Cerebrospinal fluid

Description: a clear and colorless fluid derived from blood plasma that provides mechanical support to the CNS
and transports biochemical compounds (e.g., neuromodulators) and waste products
CSF production: produced by choroid plexuses in the lateral, third, and fourth ventricles by filtration of plasma
CSF flow: lateral ventricles → third ventricle (via interventricular foramina) → fourth ventricle (via cerebral
aqueduct) → diffusion and active transfer into the subarachnoid space (via foramina of Luschka and Magendie)
→ reabsorption in the arachnoid granulations (a group of projections of the arachnoid mater into the dural
sinuses) → drainage into the dural venous sinuses
A 72-year-old woman is brought to the physician by her son for evaluation of cognitive
decline. Her son reports that she has had increased difficulty finding her way back home for
the last several months, despite having lived in the same city for 40 years. He also reports
that his mother has been unable to recall the names of her relatives and been increasingly
forgetting important family gatherings such as her grandchildren's birthdays over the last few
years. The patient has hypertension and type 2 diabetes mellitus. She does not smoke or
drink alcohol. Her current medications include enalapril and metformin. Her temperature is
37°C (98.6°F), pulse is 70/min, and blood pressure is 140/80 mm Hg. She is confused and
oriented only to person and place. She recalls 2 out of 3 words immediately and 1 out of 3
after 5 minutes. Her gait and muscle strength are normal. Deep tendon reflexes are 2+
bilaterally. The remainder of the examination shows no abnormalities. Further evaluation is
most likely to show which of the following findings?
A 72-year-old woman is brought to the physician by her son for evaluation of cognitive
decline. Her son reports that she has had increased difficulty finding her way back home for
the last several months, despite having lived in the same city for 40 years. He also reports
that his mother has been unable to recall the names of her relatives and been increasingly
forgetting important family gatherings such as her grandchildren's birthdays over the last few
years. The patient has hypertension and type 2 diabetes mellitus. She does not smoke or
drink alcohol. Her current medications include enalapril and metformin. Her temperature is
37°C (98.6°F), pulse is 70/min, and blood pressure is 140/80 mm Hg. She is confused and
oriented only to person and place. She recalls 2 out of 3 words immediately and 1 out of 3
after 5 minutes. Her gait and muscle strength are normal. Deep tendon reflexes are 2+
bilaterally. The remainder of the examination shows no abnormalities. Further evaluation is
most likely to show which of the following findings?

1. Hallucinations
2. Resting tremor
3. Positive Babinski sign
4. Generalized cerebral atrophy
5. Urinary incontinence
6. Myoclonic movements
Neuroimaging findings of focal cerebral atrophy (e.g., atrophy of the hippocampus) and generalized cerebral
atrophy (decreased brain parenchymal volume, prominent sulci, enlarged ventricles) are common in patients
with AD. Although not pathognomonic of AD, these findings help support the diagnosis. Disproportionate
atrophy of the hippocampus and/or medial temporal lobe are the most characteristic neuroimaging findings
of AD.
Alzheimer disease (AD)
Alzheimer disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia.
The clinical spectrum of AD ranges from preclinical to severe. Risk factors include age > 65 years and
genetic factors. The main histopathological features are extraneuronal β-amyloid (Aβ) plaques and
intraneuronal tau protein neurofibrillary tangles. The most common initial presentation is short-term
memory loss, which insidiously progresses to dementia with deficits in other cognitive domains. Patients
commonly have neuropsychiatric symptoms (e.g., depression, anxiety, and apathy) alongside cognitive
deficits. The diagnosis is based on clinical criteria. Specialized imaging (PET-CT) and cerebrospinal fluid
(CSF) analysis can be used to help clarify diagnostic uncertainty. There is no curative therapy; patients
should receive supportive management. Pharmacotherapy (e.g., cholinesterase inhibitors and/or
memantine) are modestly effective at slowing symptom progression. Average survival following
diagnosis usually ranges from 3 to 10 years.
The following pathophysiological mechanisms contribute to AD:
Senile plaques (neuritic plaques)
Extracellular
Located in the grey matter of the brain
Aβ protein is the main component of the plaques.
Enzymatic cleavage of transmembranous APP by β-secretase and γ-secretase → Aβ peptide aggregation →
formation of insoluble plaques → neurotoxic effect
Neurofibrillary tangles
Intracellular
Tangles are composed of hyperphosphorylated tau protein (an insoluble microtubule-associated protein).
↑ Phosphorylation (hyperphosphorylation) of tau → formation of intracellular fibrils → neurotoxic effect (number of
tangles correlates with the degree of cognitive impairment) [4]
Reduced cholinergic function
Acetylcholine deficiency is related to the degeneration of cholinergic neurons and likely plays a role in the decline of
cognitive abilities.
Other neurotransmitter systems (e.g., noradrenergic transmission) are affected less severely.
CSF biomarkers are preferred over blood/plasma biochemical markers in AD to reflect brain pathophysiology, because the brain
(interstitial fluid) is in direct contact with the CSF by unrestricted bi-directional flow of proteins and the CSF is secluded from
direct impact of the peripheral system through the restricted transportation of molecules and proteins by the blood–CSF barrier.
Therefore, CSF analysis is valuable to detect markers of neurodegenerative diseases in vivo. CSF biomarkers are related to the
three main pathological changes that occur in the AD brain (Table 1): amyloid-β (Aβ) deposition into extracellular Aβ plaques,
intracellular neurofibrillary tangles (NFT) formation, and neuronal loss.
Case
A 73-year-old woman is brought to the physician by her son because of increasing forgetfulness over the past 2 years.
Initially, she used to misplace keys and forget her dog's name or her phone number. Now, she often forgets about
what she has seen on television or read about the day before. She used to go for a walk every morning but stopped
one month ago after she became lost on her way back home. Her son has prevented her from cooking because she
has had episodes of leaving the gas stove oven on after cooking a meal. She becomes agitated when asked questions
directly but is unconcerned when her son reports her history and says he is overprotective of her. She has
hypertension, coronary artery disease, and hypercholesterolemia. Current medications include aspirin, enalapril,
carvedilol, and atorvastatin. She is alert and oriented to place and person but not to time. Vital signs are within
normal limits. Short- and long-term memory deficits are present. Her speech rhythm is normal but is frequently
interrupted as she thinks of words to frame her sentences. She makes multiple errors while performing serial sevens.
Her clock drawing is impaired and she draws 14 numbers. Which of the following is the most likely diagnosis?
A 73-year-old woman is brought to the physician by her son because of increasing forgetfulness over the past 2 years. Initially,
she used to misplace keys and forget her dog's name or her phone number. Now, she often forgets about what she has seen on
television or read about the day before. She used to go for a walk every morning but stopped one month ago after she became
lost on her way back home. Her son has prevented her from cooking because she has had episodes of leaving the gas stove oven
on after cooking a meal. She becomes agitated when asked questions directly but is unconcerned when her son reports her
history and says he is overprotective of her. She has hypertension, coronary artery disease, and hypercholesterolemia. Current
medications include aspirin, enalapril, carvedilol, and atorvastatin. She is alert and oriented to place and person but not to time.
Vital signs are within normal limits. Short- and long-term memory deficits are present. Her speech rhythm is normal but is
frequently interrupted as she thinks of words to frame her sentences. She makes multiple errors while performing serial sevens.
Her clock drawing is impaired and she draws 14 numbers. Which of the following is the most likely diagnosis?

1. Normal pressure 5. Vascular dementia

hydrocephalus
6. Creutzfeld-Jakob disease
2. Lewy body dementia
7. Normal aging
3. Frontotemporal dementia
8. Alzheimer disease
4. Pseudodementia
Alzheimer disease is the most common cause of slowly progressive memory loss. This condition typically affects the temporal
and parietal lobes first: Temporal lobe degeneration results in memory loss (misplaced keys, leaving the stove on) and
language deficits (word-finding difficulties), whereas parietal lobe degeneration results in spatial navigation problems (getting
lost during walks outside).

Normal pressure hydrocephalus is characterized by the triad of urinary incontinence, gait instability, and memory loss (“wet,
wobbly, and wacky”). Although this patient has significant memory loss, she lacks the other features of the triad, making this
diagnosis less likely. Neuroimaging would show enlarged ventricles.
 Lewy body dementia is characterized by
dementia with visual hallucinations and
parkinsonism (e.g., tremor, rigidity). Although
this patient has cognitive decline, she does
not have the visual hallucinations or motor
symptoms that are commonly seen in Lewy
body dementia.

Frontotemporal dementia is characterized by early, selective degeneration of the frontal and temporal lobes. Frontal lobe
degeneration results in behavioral and personality changes (e.g., apathy, compulsive eating, disinhibition), and temporal lobe
degeneration causes memory loss. Although this patient has memory issues, she does not have any of the classic findings of
frontal lobe degeneration. Neuroimaging in early stages would show selective atrophy of the frontal and temporal lobes, not
global atrophy.
 Pseudodementia is characterized by reversible cognitive impairment due to severe depression. This patient does not have any
mood symptoms (sadness, anhedonia, irritability) that suggest depression. Also, those with pseudodementia usually express
concern about their memory impairments, unlike this patient who says she is unconcerned with the memory lapses.

This patient's hypertension and hypercholesterolemia increase her risk for vascular dementia. However, the cognitive decline
of vascular dementia occurs in a step-wise fashion, in which the patient's cognition remains stable for a certain period, and
then declines again after another vascular event. In contrast, this patient exhibited a slowly progressive deterioration.
Creutzfeldt-Jakob disease is characterized by rapidly progressive dementia (decline that develops over weeks to months), ataxia,
and startle myoclonus. Although this patient is suffering from dementia, her decline has progressed over years and she lacks
the classic feature of startle myoclonus.

Certain cognitive declines are expected with normal aging, such as slowing of cognitive processing speed and issues with
memory retrieval. In dementia, however, cognitive deficits exceed those of normal aging and impair the actions of daily
living. Since the patient's cognitive declines impair her daily life (i.e., inability to cook safely at home, navigate her
neighborhood), they are pathologic and more severe than what would be expected with normal aging
Case
A 46-year-old woman comes to the physician for a cognitive evaluation. She is an office manager. She has had increasing
difficulties with multitasking and reports that her job performance has declined over the past 1 year. On mental status
examination, short-term memory is impaired and long-term memory is intact. Laboratory studies, including thyroid-stimulating
hormone and vitamin B12, are within the reference range. An MRI of the brain shows generalized atrophy, most pronounced in
the bilateral medial temporal lobes and hippocampi. If this patient's condition has a genetic etiology, which of the following
alterations is most likely to be found on genetic testing?
A 46-year-old woman comes to the physician for a cognitive evaluation. She is an office manager. She has had increasing
difficulties with multitasking and reports that her job performance has declined over the past 1 year. On mental status
examination, short-term memory is impaired and long-term memory is intact. Laboratory studies, including thyroid-stimulating
hormone and vitamin B12, are within the reference range. An MRI of the brain shows generalized atrophy, most pronounced in
the bilateral medial temporal lobes and hippocampi. If this patient's condition has a genetic etiology, which of the following
alterations is most likely to be found on genetic testing?

1. Noncoding hexanucleotide repeats

2. Deletion of chromosome 21q
3. Mutation in presenilin 1
4. Expansion of CAG trinucleotide repeat
5. Presence of ApoE ε4 allele
Mutations in presenilin 1 are associated with early-onset Alzheimer disease. The trait is autosomal dominant and leads to
unusually high production of beta-amyloid, which results in the early formation of amyloid plaques.
Noncoding hexanucleotide repeats are implicated in familial frontotemporal dementia (FTD). However, this patient presents
with signs and symptoms of AD, which is not associated with noncoding hexanucleotide repeats and does not manifest with
the characteristic personality and behavioral changes as well as the parkinsonism typically seen in FTD.
The deletion of chromosome 21q causes a rare syndrome that can cause a variety of manifestations, including intellectual
disability, behavioral issues, developmental delay, and abnormal facial feature, but it is not associated with AD. In contrast,
the presence of an extra copy of chromosome 21, i.e., trisomy 21 (Down syndrome), is associated with an increased risk of
early-onset Alzheimer disease due to increased amyloid precursor protein (APP) production as a result of a triplicate APP
gene.

Expansion of CAG trinucleotide repeats is found in Huntington disease. Dementia is an important component of the clinical
syndrome, but it is also accompanied by jerky, uncontrolled motor symptoms (chorea). The absence of motor involvement in
this patient makes Huntington disease extremely unlikely.
The presence of the ε4 allele of ApoE is associated with an increased risk for late-onset AD but not early-onset AD, as seen in
this patient. The protein product of this gene binds to amyloid β and is thought to initiate a series of events that accelerate
neurodegeneration.
Multiple sclerosis (MS)
Multiple sclerosis (MS) is a chronic degenerative disease of the CNS characterized by demyelination and axonal
degeneration in the brain and spinal cord, which are caused by an immune-mediated inflammatory process. The
prevalence of MS is higher among women and people in temperate regions such as Europe and North America.
Impaired vision (due to retrobulbar neuritis) is usually the first manifestation of MS; other neurological deficits
appear as the disease progresses. The most common clinical course is characterized by exacerbations followed by
periods of complete or incomplete remission. Diagnosis is made using clinical and MRI findings to identify the
dissemination of CNS lesions in time and space. Characteristic MRI findings are demyelinated sclerotic plaques
primarily located in white matter. Differential diagnoses of MS include other chronic demyelinating diseases and
neurological infections (e.g., borreliosis, neurosyphilis). Acute exacerbations of MS are usually treated with high-
dose glucocorticoids. Between exacerbations, patients may be treated with disease-modifying drugs (e.g.,
interferon beta, glatiramer acetate, natalizumab). There is currently no definitive treatment for MS.
Osmosis: Multiple sclerosis - causes, symptoms, diagnosis, treatment, pathology
Oligoclonal bands are bands of immunoglobulins that are seen
when patient’s blood serum and CSF are analyzed in parallel. It
has been known for some time that oligoclonal bands (OCB)
occur in the analysis of CSF (by isoelectric focusing) in MS
patients [48]. They are created by immunoglobulin G (IgG) and
M (IgM) produced by plasma cells in the CNS [49]. The
existence of these bands within the CSF, but not within the
serum, is a strong indicator of intrathecal antibody synthesis
and, interestingly, is found in nearly all patients with clinically
definitive MS.
The protein chitinase-3-like-1 is a glycosidase secreted by monocytes, microglia, and activated astrocytes. The physiological
role of chitinase-3-like-1 (CHI3L1) in the CNS is unknown; however, its distribution in inflammatory lesions suggests that it
might be an important component of the astrocytic response to modulate CNS inflammation CHI3L1 1 . It is usually detected
in the CSF. Cantó and colleagues showed in a multicentre longitudinal cohort study with 813 participants that the CHI3L1
concentration is an independent risk factor for the conversion from CIS to MS. High CHI3L1 levels were also associated with
faster disability progression . Although CHI3L1 is not yet clinically established, it is a promising candidate as a biomarker of
MS prognosis and probably treatment response .