{الأمراض التنكسية للجهاز العصبي المركزي} مرض الزهايمر

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CNS Degenerative Diseases

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Alzheimer Disease

Alzheimer disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is often not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. At age 60 less than 1% of persons have AD,الأمراض التنكسية للجهاز العصبي المركزي

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مرض الزهايمر

أصبح مرض الزهايمر (AD) أكثر شيوعًا في الدول المتقدمة حيث يضم السكان المزيد والمزيد من كبار السن. لا يوجد سبب معروف للمرض. غالبًا ما لا يُعرف سبب إصابة بعض الأشخاص بالخرف في سن 30 أو 40 عامًا بينما لا يتواجد آخرون حتى أواخر السبعينيات أو الثمانينيات من العمر. في عمر 60 عامًا ، يُصاب أقل من 1٪ من الأشخاص بمرض الزهايمر

  but by age 85 a fourth to a third of persons have evidence for AD. Thus, in aging populations, AD becomes more prevalent. Familial cases with a defined inheritance pattern account for about 10% of Alzheimer disease. Genetic defects in familial cases have been identified involving four different genes (Blennow et al, 2006):

Chromosome Gene

21 Amyloid Precursor Protein (APP)

19 Apolipoprotein E (ApoE)

14 Presenilin 1 (PSEN1)

1 Presenilin 2 (PSEN2)

The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis, linked to the APP, PSEN1, and PSEN2 genes. AD cases linked to an APP genetic defect on chromosome==ولكن بحلول سن 85 ، يكون لدى ربع إلى ثلث الأشخاص دليل على الإصابة بمرض الزهايمر. وبالتالي ، في شيخوخة السكان ، يصبح الزهايمر أكثر انتشارًا. تمثل الحالات العائلية ذات النمط الوراثي المحدد حوالي 10٪ من مرض الزهايمر. تم تحديد العيوب الجينية في الحالات العائلية التي تنطوي على أربعة جينات مختلفة (Blennow وآخرون ، 2006):

جين الكروموسوم

21 بروتين سلائف أميلويد (APP)

19 صميم البروتين الشحمي E (ApoE)

14 بريسنيلين 1 (PSEN1)

1 بريسنيلين 2 (PSEN2)

قد يكون لحالات "البداية المبكرة" لمرض الزهايمر لدى الأشخاص في الثلاثينيات والأربعينيات والخمسينيات من العمر أساسًا وراثيًا مرتبطًا بجينات APP و PSEN1 و PSEN2. حالات مرض الزهايمر مرتبطة بخلل وراثي APP في الكروموسوم

   21 may explain the appearance of Alzheimer disease in persons with Down syndrome surviving to middle age. APP encodes for amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, but these defects account for less than 0.5% of cases. (Lane et al 2018)

The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However,=21 قد يفسر ظهور مرض الزهايمر لدى الأشخاص ذوي متلازمة داون الذين يعيشون حتى منتصف العمر. ترميز APP لبروتين طليعة الأميلويد ، مما يؤدي إلى تكتلات ليفية من بيتا أميلويد السامة للخلايا العصبية. يرتبط حوالي نصف حالات الإصابة المبكرة بمرض الزهايمر بطفرات في جين بريسنيلين 1 على الكروموسوم 14 وجين بريسنيلين 2 على الكروموسوم 1 ، لكن هذه العيوب تمثل أقل من 0.5٪ من الحالات. (لين وآخرون 2018)

قد يكون للحالات "المتأخرة" الأكثر شيوعًا للإصابة بمرض الزهايمر والتي تحدث بعد سن الستين عيوبًا وراثية كامنة. يشفر الموقع الجيني على الكروموسوم 19 لناقل الكوليسترول يسمى البروتين الشحمي E (apoE). يمكن العثور على متغير E4 من apoE ، الذي يزيد من ترسب ليفي بيتا أميلويد ، في 40٪ من حالات الزهايمر. ومع ذلك ، فإن

  the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles. (Lane et al 2018)

Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. Biomarkers for prediction of progression to AD in persons with mild cognitive impairment have been studied. The amyloid PET scan has a high sensitivity and==إن وجود apoE4 ليس ضروريًا ولا كافيًا لتطوير مرض الزهايمر ، لذلك لا يوجد ما يبرر اختباره. يمكن العثور على الطفرات في جين تاو الذي يرمز إلى بروتين تاو ، وهو بروتين مرتبط بالأنابيب الدقيقة ، في بعض حالات الزهايمر. قد يفسر التاو غير الطبيعي الخيوط الحلزونية الموجودة في التشابك الليفي العصبي. (لين وآخرون 2018)

بغض النظر عن السبب ، يتم تشخيص مرض الزهايمر سريريًا من خلال اكتشاف فقدان الذاكرة التدريجي مع زيادة عدم القدرة على المشاركة في أنشطة الحياة اليومية. في وقت متأخر من مسار المرض ، لا يستطيع الأشخاص المصابون التعرف على أفراد الأسرة وقد لا يعرفون من هم. تمت دراسة المؤشرات الحيوية للتنبؤ بالتقدم إلى مرض الزهايمر في الأشخاص الذين يعانون من ضعف إدراكي خفيف. يتميز فحص اميلويد PET بحساسية عالية و.

  specificity for AD and may be useful when clinical findings are atypical or the patient is young. Additional markers include CSF Aß42 and tau, temporoparietal hypometabolism on 18F-FDG PET scan, and measurement of hippocampal volume. Patients with all of these markers progressed to AD, while persons without any markers did not. (Galluzzi, et al, 2013)(Johnson, et al, 2013)

The definitive diagnosis of AD is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation. The pathognomonic microscopic features of AD are: an increased number of beta-amyloid-containing neuritic plaques and neurofibrillary tangles composed of abnormally phosphorylated tau protein aggregates in cerebral cortex. (Mehta and Schneider, 2023)

Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may==الخصوصية لمرض الزهايمر وقد يكون مفيدًا عندما تكون النتائج السريرية غير نمطية أو كان المريض صغيراً. تشمل العلامات الإضافية CSF Aß42 و tau ونقص التمثيل الغذائي الصدغي الجداري على فحص التصوير المقطعي بالإصدار البوزيتروني 18F-FDG وقياس حجم الحصين. تقدم المرضى الذين يعانون من كل هذه العلامات إلى AD ، بينما الأشخاص الذين ليس لديهم أي علامات لم يفعلوا ذلك. (Galluzzi، et al، 2013) (Johnson، et al، 2013) 

يتم التشخيص النهائي لمرض الزهايمر من الناحية 

 المرضية عن طريق فحص الدماغ عند تشريح الجثة. بشكل عام ، يوجد ضمور دماغي ، خاصة في المناطق الأمامية والزمنية والجدارية. نتيجة لذلك ، هناك تمدد بطيني خارج الفراغ. السمات المجهرية المرضية للإصابة بمرض الزهايمر هي: زيادة عدد الصفائح العصبية المحتوية على بيتا اميلويد والتشابك الليفي العصبي المكون من مجاميع بروتين تاو المفسفرة بشكل غير طبيعي في القشرة المخية. (ميهتا وشنايدر ، 2023)
تتكون اللويحات العصبية من عمليات عصبية ملتوية تحيط بنواة أميلويد المركزية. يمكن للخلايا النجمية التفاعلية والخلايا الدبقية الصغيرة 

ترجم الباقي  TRANSILATE

  appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers relative to age in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent.

Neurofibrillary tangles consist of hyperphosphorylated tau protein filaments within neurons.

Other microscopic findings with AD include amyloid angiopathy and granolovacuolar degeneration. (Mirra et al, 1993)

Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer disease. Many treatment strategies are based upon reducing the loss of acetylcholine. However, such medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer disease is pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006)

Biomarkers of AD can be employed to suggest the diagnosis, but are not definitive. Positron emission tomography (PET) scans can employ radiolabeled F-fluorodeoxyglucosse (F-FDG PET), tau protein PET, and amyloid PET. The latter is the most sensitive and specific. CSF markers include detection of tau protein. (Frisoni et al, 2017) Alzheimer disease, gross.

Alzheimer disease, gross.

Alzheimer disease, gross.

Alzheimer disease, Bielschowsky silver stain, microscopic.

Alzheimer disease, thioflavin stain, microscopic.

Alzheimer disease, senile plaque, with Congo red stain, microscopic.

Alzheimer disease, neurofibrillary tangle, H and E stain, microscopic.

Alzheimer disease, neurofibrillary tangle, with Bielschowsky silver stain, microscopic.

Lewy Body Diseases

Lewy body dementia (LBD) is a clinicopathological syndrome that may account for up to 20% of all cases of dementia in older patients, typically in their seventh and eighth decades. Diseases with Lewy bodies should also be considered in the differential diagnosis of a wide range of clinical presentations including episodic disturbances of consciousness, syncope, sleep disorders, and unexplained delirium. (Weintraub and Irwin, 2022)

There are three major syndromes associated with the appearance of Lewy bodies. These are: the movement disorder known as Parkinson disease, multiple system atrophy with autonomic nervous system failure, and dementia. Parkinsonism, the most common syndrome with Lewy bodies, is a disease developing in middle age. In older persons, a mixture of cognitive, autonomic, and motor dysfunction is more common. Some older persons with dementia who are thought to have Alzheimer disease may actually have diffuse Lewy body disease, and some of those persons may be developing a movement disorder resembling Parkinson disease. Conversely, some patients initially presenting with Parkinson disease may develop manifestations of Lewy body dementia. When cognitive impairment is present with LBD, some neuropathologic features of Alzeimer dementia are usually present as well. (Mehta and Schneider, 2023)

The clinical presentation of Lewy body disease varies according to the site of Lewy body formation and associated neuronal loss. In Parkinson disease, the Lewy bodies are found in the substantia nigra of the midbrain, coupled with the loss of pigmented neurons. In persons with the dementia of diffuse Lewy body disease, there are Lewy bodies in the neocortex. Some persons have the Lewy bodies in both locations. The basal ganglia and diencephalon may also be involved in some cases. (Mehta and Schneider, 2023)

Lewy bodies are spherical, neuronal intracytoplasmic, eosinophilic inclusions comprised of abnormally truncated and phosphorylated alpha-synuclein neurofilament protein. With idiopathic Parkinson disease, Lewy bodies are typically found in the substantia nigra, nucleus basalis of Meynert, dorsal raphe, locus ceruleus, dorsal motor nucleus of the vagus nerve, and hypothalamus. In cases Lewy body dementia, cortical Lewy bodies are prominent, but there are typically findings of Alzheimer disease as well. The presence of alpha-synuclein inclusions within glial cells is characteristic of multiple system atrophy. (Kövari et al, 2009) (Mehta and Schneider, 2023) Diffuse Lewy body disease, microscopic.

Frontotemporal Dementias

Frontotemporal dementia, also called frontal lobar degeneration (FTLD) or non-specific frontal lobe dementia, has a slow, insidious onset marked in the early stages by personality changes, then progressive loss of speech (fluent or nonfluent aphasia), apathy, and finally mutism. Changes can include impulsive behaviors and disinhibition, poor insight into consquences of behavior, repetitive behaviors, loss of personal hygiene, and loss of social graces. The mean age of onset is in the 6th decade. Most cases are sporadic but 40% may be familial. The gross pathologic findings include cerebral atrophy predominantly in a frontal lobe and sometimes temporal lobe distribution. (Younes and Miller, 2020)

Microscopically, there is a spongy vacuolization of layer 2 of the frontal and temporal cortex, along with loss of neurons and gliosis, and no increase in neuritic plaques. Pick bodies may appear in 15% of cases. Some cases have been linked to mutations in the tau gene. Inclusions, both straight filaments and neurofibrillary tangles with paired helical filaments, of mutant tau protein are present. The more common variations of FTLD are given below. (Bigio, 2013)(Arvanitakis, 2010)

Pick disease is a distinctive but uncommon form of frontotemporal dementia which can appear similar to Alzheimer disease. The cerebral atrophy typically involves the frontal and temporal lobes and is so striking that it is "knife-like" in appearance. This atrophy may be asymmetrical. Microscopically, there is marked loss of cortical neurons with gliosis. Hallmarks include ballooned or swollen Pick cells and Pick bodies, neuronal intracytoplasmic inclusions of randomly arranged tau filaments that are highlighted by silver stain.

Mutations are found in the gene encoding for tau protein, associated with microtubules. The abnormal tau may be present in the microscopically apparent Pick bodies, which have partially degraded tau fibrils (called ubiquitinated, since they are positive with immunohistochemical staining for ubiquitin). (Bigio, 2013)(Perl, 2000)

Corticobasal degeneration (CBD) is classified as an akinetic rigid movement disorder consisting of progessive asymmetric rigidity and apraxia with late development of cognitive decline. However, a wider clinical spectrum, including dementia as an early finding, is possible. Postmortem gross pathologic findings include asymmetrical cortical atrophy of the posterior frontal, parietal, and the peri-Rolandic cortex contralateral to the limbs most severly affected in life. Histologic findings include focal/asymmetric neocortical atrophy, predominantly in the frontoparietal region, and ballooned achromatic neurons. Basal ganglia and nigral degeneration are often but not always present. The etiology is unknown but molecular studies indicate glial and neuronal accumulation of the tau protein as threadlike inclusions in affected areas. There is substantial pathological and clinical overlap with other neurodegenerative disorders such as Creutzfeld-Jakob disease, progessive supranuclear palsy, Alzheimer disease, and Pick disease. This can make unequivocal diagnosis difficult. (Bigio, 2013)(Boeve, 2007)(Younes and Miller, 2020)

Progressive supranuclear palsy (PSP) is classically marked by a supranuclear gaze palsy along with rigidity, but patients with this disorder may present with dementia that appears similar to Alzheimer disease. Clinical features include a gradually progressive onset at age 40 or later along with vertical supranuclear palsy and prominent postural instability with falls in the first year of disease onset, and no evidence of other diseases that could explain the foregoing features, as indicated by mandatory exclusion criteria. The pathologic diagnosis is made by the microscopic findings of globose neurofibrillary tangles and variable neuron loss with gliosis of the globus pallidus, subthalamic nucleus, periaqueductal grey matter of pons, and substantia nigra. Mutant tau protein is present in inclusions. (Bigio, 2013)(Boeve, 2007)(Younes and Miller, 2020) Pick disease, gross.

Pick disease, gross.

Progressive supranuclear palsy, globose tangle, Bielschowsky stain, microscopic.

Multi-infarct Dementia

Multi-infarct dementia (MID) can cause a dementia similar to Alzheimer disease (AD). However, no pathologic findings are present characteristic of AD. Instead, there are multiple ischemic lesions in the cerebral cortex that cumulatively result in loss of enough neurons to produce dementia. The cognitive impairment results from multiple lesions and infarcts in both white and gray matter that follow occlusions in cerebral arteries and arterioles. Most patients with MID have an incremental loss of mental function following each vascular event. Focal neurologic deficits can be present, depending upon the size and location of the infarcts. In some cases, though, there is gradual loss of mental function. Pathologically, marked cerebral arterial atherosclerosis and/or thromboembolic disease can account for the appearance of many infarcts, typically small and scattered. (McKay and Counts, 2017) Multi-infarct dementia, gross.

Huntington Disease

Huntington disease (HD) is a genetic disorder of increased CAG tandem repeat sequences in the huntingtin gene, resulting in pathologically elongated CAG‐repeat sequences which are translated into abnormally long polyglutamine stretches in the mutated huntingtin protein. The abnormal protein aggregates into intra‐neuronal inclusions, predominantly in the neostriatum with neuronal loss of GABA‐ergic medium spiny stellate projections neurons. (Rüb et al, 2016)

The HD mode of inheritance appears as autosomal dominant, with onset usually between the ages of 20 and 50 years, but most often in the 40's, with a course that averages 15 years to death. The abnormal gene, huntingtin (HTT), with increased CAG repeats encodes for a protein with a gain of toxic function through protein misfolding. Individuals without the disease have less than 36 repeats. In persons with more than 40 CAG repeats HD is present in over 99% of cases. Persons with 36 to 40 repeats have decreased penetrance and may be unaffected themselves but may transmit the disease to offspring. The greater the number of repeats, the earlier the onset of the disease. Spontanenous new mutations are uncommon. (McColgan and Tabrizi, 2018)

Affected persons may initially have diminished cognitive function, as well as behaviorial proglems including personality changes and psychiatric symptoms such as depression, schizophrenia‐like symptoms, disinhibition, restlessness, and irritability. The movement disorder may initially start with choreiform movements, followed by dystonia and then diminished movement with progressive neuronal loss in the caudate nucleus and putamen. (Rüb et al, 2016)

Pathologically there is diffuse atrophy of the caudate and putamen, along with lesser atrophy of globus pallidus and nucleus accumbens. Microscopically there is severe loss of small spiny neurons in the caudate and putamen with subsequent astrocytosis. With the loss of cells, the head of the caudate becomes shrunken and there is "ex vacuo" dilatation of the anterior horns of the lateral ventricles. There is a loss of gamma aminobutyric acid (GABA), acetylcholine and substance P. (Purdon et al, 1994) Huntington disease, gross.

Huntington disease, microscopic.

Parkinson Disease and Parkinsonism

There is a spectrum of clinical disorders with features of a movement disorder and a pathophysiology linked to abnormalities in alpha-synuclein. These alpha-synucleinopathies include not only Parkinson disease but also Lewy body disease and multiple system atrophy. Parkison-like findings can be present with the tauopathies of progressive supranuclear palsy and corticobasal degeneration. These disorders are defined by predominantly alpha-synuclein or tau protein accumulating in neurons and glia. (Dickson, 2018)

Most cases of Parkinson disease (PD) are sporadic. This syndrome covers several diseases of different etiologies which affect primarily the pigmented neuronal groups including the substantia nigra, locus ceruleus, dorsal motor nucleus of cranial nerve X and the substantia innominata. There is loss of dopaminergic neurons predominantly in the substantia nigra pars compacta and the presence of intracellular Lewy bodies composed of alpha-synuclein. Idiopathic PD commonly begins in late middle age and the course is slowly progressive. Movement problems include a festinating gait, cogwheel rigidity of the limbs, poverty of voluntary movement, and a pill rolling type of tremor at rest. In time the facies become mask-like. Usually mental deterioration does not occur but some patients may become demented as the disease progresses. The pigmented neurons are slowly lost as the disease progresses and melanin pigment can be seen within the background neuropil or within macrophages. Astrocytosis occurs secondary to neuronal loss. (Takahashi and Wakabayashi, 2001) (Eriksen et al, 2005) (Choong and Mochizuki, 2022)

Some patients with Parkinsonian symptoms also have dementia, and in these patients there are Lewy bodies in the cerebral cortex, as well as the substantia nigra. This can be termed Lewy body dementia, and it is in the differential diagnosis for Alzheimer disease. Pathologically, Lewy bodies in association with Parkinson disease are found within the cytoplasm of pigmented neurons. For a diagnosis of Lewy body dementia, the Lewy bodies must be found in the neocortex. These are homogeneous pink bodies on H&E stains with a surrounding halo. Immunohistochemical staining with antibody to alpha-synuclein is positive in these Lewy bodies. (Kosaka, 2000)

There are genetic markers for PD. Mutations in the PARK2 gene encoding for the protein parkin have been identified in some rare familial forms of PD. An autosomal dominant form with mutations in the alpha-synuclein gene has also been described. Additional genes with mutations associated with PD include DJ1 and PINK1. (Eriksen et al, 2005)

Multiple system atrophy (MSA) has overlapping features which may include movement disorder (parkinsonism), autonomic dysfunction, and cerebellar ataxia. Past literature may refer to names such as striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Most patients with MSA exhibit symptoms similar to Parkinson disease, but with alpha-synucleinopathy in oligodendroglial cells and not neurons. The clinical appearance is that of a sporadic, progressive, adult-onset disorder with autonomic dysfunction (orthostatic hypotension or urinary incontinence/retention, parkinsonism cerebellar dysfunction, and corticospinal tract signs. MSA is characterized microscopically by the appearance of glial cytoplasmic inclusions. Tau positive inclusions are present. (Bigio, 2013)(Dickson, 2018) Parkinson disease, gross.

Parkinson disease, microscopic.

Lewy bodies, microscopic.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is also known as Lou Gehrig's disease after the famous Yankee first baseman who had this disease. ALS results from loss of motor neurons. This is most striking in the anterior horn cells of spinal cord with loss of lower motor neurons, marked initially by muscle fasciculations. ALS may also involve upper motor neurons including cranial motor nuclei and Betz cells of neocortex, evidenced by spasticity of muscles. The loss motor innervation eventually leads to muscle atrophy. Astrocytosis is seen in response to the loss of motor neurons. With loss of upper motor neurons there is lateral column degeneration with gliosis, the so-called "sclerosis" of the lateral columns of spinal cord. Males are affected more commonly than females. The patients present in middle age with weakness of the extremities and may go on to develop bulbar signs and symptoms. Sphincter control, sensation, intellectual function are not affected by ALS. The course is usually 2 to 6 years after diagnosis, but patients presenting with bulbar signs and symptoms have a shorter life span because of swallowing difficulties and aspiration. The etiology is unknown. Familial cases may be association with mutations in the superoxide dismutase-1 (SOD1) gene. (Walling, 1999) (Saberi et al, 2015) Amyotrophic lateral sclerosis, gross.

Amyotrophic lateral sclerosis. microscopic.

Amyotrophic lateral sclerosis, microscopic, Luxol fast blue stain.

Amyotrophic lateral sclerosis, muscle biopsy, microscopic, trichrome stain.

Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) results from repetitive head injuries that most often occur with contact sports, but can result from other forms of repeated head trauma, and with a dose-response relationship (more trauma = more pathologic findings). Initial clinical features with each event may resemble concussion. A progression of neuropathologic findings can occur, but the key microscopic finding is the presence of abnormally phosphorylated tau protein as aggregated filaments formin neurofibrillary tangles in neurons. Initially, the tangles appear in depths of neocortical sulci in a perivascular distribution. Next, tangles may appear in superficial neocortex. Further progression involves medial temporal lobe, hypothalamus, thalamus, nucleus basalis, mammillary bodies, substantia nigra, raphe nuclei, and locus coeruleus. Eventually there are tangles throughout the brain along with progressive myelin and myelinated axon loss. Cerebral cortical atrophy may become pronounced with ventricular enlargement. (Mehta and Schneider, 2023)(McKee et al, 2023)

Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, with most sporadic cases occurring between the ages of 55 and 65, but familial or infectious cases can occur in younger adults. The course of the illness can be from a few weeks to eight years. However, the average length of survival from onset of the disease is less than a year. CJD is a uniformly fatal rapidly progressive dementia. (Markus et al, 2005)

The clinical features of CJD include dementia, often with psychiatric or behavioral disturbances, in 100% of cases. About 80% of cases are marked by the appearance of myoclonus. By electroencephalography (EEG), there are periodic biphasic or triphasic synchronous sharp-wave complexes that are superimposed upon a slow background rhythm. Both myoclonus and characteristic EEG changes may subside late in the course of disease. Other neurologic findings may include cerebellar signs, pyramidal tract signs, extrapyramidal signs, corticla visual defects, abnormal extraocular movements, lower motor neuron signs, vestibular dysfunction, seizures, sensory deficits, and autonomic abnormalities. (Tee et al, 2018)

Routine laboratory findings are not helpful. There is no dysfunction of major organ systems besides the central nervous system. Cerebrospinal fluid (CSF) will not show an increase in cells or immunoglobulins, and occasionally a mildly elevated protein. An abnormal protein called 14-3-3 can be found in the CSF by immunoassay, but this protein may be found in association with viral encephalitis and stroke. Clinical diagnosis can be made using the real-time quaking-induced conversion (RT-QuIC) assay which detects femtogram amounts of abnormal prion protein from all subtypes of sporadic CJD. The RT-QuIC assay is run on cerebrospinal fluid (CSF) and nasal olfactory mucosa. (Bongianni et al, 2016)

There are no characteristic gross pathologic features of CJD. In fact, because of the typical short course of the disease, no gross changes are seen at all. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy. The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be. The PrPres can be identified in tissues with immunohistochemical staining. (Prusiner, 1998)

The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by just 3 exons of the PRNP gene on chromosome 20. It is thought that the normal cellular prion protein, designated PrPc, is converted via a conformational change to an abnormal form of PrP, designated PrPSc, that is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation of abnormal protein, thus designated PrPres accounts for the degenerative changes in the cerebral cortex by inducing conformational change in the normal PrP, designated PrPC. The accumulation of PrPres leads to loss of neuronal cell function, vacuolization, and death. (Prusiner, 1998) (Markus et al, 2005)

These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes. Transmission via close personal contact, in the workplace, or via transfusion of blood products does not appear to occur. How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP. (Prusiner, 1998)

The presence of particular polymorphisms at codon 129 of PrP may have an influence on susceptibility to disease. The amino acids methionine (M) or valine (V) may be present. In healthy persons, both inherited PrP genes code for methionine. Many persons with sporadic CJD have abnormal phenotypes. However, subgroups of sporadic CJD can be found with all polymorphisms, but differing characteristics. (Mead, 2006)

CJD is one form of spongiform encephalopathy; others include Kuru and fatal familial insomnia. There are other forms of which can affect mammalian species besides humans. The spongiform encephalopathy known as scrapie that is seen in sheep is poorly transmissible to other species. However, bovine spongiform encephalopathy (BSE), also called "mad cow disease", can be transmitted more readily to animals other than cattle. The relationship of human spongiform encephalopathy with animal forms of this disease is not entirely clear. An outbreak of BSE among cattle in England in the 1980's was followed by the appearance of rare cases of a CJD-like illness in the 1990's that were characterized by younger age of onset, lack of characteristic EEG findings, longer course of disease, and more extensive spongiform change with plaques in the brains of affected persons. These cases are known as variant Creutzfeldt-Jakob disease (vCJD). This suggests the possibility of a relationship, but the rarity of vCJD cases, similar to the rarity of standard CJD cases, precludes compelling epidemiologic evidence. Cases of vCJD continue to appear in regions were BSE was prevalent. (Tee et al, 2018) Creutzfeldt-Jakob disease, high power microscopic.

Creutzfeldt-Jakob disease, high power microscopic.

Creutzfeldt-Jakob disease, medium power microscopic.

Creutzfeldt-Jakob disease, high power microscopic.

Variant Creutzfeldt-Jakob disease (vCJD), high power microscopic.

Creutzfeldt-Jakob disease, MRI scan.

References

Arvanitakis Z. Update on frontotemporal dementia. Neurologist. 2010;16:16-22.

Bigio EH. Making the diagnosis of frontotemporal lobar degeneration. Arch Pathol Lab Med. 2013;137:314-325.

Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet. 2006 Jul 29;368(9533):387-403.

Boeve BF. Parkinson-related dementias. Neurol Clin. 2007;25:761-781.

Bongianni M, Orr C, Groveman BR, et al. Diagnosis of Human Prion Disease Using Real-Time Quaking-Induced Conversion Testing of Olfactory Mucosa and Cerebrospinal Fluid Samples. JAMA Neurol. Published online December 12, 2016. doi:10.1001/jamaneurol.2016.4614

Choong CJ, Mochizuki H. Neuropathology of alpha-synuclein in Parkinson's disease. Neuropathology. 2022 Apr;42(2):93-103. doi: 10.1111/neup.12812.

Dickson DW. Neuropathology of Parkinson disease. Parkinsonism Relat Disord. 2018 Jan;46 Suppl 1(Suppl 1):S30-S33. doi: 10.1016/j.parkreldis.2017.07.033.

Eriksen JL, Wszolek Z, Petrucelli L. Molecular pathogenesis of Parkinson disease. Arch Neurol. 2005;62:353-357.

Lane CA, Hardy J, Schott JM. Alzheimer's disease. Eur J Neurol. 2018;25(1):59-70.

Galluzzi S, Geroldi C, Amicucci G, Bocchio-Chiavetto L, Bonetti M, Bonvicini C, Cotelli M, et al. Supporting evidence for using biomarkers in the diagnosis of MCI due to AD. J Neurol. 2013;260(2):640-50.

Glatzel M, Stoeck K, Seeger H, Lührs T, Aguzzi A. Human prion diseases: molecular and clinical aspects. Arch Neurol. 2005;62:545-552.

Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. J Nucl Med. 2013;54:476-490.

Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer's disease. Brain. 2006;129(Pt 11):2840-2855.

Kövari E, Horvath J, Bouras C. Neuropathology of Lewy body disorders. Brain Res Bull. 2009;80(4-5):203-210.

McColgan P, Tabrizi SJ. Huntington's disease: a clinical review. Eur J Neurol. 2018;25(1):24-34.

McKay E, Counts SE. Multi-Infarct Dementia: A Historical Perspective. Dement Geriatr Cogn Dis Extra. 2017 May 4;7(1):160-171. doi: 10.1159/000470836.

Mead S. Prion disease genetics. Eur J Hum Genet. 2006;14:273-281.

Mehta RI, Schneider JA. Neuropathology of the Common Forms of Dementia. Clin Geriatr Med. 2023 Feb;39(1):91-107. doi: 10.1016/j.cger.2022.07.005.

Mirra SS, Hart MN, Terry RD. Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists. Arch Pathol Lab Med. 1993;117:132-144.

Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers. Lancet Neurol. 2017;16(8):661-676.

McKee AC, Stein TD, Huber BR, et al. Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts. Acta Neuropathol. 2023 Apr;145(4):371-394. doi: 10.1007/s00401-023-02540-w.

Prusiner SB. Prions. Proc Natl Acad Sci U S A. 1998;95:13363-83.

Purdon SE, Mohr E, Ilivitsky V, Jones BD. Huntington's disease: pathogenesis, diagnosis and treatment. J Psychiatry Neurosci. 1994;19:359-367.

Rüb U, Seidel K, Heinsen H, Vonsattel JP, den Dunnen WF, Korf HW. Huntington's disease (HD): the neuropathology of a multisystem neurodegenerative disorder of the human brain. Brain Pathol. 2016 Nov;26(6):726-740. doi: 10.1111/bpa.12426.

Saberi S, Stauffer JE, Schulte DJ, Ravits J. Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants. Neurol Clin. 2015;33(4):855-76.

Takahashi H, Wakabayashi K. The cellular pathology of Parkinson's disease. Neuropathology. 2001;21:315-322.

Tee BL, Longoria Ibarrola EM, Geschwind MD. Prion Diseases. Neurol Clin. 2018 Nov;36(4):865-897. doi: 10.1016/j.ncl.2018.07.005.

Walling AD. Amyotrophic lateral sclerosis: Lou Gehrig's disease. Am Fam Physician. 1999;59:1489-1496.

Weintraub D, Irwin D. Diagnosis and Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Bodies. Continuum (Minneap Minn). 2022 Oct 1;28(5):1314-1332. doi: 10.1212/CON.0000000000001151.

Younes K, Miller BL. Frontotemporal Dementia: Neuropathology, Genetics, Neuroimaging, and Treatments. Psychiatr Clin North Am. 2020 Jun;43(2):331-344. doi: 10.1016/j.psc.2020.02.006.

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