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, 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 on 4 chromosomes (Blennow et al, 2006):
|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 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, 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 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 feature of AD are: an increased number of amyloid-containing and neuritic plaques in the cerebral cortex and neurofibrillary tangles predominantly in the hippocampus. (Mirra et al, 1993) (Frisoni et al, 2017) Criteria for diagnosis of AD combine pathologic features with clinical findings. (Hyman et al, 2012)
Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may 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. (Gomperts, 2016)
There are three major syndromes associated with the appearance of Lewy bodies. These are: the movement disorder known as Parkinson disease, 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 have a movement disorder resembling Parkinson disease. Conversely, some patients initially presenting with Parkinson disease may develop manifestations of Lewy body dementia. (Brown, 1999) (Kosaka, 2000) When cognitive impairment is present with LBD, some neuropathologic features of Alzeimer dementia are usually present as well. (Hyman et al, 2012)
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. (Kalra et al, 1996) (Kosaka, 2000)
Lewy bodies are spherical, intraneuronal, cytoplasmic, eosinophilic inclusions comprising abnormally truncated and phosphorylated intermediate neurofilament proteins, alpha-synuclein, ubiquitin, and associated enzymes. 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. (Kövari et al, 2009)
- Diffuse Lewy body disease, microscopic.
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. About 90% of cases are sporadic and the rest familial. The gross pathologic findings are similar to Pick disease, with marked atrophy in a frontal lobe and sometimes temporal lobe distribution.
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 form of frontotemporal dementia. It is an uncommon cause for dementia, but it appear similar to Alzheimer disease. The cerebral atrophy with Pick disease is lobar and typically involves the frontal and temporal lobes. This atrophy 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. Pick bodies, cytoplasmic inclusions that are highlighted by silver stain, are seen in the cortex.
Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in Pick disease. The abnormal tau may be present in the microscopically apparent Pick bodies, which have partially degraded (called ubiquitinated, since they are positive with immunohistochemical staining for ubiquitin) tau fibrils. (Bigio, 2013)(Perl, 2000)
Corticobasal degeneration (CBD) is classified as an akinetic rigid movement disorder classically 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 features 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, which predominantly involves the frontoparietal region in most cases, 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)
Multiple system atrophy (MSA) has features that overlap striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Most patients with MSA exhibit symptoms similar to Parkinson disease. 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)(Boeve, 2007)
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)
- Pick disease, gross.
- Pick disease, gross.
- Progressive supranuclear palsy, globose tangle, Bielschowsky stain, microscopic.
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. Most patients with MID have an abrupt onset of cognitive symptoms along with an incremental loss of mental function. 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. (Perl, 2000)
- Multi-infarct dementia, gross.
This autosomal dominant disease usually presents between the ages of 20 and 50 years, with a course that averages 15 years to death. Patients often present initially with choreiform movements, followed by dystonia and eventual paucity of movement as the corpus striatum (caudate nucleus and putamen) undergoes progressive neuronal loss. There is character change and eventual psychiatric problems later in the course. The genetic defect is localized to chromosome 4. The abnormal gene, huntingtin (HTT), contains trinucleotide CAG repeat sequences and encodes for a protein that, when mutated has 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)
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.
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. Patients usually present with movement problems such as a festinating gait, cogwheel rigidity of the limbs, poverty of voluntary movement, and a pill rolling type of tremor at rest. In time the patient's facies will become mask-like. Usually mental deterioration does not occur but some patients may become demented as the disease progresses. Idiopathic PD commonly begins in late middle age and the course is slowly progressive. 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. (Hughes et al, 1993) (Takahashi and Wakabayashi, 2001) (Eriksen et al, 2005)
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)
- 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.
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. (Johnson, 2005)
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. (Johnson, 2005)
- 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.
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
Gomperts SN. Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia. Continuum (Minneap Minn). 2016;22(2 Dementia):435-63.
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.
Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic study of 100 cases of Parkinson's disease. Arch Neurol. 1993;50:140-148.
Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 2012;8(1):1-13.
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.
Johnson RT. Prion diseases. Lancet Neurol. 2005;4:635-642.
Kalra S, Bergeron C, Lang AE. Lewy body disease and dementia. A review. Arch Intern Med. 1996;156:487-493.
Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer's disease. Brain. 2006;129(Pt 11):2840-2855.
Kosaka K. Diffuse Lewy body disease. Neuropathology. 2000;20 Suppl:S73-8.
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.
Mead S. Prion disease genetics. Eur J Hum Genet. 2006;14:273-281.
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.
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.
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.
Walling AD. Amyotrophic lateral sclerosis: Lou Gehrig's disease. Am Fam Physician. 1999;59:1489-1496.