Medical School · Year 2 · Neuroscience · includes a discussion video

Lecture 21: Neurodegenerative and Demyelinating Diseases

Unit 2.5: Neuroscience

Learning Objectives

By the end of this lecture, students will be able to:

1. Explain the pathophysiology of neurodegenerative diseases including the role of protein aggregation and selective neuronal vulnerability
2. Describe the clinical features, diagnosis, and management of Alzheimer's disease including disease-modifying therapies
3. Differentiate between major dementia syndromes (Alzheimer's, vascular dementia, dementia with Lewy bodies, frontotemporal dementia) based on clinical features
4. Describe the pathophysiology, clinical course types, and diagnostic criteria for multiple sclerosis
5. Explain the treatment approach to multiple sclerosis including acute relapse management and disease-modifying therapies
6. Compare neuromyelitis optica spectrum disorder and other demyelinating conditions with multiple sclerosis

Lecture Outline

I. Neurodegenerative Diseases Overview

Neurodegenerative diseases share the fundamental feature of progressive neuronal loss in specific brain regions, leading to gradual decline in cognitive, motor, or other neurological functions. Despite their varied presentations, these disorders share common pathological mechanisms that have become central to our understanding of their biology.

Protein aggregation represents the pathological hallmark of most neurodegenerative conditions. In each disease, specific proteins misfold and accumulate abnormally, forming insoluble aggregates within or around neurons. Alzheimer's disease is characterized by extracellular amyloid-beta plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Parkinson's disease and related synucleinopathies feature Lewy bodies containing aggregated alpha-synuclein. Frontotemporal dementia may involve tau or TDP-43 accumulation. Huntington's disease results from aggregation of mutant huntingtin protein with expanded polyglutamine repeats. This protein-centric classification has transformed our approach to these diseases.

Selective vulnerability explains why specific neuronal populations degenerate in each disease while others are spared. In Alzheimer's disease, hippocampal and entorhinal cortex neurons are affected early, explaining the prominent memory impairment. In Parkinson's disease, dopaminergic neurons of the substantia nigra pars compacta are selectively vulnerable, producing the characteristic motor features. In amyotrophic lateral sclerosis, upper and lower motor neurons degenerate while sensory neurons are spared. This selective vulnerability reflects intrinsic differences in neuronal properties including metabolic demands, protein handling capacity, and connectivity patterns.

Common mechanisms link these diverse conditions. Protein misfolding triggers a cascade of cellular dysfunction. Aggregated proteins may spread between neurons in a prion-like manner, following anatomical connectivity patterns. Neuroinflammation, with microglial activation and astrocyte reactivity, contributes to neuronal damage. Mitochondrial dysfunction leads to energy failure and oxidative stress. Impaired autophagy and proteasomal function compromise the cell's ability to clear abnormal proteins. Genetic factors, both causative mutations and risk-modifying variants, influence disease susceptibility and progression.

<image>Panel A displays the protein classification of neurodegenerative diseases with each disease matched to its characteristic protein aggregate (amyloid/tau, synuclein, TDP-43, huntingtin, prion). Panel B illustrates selective vulnerability with brain diagrams showing the regions affected early in each major disease (hippocampus in AD, substantia nigra in PD, frontal lobes in FTD, motor cortex/spinal cord in ALS). Panel C diagrams common pathogenic mechanisms including protein misfolding, prion-like spread, neuroinflammation, mitochondrial dysfunction, and impaired protein clearance. Panel D presents the genetic landscape showing causative mutations and risk genes for major neurodegenerative conditions.</image>

II. Alzheimer's Disease

Alzheimer's disease is the most common cause of dementia, accounting for 60-80% of cases. Its prevalence rises dramatically with age, doubling every five years after age 65, making it one of the greatest healthcare challenges of an aging population.

The pathophysiology centers on two hallmark lesions. Amyloid plaques are extracellular deposits of amyloid-beta (A-beta) peptide, derived from proteolytic cleavage of amyloid precursor protein (APP). The amyloid cascade hypothesis proposes that A-beta accumulation is the initiating event that triggers downstream pathology. Neurofibrillary tangles are intracellular aggregates of hyperphosphorylated tau protein. Normally, tau stabilizes microtubules; when hyperphosphorylated, it detaches and aggregates into paired helical filaments. The distribution of tangles correlates better with clinical symptoms than plaque burden, following a predictable pattern (Braak staging) from entorhinal cortex to hippocampus to neocortex.

Neuronal loss and synaptic dysfunction drive clinical symptoms. The hippocampus and entorhinal cortex degenerate early, explaining the characteristic memory impairment. Temporal and parietal association cortices are affected subsequently. Cholinergic neurons of the nucleus basalis of Meynert, which project widely to cortex, are particularly vulnerable, providing the rationale for cholinesterase inhibitor therapy.

Risk factors include age (the strongest), family history, and the apolipoprotein E4 (APOE4) allele—the most important genetic risk factor in sporadic disease. Heterozygotes for APOE4 have approximately 3-fold increased risk; homozygotes have approximately 12-fold risk. Cardiovascular risk factors (hypertension, diabetes, obesity, sedentary lifestyle) also increase Alzheimer's risk, suggesting vascular contributions to pathogenesis.

Clinical features progress through recognizable stages. The preclinical phase features biomarker positivity without symptoms. Mild cognitive impairment (MCI) due to Alzheimer's involves memory impairment greater than expected for age but preserved functional independence. Mild dementia adds instrumental activities of daily living (IADL) impairment—managing finances, medications, driving. Moderate dementia affects basic activities of daily living (ADL) with prominent behavioral changes. Severe dementia features near-complete dependence and minimal communication.

Diagnosis integrates clinical assessment and biomarkers. The clinical picture requires progressive memory impairment plus impairment in at least one other cognitive domain. Biomarkers include amyloid PET imaging, CSF A-beta (decreased) and tau (increased), and MRI showing hippocampal atrophy. Definitive diagnosis still requires pathological confirmation at autopsy.

<image>Panel A illustrates Alzheimer pathology at the molecular level showing APP processing to A-beta, plaque formation, tau hyperphosphorylation, and tangle formation. Panel B displays Braak staging with brain images showing the progression of neurofibrillary tangle distribution from entorhinal cortex through hippocampus to neocortical involvement. Panel C correlates pathological stages with clinical symptoms across the disease spectrum from preclinical to severe. Panel D presents diagnostic biomarkers including amyloid PET, CSF markers, and MRI atrophy patterns.</image>

III. Alzheimer's Disease Management

Treatment of Alzheimer's disease encompasses symptomatic therapy, emerging disease-modifying approaches, and comprehensive supportive care.

Cholinesterase inhibitors remain the mainstay of symptomatic treatment. These drugs increase synaptic acetylcholine by inhibiting its breakdown, partially compensating for the cholinergic deficit. Donepezil inhibits acetylcholinesterase, is given once daily, and is approved for all stages. Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase and is available as a patch formulation that reduces gastrointestinal side effects. Galantamine combines acetylcholinesterase inhibition with nicotinic receptor modulation. The efficacy of these agents is modest—they may slow decline temporarily but do not alter disease trajectory. Common side effects include nausea, diarrhea, and bradycardia.

Memantine, an NMDA receptor antagonist, provides additional benefit in moderate-to-severe disease. By blocking excessive glutamatergic stimulation, memantine may reduce excitotoxicity. It is commonly combined with a cholinesterase inhibitor in later stages.

Disease-modifying therapies targeting amyloid have recently reached clinical application. Aducanumab, a monoclonal antibody against aggregated A-beta, received controversial FDA accelerated approval in 2021 based on amyloid reduction as a surrogate endpoint. Lecanemab, also targeting A-beta, received FDA approval in 2023 after demonstrating modest slowing of cognitive decline in early Alzheimer's disease. Donanemab showed similar results in phase 3 trials. These anti-amyloid antibodies reduce brain amyloid burden and slow clinical decline by approximately 25-35% in early disease, but require careful patient selection (confirmed amyloid pathology) and carry risks including amyloid-related imaging abnormalities (ARIA)—cerebral edema and microhemorrhages.

Supportive care is essential throughout the disease. Behavioral symptoms (agitation, aggression, psychosis) are common and distressing; non-pharmacological approaches (structured environment, routine, caregiver education) should be tried first, with medications reserved for severe symptoms. Safety concerns include driving (assessment and eventual cessation), wandering, falls, and firearm access. Caregiver support through education, support groups, and respite care is crucial—caregiver burden is substantial. Advanced care planning discussions should occur early, while the patient can participate, addressing goals of care, healthcare proxy, and end-of-life preferences.

<image>Panel A diagrams the cholinergic hypothesis and mechanism of cholinesterase inhibitors at the synapse, showing how increased acetylcholine availability partially compensates for neuronal loss. Panel B illustrates the mechanism of anti-amyloid antibodies showing binding to A-beta plaques, microglial recruitment, and plaque clearance. Panel C displays ARIA (amyloid-related imaging abnormalities) on MRI with examples of cerebral edema and microhemorrhages. Panel D outlines comprehensive supportive care domains including behavioral management, safety assessment, caregiver support, and advance care planning.</image>

IV. Other Dementia Syndromes

While Alzheimer's disease is the most common dementia, other syndromes have distinct features that guide diagnosis and management.

Vascular dementia results from cerebrovascular disease—strokes, chronic small vessel disease, or both. The presentation varies with the pattern of vascular injury. Multi-infarct dementia follows discrete strokes with stepwise deterioration corresponding to each event. Subcortical ischemic vascular dementia from diffuse small vessel disease produces a more gradual course with prominent executive dysfunction, psychomotor slowing, gait disturbance, and early urinary symptoms. Brain imaging shows infarcts, lacunes, or extensive white matter hyperintensities. The treatment approach emphasizes secondary stroke prevention through vascular risk factor control. Vascular pathology commonly coexists with Alzheimer pathology (mixed dementia).

Dementia with Lewy bodies (DLB) represents the second most common degenerative dementia. It shares alpha-synuclein pathology with Parkinson's disease but with earlier and more prominent cognitive symptoms. Core clinical features include fluctuating cognition with pronounced variations in attention and alertness, recurrent visual hallucinations that are typically well-formed and detailed (people, animals), spontaneous parkinsonism, and REM sleep behavior disorder (acting out dreams, often preceding cognitive symptoms by years). A crucial characteristic is severe sensitivity to neuroleptic medications, which can cause dramatic worsening or neuroleptic malignant syndrome—antipsychotics should be avoided or used with extreme caution. Cholinesterase inhibitors are often helpful, particularly for hallucinations.

Frontotemporal dementia (FTD) encompasses a group of disorders affecting the frontal and temporal lobes, typically presenting earlier than Alzheimer's disease (often between ages 45-65). The behavioral variant (bvFTD) features progressive personality change: early behavioral disinhibition, apathy, loss of empathy, perseverative or compulsive behaviors, hyperorality, and dietary changes. Executive function is impaired while memory may be relatively preserved early. Primary progressive aphasias represent language-predominant variants: semantic variant PPA features progressive loss of word and object meaning, while nonfluent variant PPA produces effortful, agrammatic speech with relatively preserved comprehension. Pathologically, FTD may involve tau, TDP-43, or FUS protein accumulation. Genetic causes (C9orf72 repeat expansion, MAPT mutations, GRN mutations) account for 30-50% of cases.

The differential diagnosis among dementias relies on careful clinical characterization. Memory impairment is early and prominent in Alzheimer's disease but may appear later in FTD. Visual hallucinations and parkinsonism suggest DLB. Early personality change and disinhibition point to bvFTD. Stepwise progression with focal neurological signs indicates vascular dementia.

<image>Panel A compares brain imaging across dementia types: hippocampal atrophy in Alzheimer's, strategic infarcts and white matter changes in vascular dementia, occipital hypometabolism in DLB, and frontal/temporal atrophy in FTD. Panel B illustrates the core features of DLB with icons representing fluctuations, hallucinations, parkinsonism, and REM sleep behavior disorder. Panel C shows the anatomical and clinical variants of frontotemporal dementia with behavioral, semantic, and nonfluent presentations. Panel D creates a comparison matrix differentiating the major dementias by age of onset, presenting features, memory involvement, motor features, and hallucinations.</image>

V. Other Neurodegenerative Conditions

Several additional neurodegenerative diseases warrant discussion.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease affecting both upper motor neurons (in motor cortex) and lower motor neurons (in brainstem and spinal cord). The combination of UMN and LMN signs in the same territory is the clinical hallmark: weakness with both spasticity (UMN) and fasciculations and atrophy (LMN). Limb-onset (70%) presents with asymmetric weakness in an arm or leg; bulbar-onset (30%) presents with dysarthria and dysphagia. Notably spared are sensation, eye movements (until late), and bladder function. Cognition may be affected, with up to 50% showing some cognitive change and 15% meeting criteria for frontotemporal dementia (ALS-FTD overlap). The disease progresses relentlessly, with median survival of 3-5 years, usually from respiratory failure. Treatment includes riluzole (modest survival benefit), edaravone (slows functional decline modestly), and supportive care including respiratory support (noninvasive ventilation) and nutritional support (PEG tube).

Progressive supranuclear palsy (PSP) is a tauopathy presenting with early postural instability and falls (often backward), vertical supranuclear gaze palsy (particularly downgaze), axial rigidity greater than limb rigidity, and executive dysfunction. Unlike Parkinson's disease, the rigidity is axial-predominant, the gaze palsy is characteristic, and response to levodopa is poor. The disease progresses more rapidly than Parkinson's disease.

Corticobasal degeneration (CBD) is another tauopathy featuring markedly asymmetric rigidity and dystonia, often affecting one limb that may display "alien limb" phenomenon (involuntary movements experienced as foreign). Cortical sensory loss and apraxia are prominent. Like PSP, it responds poorly to dopaminergic therapy.

Huntington's disease results from a CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. Inheritance is autosomal dominant with full penetrance when repeats exceed 40. The clinical triad comprises chorea (involuntary, dance-like movements), cognitive decline (particularly executive dysfunction), and psychiatric symptoms (depression, irritability, psychosis). Brain imaging shows characteristic caudate atrophy. The phenomenon of anticipation means successive generations experience earlier onset and more severe disease due to repeat expansion during transmission. Treatment is symptomatic; tetrabenazine and deutetrabenazine reduce chorea by depleting dopamine.

<image>Panel A illustrates ALS pathophysiology showing upper motor neuron degeneration in motor cortex and lower motor neuron degeneration in spinal cord, with the characteristic combination of UMN and LMN signs. Panel B demonstrates the eye movement findings in PSP with impaired vertical gaze, particularly downgaze, while horizontal movements are relatively preserved. Panel C shows CBD features including alien limb phenomenon and asymmetric motor findings. Panel D presents Huntington's disease genetics with the CAG repeat expansion, autosomal dominant inheritance pattern, anticipation phenomenon, and characteristic caudate atrophy on imaging.</image>

VI. Multiple Sclerosis Overview

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, representing the most common cause of non-traumatic neurological disability in young adults.

Epidemiology reveals important patterns. Prevalence in the United States is approximately 1 million, with women affected three times more often than men. Peak onset is between ages 20-40. A striking geographic gradient exists: risk increases with latitude, higher in temperate climates than equatorial regions. This observation, combined with migration studies, suggests environmental factors operating in early life. Risk factors include Epstein-Barr virus infection (nearly universal in MS patients, suggesting a causal role), low vitamin D levels, smoking, and genetic susceptibility (strongest association with HLA-DRB1*15:01).

The pathophysiology involves immune-mediated attack on CNS myelin. Both T cells and B cells participate. Autoreactive T cells cross the blood-brain barrier and mount an inflammatory response against myelin antigens. B cells contribute through antibody production and antigen presentation. The resulting inflammation causes demyelination—destruction of the myelin sheath surrounding axons. Acute lesions (plaques) feature inflammation, demyelination, and edema. With remyelination and resolution of inflammation, symptoms may improve. However, chronic lesions show gliosis (scarring, the "sclerosis" of the disease name) and axonal damage. This axonal injury, accumulating over time, underlies progressive disability.

Clinical course types define the patterns of disease activity. Relapsing-remitting MS (RRMS), accounting for approximately 85% at onset, features discrete attacks (relapses) of neurological dysfunction with subsequent partial or complete recovery. Secondary progressive MS (SPMS) develops when patients with RRMS transition to gradual worsening independent of relapses. Primary progressive MS (PPMS), approximately 15% at onset, features gradual worsening from disease onset without distinct relapses. Clinically isolated syndrome (CIS) describes a first clinical episode suggestive of MS. Radiologically isolated syndrome refers to MS-typical MRI findings discovered incidentally without clinical symptoms.

Common clinical manifestations reflect the predilection for certain CNS regions. Optic neuritis causes unilateral vision loss with pain on eye movement. Sensory symptoms include numbness, tingling, and Lhermitte's sign (electrical sensation down the spine with neck flexion). Motor symptoms include weakness and spasticity. Cerebellar involvement produces ataxia, tremor, and dysarthria. Brainstem lesions cause diplopia, facial weakness, and vertigo. Bladder dysfunction (urgency, frequency, incontinence) is common. Fatigue, often disabling, affects most patients. Cognitive impairment, particularly affecting processing speed and memory, occurs in 40-70%.

<image>Panel A displays the epidemiology of MS with a world map showing prevalence gradient by latitude and demographic information. Panel B illustrates the immunopathophysiology at the blood-brain barrier showing T cell and B cell entry, myelin attack, demyelination, and gliosis. Panel C compares clinical course types with graphs showing disability over time in RRMS (stepwise), SPMS (initial relapses then progression), and PPMS (steady progression). Panel D presents common symptoms organized by anatomical location (optic nerve, brainstem, spinal cord, cerebellum, cerebrum).</image>

VII. Multiple Sclerosis Diagnosis

The diagnosis of MS requires demonstrating dissemination of disease in both space (multiple CNS locations) and time (evidence of ongoing or repeated disease activity), while excluding alternative diagnoses.

The McDonald Criteria (most recently updated in 2017) formalize the diagnostic requirements. A patient presenting with a typical clinical attack affecting one CNS site needs additional evidence of dissemination in space (DIS) and dissemination in time (DIT). Clinical evidence (a second attack) can satisfy these criteria, but MRI and CSF findings can substitute for clinical evidence, allowing earlier diagnosis.

MRI findings are central to diagnosis. T2-weighted and FLAIR sequences reveal hyperintense lesions in characteristic locations: periventricular (the classic "Dawson's fingers" appearing perpendicular to the ventricles), juxtacortical (at the gray-white junction), infratentorial (brainstem, cerebellum), and spinal cord (often multiple levels, partial cross-section). Gadolinium enhancement indicates active inflammation (blood-brain barrier breakdown), distinguishing new lesions. T1 hypointense lesions ("black holes") suggest axonal damage and tissue destruction. Demonstrating DIS requires lesions in at least two of the four characteristic locations. Demonstrating DIT requires a new lesion on follow-up MRI or the simultaneous presence of enhancing and non-enhancing lesions.

Cerebrospinal fluid analysis supports the diagnosis. Oligoclonal bands—immunoglobulin G bands present in CSF but not in serum—are found in over 95% of MS patients, indicating intrathecal antibody synthesis. An elevated IgG index similarly reflects intrathecal IgG production. Mild lymphocytic pleocytosis may be present but usually fewer than 50 cells. Normal CSF glucose and protein help exclude other conditions.

The differential diagnosis includes several important mimics. Neuromyelitis optica spectrum disorder (NMOSD) presents with severe optic neuritis and longitudinally extensive transverse myelitis; the aquaporin-4 antibody is the diagnostic biomarker. Acute disseminated encephalomyelitis (ADEM) is typically monophasic and post-infectious. Neurosarcoidosis shows systemic involvement. Cerebral small vessel disease causes white matter changes but typically in an older population with vascular risk factors. Vitamin B12 deficiency can cause myelopathy with posterior column involvement. Systemic lupus erythematosus and other connective tissue diseases may have CNS manifestations.

<image>Panel A presents a flowchart of the McDonald Criteria showing how clinical attacks, MRI findings, and CSF results combine to establish diagnosis. Panel B displays characteristic MRI findings in MS: periventricular lesions with Dawson's fingers on FLAIR, gadolinium-enhancing active lesion, spinal cord lesion, and T1 black holes. Panel C illustrates CSF oligoclonal bands with the characteristic pattern of bands present in CSF but absent in serum. Panel D creates a comparison table differentiating MS from its key mimics (NMOSD, ADEM, neurosarcoidosis) based on clinical, imaging, and laboratory features.</image>

VIII. Multiple Sclerosis Management

Treatment of MS addresses acute relapses, long-term disease modification, and symptomatic management.

Acute relapse treatment aims to accelerate recovery. High-dose intravenous methylprednisolone (typically 1 gram daily for 3-5 days) is standard; oral high-dose steroids may be equivalent. Corticosteroids shorten relapse duration and speed recovery but do not affect long-term disability. Plasma exchange (plasmapheresis) may benefit severe relapses refractory to steroids, particularly those affecting critical functions like vision or ambulation.

Disease-modifying therapies (DMTs) reduce relapse frequency and new MRI lesions, with varying efficacy and safety profiles. Injectable therapies include interferon-beta preparations (multiple formulations) and glatiramer acetate, which have moderate efficacy and long safety records. Oral therapies offer convenience: fingolimod and other sphingosine-1-phosphate receptor modulators sequester lymphocytes in lymph nodes (cardiac monitoring required at initiation); dimethyl fumarate has immunomodulatory effects; teriflunomide inhibits pyrimidine synthesis; cladribine is an oral purine analog given as brief treatment courses.

Higher-efficacy infusion therapies include natalizumab, which blocks lymphocyte entry into the CNS with highly effective disease control but carries risk of progressive multifocal leukoencephalopathy (PML) from JC virus, requiring JCV antibody monitoring. Ocrelizumab and other anti-CD20 monoclonal antibodies deplete B cells; ocrelizumab is notably the first therapy approved for primary progressive MS. Alemtuzumab causes profound lymphocyte depletion with long-lasting effects but significant risks including autoimmune thyroid disease and immune thrombocytopenia.

The treatment approach increasingly favors early, highly effective therapy to prevent irreversible disability. Treatment selection considers disease activity, patient factors (pregnancy planning, comorbidities, preferences), and safety monitoring requirements.

Symptomatic treatment addresses the many manifestations of MS. Spasticity responds to baclofen, tizanidine, and physical therapy. Fatigue management includes amantadine and modafinil. Bladder dysfunction may require anticholinergics (for overactivity) or catheterization. Depression is common and treatable with SSRIs. Neuropathic pain responds to gabapentin or duloxetine. Gait impairment may benefit from dalfampridine, a potassium channel blocker that improves nerve conduction.

<image>Panel A displays the MS DMT landscape organized by efficacy (moderate vs. high) and route (injectable, oral, infusion) with key agents in each category. Panel B illustrates mechanism of action for major DMT classes: interferon (immunomodulation), fingolimod (lymphocyte sequestration), natalizumab (blocking CNS entry), and ocrelizumab (B cell depletion). Panel C presents safety monitoring requirements for high-risk therapies including JCV antibody testing for natalizumab and cardiac monitoring for fingolimod. Panel D outlines symptomatic management for common MS symptoms with first-line treatment options.</image>

IX. Other Demyelinating Diseases

Several other inflammatory demyelinating conditions share features with MS but have distinct characteristics requiring different management approaches.

Neuromyelitis optica spectrum disorder (NMOSD) was historically considered a variant of MS but is now recognized as a distinct disease. The discovery of antibodies against aquaporin-4 (AQP4), a water channel concentrated in astrocyte foot processes, transformed understanding—NMOSD is primarily an astrocytopathy, with demyelination occurring secondarily. Clinical attacks are typically severe and include bilateral or sequential optic neuritis (often more severe than in MS) and transverse myelitis with longitudinally extensive spinal cord lesions spanning three or more vertebral segments. Brain MRI may be normal or show atypical lesions (around the aqueduct, in the area postrema causing intractable hiccups and vomiting). The AQP4 antibody (NMO-IgG) is present in approximately 80% and is highly specific. Unlike MS, NMOSD is not treated with standard MS DMTs—interferon may actually worsen disease. Treatment emphasizes immunosuppression with rituximab (anti-CD20), eculizumab (complement inhibitor), or inebilizumab.

MOG antibody disease (MOGAD) is another recently characterized condition involving antibodies against myelin oligodendrocyte glycoprotein (MOG) on the outer myelin surface. Presentations include optic neuritis (often bilateral), ADEM-like illness (particularly in children), and transverse myelitis. The clinical phenotype differs from AQP4-positive NMOSD: patients are often younger, recovery is generally better, and brain lesions may be more prominent. Treatment includes corticosteroids, IVIG, and immunosuppression for relapsing disease.

Acute disseminated encephalomyelitis (ADEM) is typically a monophasic, post-infectious demyelinating illness occurring primarily in children. It follows a viral illness or, rarely, vaccination by 1-4 weeks. Clinical features include encephalopathy (required for diagnosis), multifocal neurological deficits, and fever. MRI shows large, bilateral, somewhat fluffy white matter lesions. Treatment is high-dose corticosteroids with generally good prognosis. The primary differential diagnostic consideration is a first attack of MS, but the presence of encephalopathy and the imaging characteristics favor ADEM.

Central pontine myelinolysis (osmotic demyelination syndrome) results from rapid correction of hyponatremia. The rapid osmotic shift causes demyelination predominantly in the central pons, though extrapontine sites may be involved. Clinical features include quadriparesis, dysarthria, dysphagia, and potentially "locked-in" syndrome. Prevention is paramount: sodium should be corrected slowly, not exceeding 8-10 mEq/L per 24 hours. Treatment is supportive; some patients recover substantially.

<image>Panel A compares MS and NMOSD pathophysiology: MS as a primary demyelinating disease versus NMOSD as an astrocytopathy with AQP4 as the target. Panel B displays characteristic imaging in NMOSD: longitudinally extensive transverse myelitis spanning multiple segments and optic nerve enhancement. Panel C illustrates ADEM features including the post-infectious timeline, encephalopathy, and bilateral large white matter lesions on MRI. Panel D diagrams central pontine myelinolysis showing the relationship between rapid sodium correction and pontine demyelination with characteristic imaging findings.</image>

X. Prion Diseases

Prion diseases represent a unique category of neurodegenerative conditions caused by the accumulation of misfolded prion protein (PrP). Unlike other proteins implicated in neurodegeneration, the pathogenic prion form (PrPSc, scrapie form) is transmissible—it can induce normal cellular prion protein (PrPC) to misfold, creating a self-propagating cascade.

Creutzfeldt-Jakob disease (CJD) is the most common human prion disease. Sporadic CJD, accounting for approximately 85% of cases, arises spontaneously without known cause—presumably from stochastic misfolding of PrPC. The median age at onset is about 65 years. Clinical presentation features rapidly progressive dementia, often with prominent psychiatric symptoms initially. Myoclonus is characteristic. Cerebellar ataxia and visual disturbances are common. Progression is relentless, with death typically within one year of symptom onset.

Diagnostic features aid recognition. EEG may show periodic sharp wave complexes, though this finding is not universal. MRI demonstrates characteristic patterns: cortical ribboning (high signal in the cortical ribbon on diffusion-weighted imaging, DWI) and basal ganglia hyperintensity. CSF markers include elevated 14-3-3 protein and tau, though these are nonspecific. The real-time quaking-induced conversion (RT-QuIC) assay, which detects the ability of CSF prion seeds to induce misfolding of recombinant PrP, has high sensitivity and specificity.

Other prion diseases include familial CJD (mutations in the PRNP gene), iatrogenic CJD (transmitted through contaminated neurosurgical instruments, dura mater grafts, or human growth hormone), and variant CJD (linked to bovine spongiform encephalopathy, "mad cow disease"—younger patients, psychiatric prodrome, "pulvinar sign" on MRI). Fatal familial insomnia, another PRNP mutation-associated disease, presents with progressive insomnia, autonomic dysfunction, and dementia. Gerstmann-Sträussler-Scheinker syndrome features cerebellar ataxia and dementia with familial inheritance. Kuru was transmitted through ritualistic cannibalism in Papua New Guinea and is now essentially extinct.

Infection control is critical because prions are extraordinarily resistant to standard decontamination. They are not inactivated by autoclaving, formalin, or ionizing radiation. Instruments potentially contaminated with prions require special sterilization (prolonged autoclaving at higher temperatures with NaOH or sodium hypochlorite) or single-use disposal. There is no treatment—prion diseases are universally fatal.

<image>Panel A diagrams the prion protein conversion showing normal PrPC and how interaction with PrPSc template induces misfolding, creating an exponential cascade. Panel B displays CJD diagnostic imaging: DWI showing cortical ribboning and basal ganglia hyperintensity. Panel C illustrates the characteristic EEG pattern with periodic sharp wave complexes. Panel D presents the spectrum of human prion diseases with their causes (sporadic, genetic, acquired) and distinguishing features.</image>

Summary

• Neurodegenerative diseases share common themes: protein aggregation (amyloid/tau, synuclein, TDP-43, huntingtin), selective neuronal vulnerability, prion-like spread, and neuroinflammation
• Alzheimer's disease: amyloid plaques and tau tangles causing hippocampal-predominant atrophy; progressive memory loss; treat with cholinesterase inhibitors, memantine; new anti-amyloid antibodies (lecanemab) show modest disease modification
• Other dementias: vascular (stepwise or progressive, executive dysfunction), DLB (fluctuations, hallucinations, parkinsonism, neuroleptic sensitivity), FTD (early behavioral change or language variants, younger onset)
• ALS: combined UMN and LMN signs, preserved sensation; median survival 3-5 years; riluzole, supportive care
• MS: immune-mediated demyelination; 85% relapsing-remitting at onset; diagnosis requires dissemination in space and time (McDonald Criteria); treat relapses with steroids, modify disease course with DMTs
• MS treatment spectrum: moderate efficacy (interferons, glatiramer) to high efficacy (natalizumab, ocrelizumab); early effective treatment prevents disability
• NMOSD: distinct from MS; AQP4 antibody; longitudinally extensive myelitis and severe optic neuritis; treat with rituximab, eculizumab, not MS DMTs
• CJD: rapidly progressive dementia, myoclonus; DWI cortical ribboning; RT-QuIC diagnostic; universally fatal

Key Terms

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