisit fungsi kognisi >2• Tidak ada gangguan tingkat kesadaran• Awitan antara umur 40-90 tahun, atau sering >65 tahun• Tidak ada kelainan sistematik atau penyakit otak lainnya2. Diagnosis tersangka penyakit alzheimer ditunjang oleh:• Perburukan progresif fungsi kognisi spesifik seperti berbahasa, ketrampilan motorik, dan persepsi• ADL terganggu dan perubahan pola tingkah laku• Adanya riwayat keluarga, khususnya kalau dikonfirmasikan dengan neuropatologi• Pada gambaran EEG memberikan gambaran normal atau perubahan non-spesifik seperti peningkatan aktivitas gelombang lambat• Pada pemeriksaan CT Scan didapatkan atropi serebri3. Gambaran lain tersangka diagnosa penyakit alzheimer setelahdikeluarkan penyebab demensia lainnya terdiri dari:• Gejala yang berhubungan dengan depresi, insomnia, inkontinentia, delusi, halusinasi, emosi, kelainan seksual, berat badan menurun• oKelainan neurologi lain pada beberapa pasien, khususnya penyakit padastadium lanjut dan termasuk tanda-tanda motorik seperti peningkatan tonus otot, mioklonus atau gangguan berjalan• Terdapat bangkitan pada stadium lanjut4. Gambaran diagnosa tersangka penyakit alzheimer yang tidak jelasterdiri dari:• Awitan mendadak• Diketemukan gejala neurologik fokal seperti hemiparese, hipestesia, defisit lapang pandang dan gangguan koordinasi

• Terdapat bangkitan atau gangguan berjalan pada saat awitan5. Diagnosa klinik kemungkinan penyakit alzheimer adalah:• Sindroma demensia, tidak ada gejala neurologik lain, gejala psikiatri atau kelainan sistemik yang menyebabkan demensia• Adanya kelainan sistemik sekunder atau kelainan otak yang menyebabkan demensia, defisit kognisi berat secara gradual progresif yang diidentifikasi tidak ada penyebab lainnya

6. Kriteria diagnosa pasti penyakit alzheimer adalah gabungan dari kriteria klinik tersangka penyakit alzheimer dab didapatkan gambaran histopatologi dari biopsi atau otopsi:• autopsi tampak bagian otak mengalami atropi yang difus dan simetri,• secara mikroskopik tampak bagian kortikal otak mengalami neuritis plaque dan degenerasi neurofibrillary

PEMERIKSAAN PENUNJANG1. NeuropatologiDiagnosa definitif tidak dapat ditegakkan tanpa adanya konfirmasi neuropatologi. Secara umum didapatkan:• atropi yang bilateral, simetris lebih menonjol pada lobus temporoparietal, anterior frontal, sedangkan korteks oksipital, korteks motorik primer, sistem somatosensorik tetap utuh• berat otaknya berkisar 1000 gr (850-1250gr).Kelainan-kelainan neuropatologi pada penyakit alzheimer terdiri dari:a. Neurofibrillary tangles (NFT)Merupakan sitoplasma neuronal yang terbuat dari filamen-filamen abnormal yang berisi protein neurofilamen, ubiquine, epitoque. Densitas NFT berkolerasi dengan beratnya demensia.

b. Senile plaque (SP)Merupakan struktur kompleks yang terjadi akibat degenerasi nerve ending yang berisi filamen-filamen abnormal, serat amiloid ektraseluler, astrosit, mikroglia. Amloid prekusor protein yang terdapat pada SP sangat berhubungan dengan kromosom 21. Senile plaque ini terutama terdapat pada neokorteks, amygdala, hipokampus, korteks piriformis, dan sedikit didapatkan pada korteks motorik primer, korteks somatosensorik, korteks visual, dan auditorik. Senile plaque ini juga terdapat pada jaringan perifer. densitas Senile plaque berhubungan dengan penurunan kolinergik.Kedua gambaran histopatologi (NFT dan senile plaque) merupakan gambaran karakteristik untuk penderita penyakit alzheimer.

c. Degenerasi neuronPada pemeriksaan mikroskopik perubahan dan kematian neuron pada penyakit alzheimer sangat selektif. Kematian neuron pada neokorteks terutama didapatkan pada neuron piramidal lobus temporal dan frontalis. Juga ditemukan pada hipokampus, amigdala, nukleus batang otak termasuk lokus serulues, raphe nukleus dan substanasia nigra. Kematian sel neuron kolinergik terutama pada nukleus basalis dari meynert, dan sel noradrenergik terutama pada lokus seruleus serta sel serotogenik pada nukleus raphe dorsalis, nukleus tegmentum dorsalis. Telah ditemukan faktor pertumbuhan saraf pada neuron kolinergik yang berdegenerasi pada lesi merupakan harapan dalam pengobatan penyakit alzheimer.

d. Perubahan vakuolerMerupakan suatu neuronal sitoplasma yang berbentuk oval dan dapat menggeser nukleus. Jumlah vakuoler ini berhubungan secara bermakna dengan jumlah NFT dan SP , perubahan ini sering didapatkan pada korteks temporomedial, amygdala dan insula. Tidak pernah ditemukan pada korteks frontalis, parietal, oksipital, hipokampus, serebelum dan batang otak.

e. Lewy bodyMerupakan bagian sitoplasma intraneuronal yang banyak terdapat pada enterhinal, gyrus cingulate, korteks insula, dan amygdala. Sejumlah kecil pada korteks frontalis, temporal,

parietalis, oksipital. Lewy body kortikal ini sama dengan immunoreaktivitas yang terjadi pada lewy body batang otak pada gambaran histopatologi penyakit parkinson. Hansen et al menyatakan lewy body merupakan variant dari penyakit alzheimer.

2. Pemeriksaan neuropsikologikPenyakit alzheimer selalu menimbulkan gejala demensia.• Fungsi pemeriksaan neuropsikologik ini untuk menentukan ada atau tidak adanya gangguan fungsi kognitif umum danmengetahui secara rinci pola defisit yang terjadi.• Test psikologis ini juga bertujuan untuk menilai fungsi yang ditampilkan oleh beberapa bagian otak yang berbeda-beda seperti gangguan memori, kehilangan ekspresi, kalkulasi, perhatian dan pengertian berbahasa.Evaluasi neuropsikologis yang sistematik mempunyai fungsi diagnostik yang penting karena:a. Adanya defisit kognisi: berhubungan dgn demensia awal yang dapat diketahui bila terjadi perubahan ringan yang terjadi akibat penuaan yang normal.b. Pemeriksaan neuropsikologik secara komprehensif : untuk membedakan kelainan kognitif pada global demensia dengan deficit selektif yang diakibatkan oleh disfungsi fokal, faktor metabolik, dan gangguan psikiatric. Mengidentifikasi gambaran kelainan neuropsikologik yang diakibatkan oleh demensia karena berbagai penyebab.

The Consortium to establish a Registry for Alzheimer Disease (CERALD) menyajikan suatu prosedur penilaian neuropsikologis dengan mempergunakan alat batrey yang bermanifestasi gangguan fungsi kognitif, dimana pemeriksaannya terdiri dari:1. Verbal fluency animal category2. Modified boston naming test3. mini mental state4. Word list memory5. Constructional praxis6. Word list recall7. Word list recognition

Test ini memakn waktu 30-40 menit dan <20-30 menit pada kontrol3. CT Scan dan MRIMerupakan metode non invasif yang beresolusi tinggi untuk melihat kwantifikasi perubahan volume jaringan otak pada penderita Alzheimer antemortem.

CT scan:• menyingkirkan kemungkinan adanya penyebab demensia lainnya selain alzheimer seperti multiinfark dan tumor serebri. Atropi kortikal menyeluruh dan pembesaran ventrikel keduanya merupakan gambaran marker dominan yang sangat spesifik pada penyakit ini• Penipisan substansia alba serebri dan pembesaran ventrikel berkorelasi dengan beratnya gejala klinik dan hasil pemeriksaan status mini mentalMRI:• peningkatan intensitas pada daerah kortikal dan periventrikuler (Capping anterior horn

pada ventrikel lateral). Capping ini merupakan predileksi untuk demensia awal. Selain didapatkan kelainan di kortikal, gambaran atropi juga terlihat pada daerah subkortikal seperti adanya atropi hipokampus, amigdala, serta pembesaran sisterna basalis dan fissura sylvii.• MRI lebih sensitif untuk membedakan demensia dari penyakit alzheimer dengan penyebab lain, dengan memperhatikan ukuran (atropi) dari hipokampus.4. EEGBerguna untuk mengidentifikasi aktifitas bangkitan yang suklinis. Sedang pada penyakit alzheimer didapatkan perubahan gelombang lambat pada lobus frontalis yang non spesifik5. PET (Positron Emission Tomography)Pada penderita alzheimer, hasil PET ditemukan:• penurunan aliran darah• metabolisma O2• dan glukosa didaerah serebral• Up take I.123 sangat menurun pada regional parietal, hasil ini sangat berkorelasi dengan kelainan fungsi kognisi danselalu dan sesuai dengan hasil observasi penelitian neuropatologi6. SPECT (Single Photon Emission Computed Tomography)Aktivitas I. 123 terendah pada refio parieral penderita alzheimer. Kelainan ini berkolerasi dengan tingkat kerusakan fungsional dan defisit kogitif. Kedua pemeriksaan ini (SPECT dan PET) tidak digunakan secara rutin.7. Laboratorium darahTidak ada pemeriksaan laboratorium yang spesifik pada penderita alzheimer.Pemeriksaan laboratorium ini hanya untuk menyingkirkan penyebab penyakit demensia lainnya seperti pemeriksaan darah rutin, B12, Calsium, Posfor, BSE, fungsi renal dan hepar, tiroid, asam folat, serologi sifilis, skreening antibody yang dilakukan secara selektif.

g. PenatalaksanaanPengobatan penyakit alzheimer masih sangat terbatas oleh karena penyebab dan patofisiologis masih belum jelas.

Pengobatan simptomatik:1. Inhibitor kolinesterase• Tujuan: Untuk mencegah penurunan kadar asetilkolin dapat digunakan anti kolinesterase yang bekerja secara sentral• Contoh: fisostigmin, THA (tetrahydroaminoacridine), donepezil (Aricept), galantamin (Razadyne), & rivastigmin• Pemberian obat ini dikatakan dapat memperbaiki memori dan apraksia selama pemberian berlangsung• ESO: memperburuk penampilan intelektual pada orang normal dan penderita Alzheimer, mual & muntah, bradikardi, ↑ HCl, dan ↓ nafsu makan.

2. Thiaminpada penderita alzheimer didapatkan penurunan thiamin pyrophosphatase dependent

enzym yaitu 2 ketoglutarate (75%) dan transketolase (45%), hal ini disebabkan kerusakan neuronal pada nukleus basalis.• contoh: thiamin hydrochlorida• dosis 3 gr/hari selama 3 bulan peroral,• tujuan: perbaikan bermakna terhadap fungsi kognisi dibandingkan placebo selama periode yang sama.

3. Nootropik• Nootropik merupakan obat psikotropik.• Tujuan: memperbaiki fungsi kognisi dan proses belajar. Tetapi pemberian 4000 mg pada penderita alzheimer tidak menunjukkan perbaikan klinis yang bermakna.tapi mahal bokkkk

4. KlonidinGangguan fungsi intelektual pada penderita alzheimer dapat disebabkan kerusakan noradrenergik kortikal.• Contoh: klonidin (catapres) yang merupakan noradrenergik alfa 2 reseptor agonis• Dosis:maksimal 1,2 mg peroral selama 4 minggu• Tujuan: kurang memuaskan untuk memperbaiki fungsi kognitif

5. HaloperiodolPada penderita alzheimer, sering kali terjadi:• gangguan psikosis (delusi, halusinasi) dan tingkah laku: Pemberian oral Haloperiod 1-5 mg/hari selama 4 minggu akan memperbaiki gejala tersebut• depresi : tricyclic anti depresant (amitryptiline 25-100 mg/hari)

6. Acetyl L-Carnitine (ALC)Merupakan suatu subtrate endogen yang disintesa didalam miktokomdria dengan bantuan enzym ALC transferase.• Tujuan: meningkatkan aktivitas asetil kolinesterase, kolin asetiltransferase.• Dosis:1-2 gr/hari/peroral selama 1 tahun dalam pengobatan,• Efek: memperbaiki atau menghambat progresifitas kerusakan fungsi kognitif.

Suportif1. seakan hanya memberikan rasa puas pada penderita dankeluarga2. Pemberian obat stimulan, vitamin B, C, dan E belum mempunyai efek yang menguntungkan.

Pencegahan↓ resiko:Sayur, roti, gandum, sereal, minyak zaitun, ikan, & anggur merahVitamin: B12, B3, C, & asam folatPengguanaan NSAID jangka panjang

↑ resiko:Reiko yang berhubungan dengan kardiovaskular, hiperkolesterolmia, hipertensi, & diabetes

Selain farmakoterapi, ada beberapa terapi lain, seperti :Dapat dilakukan oleh “care-giver”

1. Intervensi psikososial. Terapi ini dapat digunakan dalam masa ‘mild’ sampai ‘moderate’ dalam tahap demensia. Treatment meliputi konseling, psikoterapi, terapi orientasi, ‘behavioral reinforcement’, dan ‘cognitive rehabilitation training’.Terdiri dari beberapa pendekatan:• Perilaku• emosi• kongisi• stimulus

2. Imunoterapi, yakni menyuntikkan vaksin toksin beta-amyloid untuk melatih sistem imun tubuh sehingga dapat menghancurkan beta-amyloid dan menghentikan timbulnya penyakit ini.

3. Terapi ‘pekerjaan dan gaya hidup’. Modifikasi dari lingkungan dan gaya hidup pasien Alzheimer dapat memperbaiki kemampuan fungsional dan meringankan pekerjaan pengasuh, seperti memberi label pada perangkat rumah tangga, mengamankan perangkat yang berbahaya untuk mencegah terjadinya luka karena aktivitas sehari-hari, mengajak pasien untuk berinteraksi sosial, dan stimulasi visual seperti memberi warna pada perangkat rumah tangga, yang juga dapat menambah nafsu makan.

4. Terapi alternatif, menggunakan kombinasi ramuan herbal dengan suplemen diet, misalnya vit.E.

h. PrognosisDari pemeriksaan klinis 42 penderita probable alzheimer menunjukkan bahwa nilai prognostik tergantung pada 3 faktor yaitu:1. Derajat beratnya penyakit2. Variabilitas gambaran klinis3. Perbedaan individual seperti usia, keluarga demensia dan jenis kelaminKetiga faktor ini diuji secara statistik, ternyata faktor pertama yang paling mempengaruhi prognostik penderita alzheimer.

Pasien dengan penyakit Alzheimer:• mempunyai angka harapan hidup rata-rata 4-10 tahun sesudah diagnosis• dan biasanya meninggal dunia akibat infeksi sekunder.

i. Komplikasi• Infeksi

• Malnutrisi• Kematian

j. Kesimpulan

Penyakit alzheimer sangat sukar di diagnosa hanya berasarkan gejalagejala klinik tanpa dikonfirmasikan pemeriksaan lainnya seperti neuropatologi, neuropsikologis, MRI, SPECT, PET. Sampai saat ini penyebab yang pasti belum diketahui, tetapi faktor genetik sangat menentukan (riwayat keluarga), sedangkan faktor lingkungan hanya sebagai pencetus ekspresi genetik. Pengobatan pada saat ini belum mendapatkan hasil yang memuaskan, hanya dilakukan secara empiris, simptomatik dan suportif untuk menyenangkanpenderita atau keluarganya.

What is Dementia?

Stock.xchng VI @ http://www.sxc.hu

The word dementia is derived from two Latin words meaning "away" and "mind". Dementia is not a specific disease but a descriptive term for a collection of symptoms that can be caused by a number of disorders that affect the brain.

Dementia involves an acquired chronic deterioration of intellectual function and other cognitive skills severe enough to interfere with one’s ability to perform activities of daily living (ADLs) and one’s ability to maintain relationships [1].

The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) defines dementia as "a general progressive deterioration of cognitive status in comparison to previous level of functioning that is often accompanied by changes in psychological and emotional states such as depression, agitation, aggression and apathy" [2].

Dementia is a major medical, social and economic problem that will get worse in the future as the number of older people in the population increases.

Dementia is often confused with Delirium

DEMENTIA DELIRIUM

generally progressive and irreversible in generally reversible in nature as

nature as less than 5% of dementias are reversible [3]

approximately 90% of delirium cases are reversible [4]

non-fluctuating with a normal level of consciousness

fluctuating symptoms

effects one’s ability to function independently

hallucinations and delusions may be present

is not a normal part of the aging process patients with an underlying history of dementia are more susceptible to developing delirium

For more comparisons between dementia and delirium, follow this link.

Don't forget - memory loss in isolation does not always mean dementia!

Prevalence Rates

Dementia is a growing health care problem [5]. Figure 1 shows the DOUBLING rule - dementia rates double every 5 years after the age of 65.

caption

The Canadian Study of Health and Aging Working Group (CSHA) estimates that in 2011, there will be 145,300 new cases of dementia, and of these new cases, 92, 900 will be women and 52, 400 will be men [6]. This estimate shows that dementia rates are twice as high in women compared to men, making dementia an important health care issue for women. More research is needed to gain sex-specific data in the pathophysiology, clinical presentation and treatment of dementia. Currently, most sex-based data that is available has been gathered via post hoc analysis.

Sex and Dementia Rates

Dementia is an important issue for older women and men. The population is aging in Canada and across most of the world and thus the proportion of older people will rise over the next few decades. The most rapid increase will be in those over 85 years of age, a group identified by the term the "oldest old" [7]. As the average life expectancy is longer for women than men, there will be a higher proportion of women in this oldest age group.

As age is a major risk factor for the development of dementia, these women will be at a much higher risk. As shown in the figure below, in the 85 plus age group, women far outnumber men for the prevalence of Alzheimer’s Disease. On the other hand, vascular dementia is more prevalent in men.

caption

Alzheimer’s Disease is the most common form of dementia [8]. The other common sub-types of dementia are also shown below.

caption

For more Canadian statistics from Alzheimer Toronto,follow this link.

Making the Diagnosis of Dementia

In order to make an accurate diagnosis you must:

Stock.xchng VI @ http://www.sxc.hu rule out other conditions that may have similar symptoms as dementia but

may be treatable e.g. hypothyroidism, depression, vitamin deficiencies etc.

rule out other possible causes of confusion such as poor vision or hearing, side effects of drugs etc.

An accurate diagnosis of dementia is important in order to:

implement an appropriate treatment plan

access information and support from the heath care system and the community support groups

assist the patient and family to plan and make arrangements for the future

Dementia is commonly under-diagnosed in primary health care settings because of the multiple etiologies and the wide range of symptoms at the time of presentation [9].

DSM-IV Diagnostic Criteria for Dementia

short term memory impairment (amnesia)

and at least one of:

language disturbance (aphasia)

impaired ability to carry out motor activities or ADLs (apraxia)

failure to recognize/identify familiar objects (agnosia)

poor executive functioning (planning, organizing, abstracting, disinhibition and inappropriate behaviour) [10]

Diagnosis

Currently, there is no single test that is available to detect and diagnose dementia in clinical practice. Instead the diagnosis of dementia is based on a combination of history taking and physical and neurological exams. Further investigations, such as lab tests and imaging studies, assist to differentiate the types of dementia.

History Taking Tips

build a rapport with the patient and their family/caregivers obtain information on the time of onset, progression, pattern of decline of

cognition and function, family history of dementia etc. assess problem solving abilities, behavioural changes and psychiatric

symptoms

The interviewer must modify her or his style to accommodate the patient being interviewed. For example, if the patient has cognitive deficits, the clinician will need to change the style and extent of history taking and interview to the patient’s capacity while respecting boundaries and preserving patient dignity at all times [11].

Obtain permission to talk with other care providers and the family physician if you not the primary care provider yourself.

For more information on how to conduct a proper patient history, consult the Practical Guide to Clinical Medicine Website. [12]

Examination

In the case of dementia a complete examination includes:

full physical examination, including neurological exam cognitive assessment including mini mental status examination (MMSE)

For more information on how to conduct full physical and neurological exams consult the Practical Guide to Clinical Medicine Website[11].

This video reviews the neurological exam in patients with dementia

Cognitive Assessment

Mini Mental State Examination

The most commonly used test to screen cognition is the Mini Mental State Examination (MMSE). The MMSE looks at various cognitive domains such as learning, language and short term memory.

The MMSE is a valid and reliable screening instrument. The sensitivity of MMSE for dementia ranges from 71 to 92%, and the specificity ranges from 56 to 96% [13]. A literature review from 1990 to 1999 showed that the MMSE provides a global score of cognitive ability that correlates with daily function [14]. Hence, the results of the MMSE in conjunction with a history and physical assessment can assist in differential diagnosis of cognitive impairment resulting from various dementia sub-types [15]. However, limitations of the MMSE include it is not reliable when administered through an interpreter to non-English speaking patients; and it lacks sensitivity in picking up very mild cognitive changes [16]. Full instructions and test questions in PDF form can be accessed online through the Regional Geriatric Assessment Programme of Ottawa-Carleton.

Montreal Cognitive Assessment

The Montreal Cognitive Assessment (MoCA) is another test that was designed as a rapid screening instrument for mild cognitive dysfunction [17]. It assesses different cognitive domains including attention and concentration, executive functioning, memory and orientation. It takes about 10 minutes to administer making it a practical tool to use in a clinical setting. It is available in a number of languages. Sensitivity and specificity studies have also been performed on the MoCA [18]. To access the results of these studies and the instructions on administration of the test, click on the MoCA website.

Other Investigations

routine labs: complete blood count, fasting blood sugar, thyroid stimulating hormone, calcium, electrolytes, urea and creatinine

specific labs: B12, folate levels, liver function tests for most patients who have a clinical presentation consistent with AD with

typical cognitive symptoms or presentation, only the above basic set of tests need to be completed

extensive investigations are not required unless a reversible cause of dementia is suspected [19]

Brain Imaging

Computerized Tomography (CAT): role in detecting certain causes of dementia such as VaD, tumor, NPH or subdural hematoma

Magnetic Resonance Imaging (MRI): helps to visualize white matter lesions

Functional Imaging: Positron Emission Technology (PET scans) and Functional Magnetic Resonance Imaging (fMRI): mainly used for research purposes only and not in clinical settings

Image:UCSLGZJM.jpg

for more information on neuroimaging, follow this link.[20]

Others

EEG: used in patients in whom seizure disorder is suspected lumbar puncture to analyze the cerebrospinal fluid (CSF): used to rule out

infection, inflammation, malignancy in complex cases, a referral to specialists such as geriatrics,

psychogeriatrics or neurology may be required

How well do you know your diagnostic tools ?

Differential Diagnosis

The recognition of dementia is a two-step process. Clinicians must first determine whether dementia exists or not. In order to do so, other possible disorders such as those described below must first be ruled out. Once this has occurred, specific causes of dementia can be identified [21].

Delirium

acute confusional state that develops over a short period of time disturbance of consciousness with reduced attention span change in cognition present i.e. memory deficit, disorientation, language

disturbance there is usually evidence of a medical cause e.g. drugs, infections,

metabolic disorder and electrolytes/fluid imbalance [22]

Depression

very common in the elderly population symptoms of weight loss or depressed mood lasting at least two weeks and

a change from previous level plus any 4 of the following: weight loss, insomnia/hypersomnia, fatigue,

feelings of worthlessness/guilt, psychomotor agitation, decreased concentration, recurrent thoughts of death or suicidal ideation

may have patchy cognitive losses on testing [23]

Mild Cognitive Impairment (MCI)

impairment in memory only all other cognitive functions are spared preserved basic day to day functioning no other obvious medical or psychiatric explanation for the memory

problems 10-15% of patients with MCI will progress to dementia per year,

particularly the amnesic type MCI [24]

Summary of the 3 D’s

. Dementia Delirium Depression

Onset Gradual Acute Recent

Reversibility Usually irreversible (95%) [25]

Usually reversible (90%) [26]

Reversible with treatment

Alertness Usually constant Prominent fluctuations Usually constant

Memory Loss Often unaware of memory loss

Inattention is more common

Often c/o memory loss

Miscellaneous Normal/mildly slow EEG waves

Patients with dementia at higher risk

May be family hx of depression

Diagnostic Disclosure

Making the disclosure of a dementia diagnosis to the patient and family, taking into account the risk of depression, is essential and can be challenging for physicians. A qualitative study was conducted with 30 patients and caregivers to examine the disclosure process [27]. Based on the findings on this study, ten recommendations to improve the process of disclosure of dementia were made. They are as follows:

an overwhelming majority of patients and caregivers supported full disclosure. Gradual disclosure with upfront discussion of possibilities and giving information through the assessment process was the preferred method of full disclosure

professionals need to be prepared for the emotional response of the patient and caregiver

provide a non-threatening setup for the meeting, comfortable chairs, circle setup etc.

ensure caregivers are there for support and provide follow up as needed ensure there are familiar providers/professionals who can establish a link

with the patient during disclosure (i.e. in specialty settings) the treating physician should be the person disclosing, other team

members (e.g. nurse) can also play a major role during disclosure use/show empathy, provide a balance of hope and realism ensure enough information is provided, use plain language and avoid

jargon use diagrams or flow charts if possible, and provide a written summary of

findings offer resources and follow up for more information on disease process

Special Considerations

Other factors that a physician should consider include:

initiation of therapy for cognitive, behaviour and mood symptoms referral to groups such as the Alzheimer’s Society of Canada and

Community Care Access Centers which offer services, education and support groups for patients and their families or caregivers

legal issues including updating of documents such as wills, advanced directives for medical care and designation of power of attorney

vocational issues for those who may still be employed driving capacity needs to be assessed and other safety concerns may need

to be examined[28] planning for future care needs of the patient

Alzheimer’s Disease (AD)

first described by Alois Alzheimer in 1907 the most common type of dementia accounting for 50-60% of all

dementias [29]

neurofibrillary tangles are also present as a result of abnormal tau protein production (hyper-phosphorylation of tau protein) which impede the delivery of neurotransmitters along the axons and cause cell death [30]

widespread cortical atrophy is associated with the above changes; the medial temporal lobes are particularly affected in AD

there are 2 types of AD: 1) sporadic type which is the most common form that occurs after the age of 65 and accounts for 90-95% of all cases and 2) familial autosomal dominant type which occurs as early as age 30 and accounts for 5-10% of all cases [31]

common signs and symptoms include memory loss, language deficits, decreased executive functioning and personality changes

for more information on living with AD, click on Alzheimer’s Society Website

there is an abnormal processing of the amyloid precursor protein in the brain cells which leads to the accumulation of beta amyloid and the formation of neuritic plaques (shown here) that cause cell death [32]

Vascular Dementia (VaD)

the second most common type of dementia accounting for 5-10% of all dementias [33]

VaD can result from a number of syndromes associated with cerebrovascular disease and is characterized by an abrupt onset and a stepwise decline [34]

can occur as a result of either a ischemic, hypoperfused or hemorrhagic brain lesion [35]

subcortical ischemic vascular dementia refers to lesions that involve the basal ganglia, cerebral white matter and the brainstem and is the most common cause of cognitive decline and VaD in the elderly [36]

it occurs as a result of two mechanisms which often can overlap: 1) ischemic injury leading to complete infarction i.e. lacunar infarcts and microinfarcts or 2) incomplete infarctions of the cerebral white matter [37]

Roman et al (2002) note that a significant proportion of subcortical lacunes are clinically silent and unnoticed until cognitive function deteriorates; this signifies the importance of primary prevention [38]

common signs and symptoms include loss of executive functioning, decreased memory (particularly retrival problem), mood disorders, slowed thinking and gait disturbances

Mixed Type

increasing evidence shows that VaD and AD often coexist in older patients and is called mixed dementia

cardiovascular disease (CVD) is the pathology and VaD is the disorder and VaD with no AD pathology is relatively uncommon as shown in the figure below

any patients have overlap of AD and significant CVD over 60% of patients diagnosed with AD also have incomplete white

matter infarction on imaging [39] cerebral ischemia and amyolid deposits may synergize to produce AD and

vascular changes in the brain [40] a great deal of research is currently being conducted to clarify these

mechanisms

Lewy Body Dementia (LBD)

first described by Dr. Levi in 1912 a form of progressive dementia identified by abnormal structures in

neurons called “Lewy bodies“ which are composed mainly of a protein called alpha synuclein and are distributed in the cortex and the midbrain [41]

the mechanism that leads to the formation of Lewy bodies is unknown cerebral atrophy is present along with neurofibrillary tangles, however,

minimal neuritic plaques are seen LBD has a greater frequency of depressive and psychotic symptoms with a

fluctuating level of consciousness and cognitive symptoms occurring within one year of the onset of Parkinsonian motor symptoms [42]

more information can be obtained on the Lewy Body Dementia Association website

Frontotemporal Dementia (FTD)

effects primarily the frontal and temporal lobes of the brain and has a more rapid progression than the other subtypes of dementia [43]

neuropathology shows marked lobar atrophy of the frontal and temporal lobes as shown here [44]

Pick’s Disease is one type of FTD; the cerebral cortex has ballooned cells called Pick cells with intraneuronal inclusions called Pick bodies [45]

symptoms show behavioural changes such as as loss of social awareness, disinhibition and other frontal release signs such as the grasp sign on physical exam

cause is still unknown, however there is a strong genetic component as FTD tends to run in families and approximately 40% of cases are believed to be hereditary [46]

more information can be obtained from the Pick’s Disease Support Group

Cheat Sheet for Dementia Subtypes

As there are numerous subtypes of dementia, it can be difficult to distinguish between the subtypes. The following table summarizes four subtypes of dementia on various domains. [47][48]

Sex, Gender and Pathology

Female sex, among many other risk factors in dementias, has been associated with an increased risk of the development of AD.

Barnes et al (2004) used data from 141 older Catholic clergy members to assess clinico-pathological correlation between two sexes [1]. The subjects in the study underwent an annual examination and a brain autopsy at death. Their results showed that:

women tended to have more global AD pathology and neurofibrillary tangles but the same amount of neuritic plaques [49]

the relation of global AD pathology to clinical diagnosis differed between men and women as each additional unit of AD pathology was associated with a three fold increase in odds of clincial AD in men compared to 20 fold increase in odds of clinical AD in women [50]

hence, this data suggests that AD pathology is more likely to be clinically expressed as dementia in women than in men [51]

Further research needs to be conducted to look at pathology in other dementia sub-types. New methods need to be developed that are sensitive in diagnosing pathological gender differences early on in the disease process to allow for intervention and maximize quality of life.

Sex, Gender and Risk Factors

The cause of dementia is unknown but certain risk factors have been shown to be linked in its development. Women have two times a higher risk of developing dementia, specifically AD, than men. The main risk factors for dementia are age, family history and APOE status and the presence of traditional vascular risk factors such as hypertension, diabetes mellitus (DM) and hypercholesterolemia. New risk factors that are emerging and currently being researched include increased homocysteine levels, obesity, estrogen use and metabolic syndrome [52].

Age

age is the strongest risk factor for dementia as the prevalence of AD doubles every 5 years beyond the age of 65 [53]

the rates of dementia are higher among women as women tend to live longer and compromise a greater proportion of those in the "oldest old" age group

Family History

first degree relatives with dementia have a 10-30% risk of developing AD [54]

in familial autosomal dominant AD, a genetic connection has been shown as in certain families, it is passed directly from one generation to another through a dominant inheritance pattern

follow this link to find out more about heredity: Alzheimer Society Information on AD and heredity

Estrogen

cognitive decline is often accelerated in women after menopause as studies show that there are sex-based differences in the ageing of the brain

it is possible that estrogen may function as a mild vasodilator and increase the blood flow in the brain, hence having a protective effect in pre-menopausal women [55]

results of various longitudinal stuides suggested a beneficial effect of estrogen therapy on cognitive function in symptomatic post-menopausal women; however, the results of a large recent clinical trial, the Women’s Health Initiative Study (WHIMS) does not support this in women over 65 years [56]

this trial demonstrated an increased occurrence of dementia in postmenopausal women who received combined estrogen-progestin therapy [57]

hence, the routine therapeutic use of estrogen in women over age 65 is not justified based on the existing evidence [58]

APOE (Apolipoprotein E epsilon) Gene

the APOE gene is carried on chromosome 19 and has 3 alleles: APOE e2, APOE e3 and APOE e4 and is the most significant known genetic risk factor for dementia [59][60]

APOE e4 is associated increasing the likelihood of late onset AD, raising total cholesterol levels and shifting the age onset an average of 5-20 years earlier depending on the number of alleles present [61][62]

this genotype seems to have greater effects on women with respect to hippocampal pathology and memory performance

Vascular Risk Factors

prevalence of hypertension(HTN) is greater in men than in women until age of 60 years and then it is higher in women; women also have a higher rate of silent ischemia and cerebral white matter changes associated with HTN and diabetes making them more vulnerable to development of dementia [5]

low BP may be associated with cognitive impairment implying that a certain level of BP is needed to maintain adequate cerebral perfusion to preserve cognitive ability [63]

the Kunghsholmen project which had a proportion of 81.7% women in their sample size showed that diastolic BP <70 mmHg in those greater than 75 years was associated with increased incidence of AD and dementia [64]

diabetes has been associated with lower levels of cognitive function and greater cognitive decline in those over 65 and this is a concern for women as diabetes is increasing in frequency to a greater extent in women than in men [65]

Other Risk Factors

obesity in the middle age increases the risk of future dementia; for every one point gain in BMI, the risk of temporal lobe atrophy increased by 13 to 16% [66]

homocysteine has been shown to be a risk factor for stroke, heart disease and VaD through its association with small blood vessel and endothelial dysfunction

increased levels of homocysteine are a strong independent risk factor for the development of dementia based on the Framingham Study [67]

presence of Mild Cognitive Impairment (MCI)

Stages of Alzheimer’s Disease

The analogy of one’s mind as a multi-layered onion is one way of thinking of dementia [68]. Starting in childhood, successive layers are added over the years as one acquires new memories and skills. Dementia results in the slow peeling away of the onion layers, in which the more recently acquired items are lost first, followed by the more remote memories and skills and eventually even the most basic skills including eating, walking and speaking are peeled away and lost [69]. This process is also called retrogenesis.

A number of staging systems have been developed to help understand how the disease progresses and for making future plans. One staging system classifies Alzheimer’s Disease in three stages: early, middle and late. Another staging system, known as the Reisberg Scale, divides the disease into seven stages [70]. The length of each stage will vary and stages may overlap.

Early Stage

loss of short term memory inability to learn and recall new information language deficits (e.g. inability to find words, lose track of conversation) mood swings and personality changes

person can compesate for cognitive deficits and continue to function independently [71]

Middle Stage

decreased long term memory supervision and increased assistance required for ADLs and IADLs agitation, hostility, aggressiveness, uncooperativeness, apathy "sundowning" i.e. increased behavioural problems in the evenings such as

fatigue, disrupted sleep/wake cycles wandering, rummaging and repetitive behaviour altered appetite, sleep and sexual behaviour delusional thinking i.e. suspiciousness of family and friends hallucinations may occur in 10-15% of patients [72]

Late Stage

can’t recognize self or family complete deterioration of personality little capacity for self care patients eventually become bed-ridden and unable to function [73]

Living the Diagnosis

In 1995 American artist William Utermohlen was diagnosed with Alzheimer’s Disease.[74]

He began a series of self portraits that vividly portray the effect of the disease. An article in the New York Times has a number of the portraits and a slide show available. Mr. Utermohlen’s medical findings and an analysis of his work are available in a 2001 paper published in The Lancet[75].

Treatment of Dementia

there is currently no cure for most dementias nor treatment that can restore mental function

current treatment focuses on correcting all reversible factors and slowing down the irreversible factors to help improve function [76]

treatment can be divided into pharmacological and non-pharmacological therapies

Pharmacological Therapy

Cholinesterase Inhibitors (ChEI’s)

several medications are available for patients with AD that ease symptoms by slowing down the decline of memory, language and thinking abilities [11]

the Canadian Consensus Conference on Dementia recommends that cholinesterase inhibitors (ChEIs) be used for standard symptomatic treatment of mild to moderate AD [11]

ChEIs focus on correcting the cholinergic deficiency in the central nervous system [77]

currently three ChEIs are marketed for treatment of AD; these are donepezil, rivastigmine, galantamine for treatment of cognitive symptoms of mild to moderate AD [78]

usually improved cognitive abilities are seen in the fist 2-3 months, followed by a slowing down of the progression of the symptoms [79]

a recent meta-analysis of 16 randomized, double blind, placebo-controlled trials examined the effect on ChEIs on cognitive status confirmed that AD patients treated with ChEIs have a modest but significant therapeutic effect [80]

a more recent review of 19 randomized controlled trials concluded that the methodological quality of the trials being reviewed was poor with missing data on patient dropout from the treatment arm and affecting intention to treat analysis, thereby the beneficial effects of previously described may not be as strong [81]

future studies are clearly needed that look at long term effects of these drugs in both sexes as well as clinical outcomes such as function and behaviour and delaying institutionalization and the reduction of caregiver burden

Side effects of ChEIs

A recent meta-analysis of 16 randomized, double blind, placebo-controlled trials examined the side effects and adverse events caused by the use of ChEIs[82] found that:

AD patients treated with ChEIs have a significantly higher rate of adverse events [83] (examples of adverse events include nausea, vomiting, diarrhea, abdominal pain, fatigue and weight loss etc.)

the tolerability of ChEIs was an issue and the proportion of patients in whom adverse events emerged during treatment was 8% higher than those receiving placebo [84]

there is weak evidence that women experience more adverse effects than men, possibly due to a lower body weight [85]

ChEIs can also have a vagotonic effect on the SA and AV nodes, leading to bradycardia and heart block especially in those patients with coexisting cerebrovascular disease [86]

Memantine

Memantine was approved for sale in Canada in 2004 for use in moderate to severe dementia, it is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that blocks the effects of excessive glutamate while still preserving physiologic activation of NMDA receptors required for learning and memory [87]

by blocking the effects of abnormal glutamate activity, memantine prevents neuronal cell death and cognitive dysfunction [88]

in a 1999 randomized, placebo controlled trial of 150 patients with AD or VaD, the treatment group showed better functional outcomes and reduced care dependence as compared to placebo group [89]

memantine is well tolerated and safe in reported trials and can be co-administered with ChEIs safely

the most common reported side effect is dizziness [90]

Vascular Dementia

Treatment for VaD involves controlling the vascular risk factors such as blood pressure, cholesterol levels, diabetes etc.

the strongest evidence available to date involves the use of anti-hypertensive agents - randomized placebo controlled trials (PROGRESS, HOPE trials) have found that anti-hypertensive agents reduce the incidence of dementia in elderly patients [91]

each 1 mmHg decrease in BP in mid-life is equal to a 1% less chance of developing dementia in later years [92]

a recent meta-analysis found that ChEis are associated with differential risks for death in VaD, from no risk to substantially increased risk - this is likely due to the heterogeneity of risk factors in VaD and further studies are required to know the overall effectiveness and safety of these drugs and what patient benefits the most [93]

Immunotherapy

abnormal accumulation of proteins in the brain is associated with dementia immunization against amyloid-beta in Alzheimer’s disease to prevent the

onset of amyloid-beta accumulation is currently under investigation in transgenic mouse models, active immunization with amyloid-beta

results in the removal of amyloid-beta plaques via the generation of amyloid-beta antibodies resulting in improvement in cognitive function [94]

an active peptide vaccine consisting of amyloid-beta antibodies was halted in 2002 because 6 percent of participants developed complications such as neurological decline, lymphocytosis of the cerebrospinal fluid and altered signal intensities in cerebral white matter [95]

active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised [96]

immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and synuclein are in the early stages of development [97]

Other Medications

anti-depressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants and monamine oxidase inhibitors (MAOIs) have all been used

medications to treat behavioural symptoms of dementia i.e. agitation, psychosis, mood swings etc. such as antipsychotics, neuroleptics are also commonly used to try and help people with dementia

Non-pharmacological Approaches

open communication between patients, families and health care professionals with clear discussion of diagnosis, prognosis and treatment options

educating and providing support to patients, families and caregivers creating supportive environments with structure and routine, such as day

hospitals and respite care, to allow patients to function to their maximum capacity

referral to allied health professionals such as occupational therapists to assist patients and families with daily routines and for other cognitive and behavioural strategies; physical therapists to help patients maintain mobility; and social workers to assist patients and families with future planning

Luijpen et al (2003) showed that physical activity and tactile stimulation had a positive effect on cognitive functioning and on the patient-caregiver

relationship, making this an important non-pharmacological therapy that can be used [98]

discussion of the future with respect to issues such as medical directives, institutionalization, power of attorneys, finances etc. needs to occur in the early to mid stages of dementia to allow the patient to take part and express their wishes

Ensuring a safe environment for all seniors

This Virtual Homevisit was created by Dr. Gustavo Duque and the McGill Molson Medical Informatics group, it is used with permission. The safety issues highlighted in this game are important for all seniors, especially those with cognitive impairment.

The reading material links from the game are not working at the moment. The following links will take you to the documents:

Reading Material 1 [99] Reading Material 2 patient handout from Health Canada and the Public Health Agency of

Canada[100] patient handout from the Centre for Disease Control in the USA.[101]

Behavioural Issues

Behavioural and psychological symptoms are common in those with dementia and can impair the quality of life of the patient and caregiver.

50% of those with dementia display depressive symptoms and 60-80% exhibit agitated behaviour at some point during the course of the disease [102] these issues can be very distressing for family and friends to witness and can lead to the institutionalization of the demented

wandering is a common behaviour in those with dementia and is related to short term memory loss and the inability to reason or to make judgments [103]

wandering can occur at any time of the day or night and may appear to be aimless or may be focused on pursuing a particular goal or destination [104]

Safely Home is a nationwide program and registry developed by the Alzheimer Society of Canada in partnership with Royal Canadian Mounted Police to help find the person who is lost and help them return home safely, for more information on this registry program and how to register follow this link.

Ethical Issues

the loss of insight and decreased ability to make decisions must always be balanced against preservation of patient autonomy [105]

important issues requiring decisions include: informed consent and decision making in care and medical management, participation in research trials, end of life decisions etc. [106]

always use standardized tools for the assessment of patient capacity and competency[107]

the wishes of the person with dementia should be respected and guide all end of life care decisions

The Alzheimer Society of Canada publishes an excellent resource called "Tough Issues" which deals with many of these difficult issues and more information can be found on their website

Driving

driving demands quick reaction times, concentration and the ability to exercise good judgment and make quick decisions [108]

all of these skills are impaired in those with dementia and thus there is an increased risk of motor vehicle crash

loss of one’s license can lead to feelings of decreased independence, freedom and mobility which can have profound effects on the individual and place additional strain on caregivers who must now assume this responsibility [109]

physicians are obligated to report any concerns about driving, however, it may be difficult for a physician to accurately assess a patient’s competency to drive in an office setting

the Dementia Network of Ottawa Carleton provides an algorithm for family physicians to follow to assess driving and provides local community resources for formal assessment of driving skills

Transition to Institutionalized Care

A large number of people with dementia are cared for at home initially; however, as the disease progresses it may be overwhelming to meet the demands of care despite the help of community support services and support groups and alternate options may need to be considered. Possibilities include: respite care, group homes, retirement homes or long term care in nursing homes.

The decision to place a loved one usually occurs approximately 7 years into the course of the disease and can be a difficult one, often filled with anguish, self doubt and guilt.[110]Women may be at higher risk for these feelings as they are traditionally seen by society as caregivers and will delay placement of a family member even at the expense of their own health and well being.[111]

Caregiving in Dementia

Caregiving can include the monitoring of the status of a person in need, responsibility for accessing and communicating with health care professionals and the comprehensive direct care of the person (nutritional, organizational, functional, financial....).

absence of caregiver(s) and higher perceived caregiver burden are major predictors of earlier institutionalization of those with dementia [112]

caregiver burden is defined as the physical, emotional and financial toll of providing care that can lead to increased illnesses, depression and mortality in those providing care [113]

up to 50% of caregivers experience psychiatric symptoms during their caregiving but many also report a sense of accomplishment in keeping their loved ones at home [114]

The Alzheimer Society of Canada provides ten warning signs of caregiver stress along with strategies to help reduce this stress

Gender and Caregiving

Caregiving is gendered - the majority of caregivers are women

social factors generally make women more likely to take on the caregiving role and be more heavily involved in caregiving activities than men [115]

over 70% of informal caregivers are women, mostly wives, daughters and daughters in-law [116]

30% of female informal caregivers are also employed and working in the community and may also be providing care to their own family at the same time [117] this places unique stresses on women that are different from what is experienced by male caregivers

a recent study found that female caregivers had lower scores on 7 out of the 8 scales on the SF-36 Quality of Life Questionnaire vs. males and an overall decreased quality of life as a result of more emotional and physical health problems [118]

one of the future concerns for society is caregiving issues for the older female population with dementia