Researchers find link between concussions and Alzheimer’s disease

Boston University School of Medicine

New research has found concussions accelerate Alzheimer’s disease–related brain atrophy and cognitive decline in people who are at genetic risk for the condition. The findings, which appeared in the journal Brain, show promise for detecting the influence of concussion on neurodegeneration.

Moderate–to–severe traumatic brain injury is one of the strongest environmental risk factors for developing neurodegenerative diseases such as late–onset Alzheimer’s disease, although it is unclear whether mild traumatic brain injury or concussion also increases this risk.

BUSM researchers studied 160 Iraq and Afghanistan war veterans, some who had suffered one or more concussions and some who had never had a concussion. Using MRI imaging, the thickness of their cerebral cortex was measured in seven regions that are the first to show atrophy in Alzheimer’s disease, as well as seven control regions.

“We found that having a concussion was associated with lower cortical thickness in brain regions that are the first to be affected in Alzheimer’s disease,” explained corresponding author Jasmeet Hayes, PhD, assistant professor of psychiatry at BUSM and research psychologist at the National Center for PTSD, VA Boston Healthcare System. “Our results suggest that when combined with genetic factors, concussions may be associated with accelerated cortical thickness and memory decline in Alzheimer’s disease relevant areas.”

Of particular note was that these brain abnormalities were found in a relatively young group, with the average age being 32 years old. “These findings show promise for detecting the influence of concussion on neurodegeneration early in one’s lifetime, thus it is important to document the occurrence and subsequent symptoms of a concussion, even if the person reports only having their “bell rung” and is able to shake it off fairly quickly, given that when combined with factors such as genetics, the concussion may produce negative long–term health consequences,” said Hayes.

The researchers hope that others can build upon these findings to find the precise concussion–related mechanisms that accelerate the onset of neurodegenerative diseases such as Alzheimer’s disease, chronic traumatic encephalopathy, Parkinson’s and others. “Treatments may then one day be developed to target those mechanisms and delay the onset of neurodegenerative pathology,” she added.

Takeaway

• Cognitive decline in early Alzheimer’s disease (AD) is linked to periodontitis, independent of baseline cognition.

Study design

• 60 community residents (mean 77.7±8.6 years; 51% men) with mild/moderate AD underwent cognitive, dental, and blood testing at baseline and at 6 months (n=52).

Key results

• Baseline periodontitis (in 37.3%), diagnosed by a dental hygienist blinded to cognitive outcomes, was associated with a sixfold increase in rate of cognitive decline on the ADAS-cog and with increase in blood pro-inflammatory markers over 6 months, but not with baseline ADAS-cog.

Limitations

• Small sample; limited follow-up duration.

Why this matters

• Elevated antibodies to periodontal bacteria have been associated with increased systemic pro-inflammatory state, and elevated serum pro-inflammatory cytokines have been associated with increased cognitive decline in AD.
• Increased cognitive decline with periodontitis may be mediated through systemic inflammation, suggesting potential therapeutic interventions.
• If the findings are confirmed in larger studies, treatment of periodontitis may help prevent decline in AD.

Periodontitis is common in the elderly and may become more common in Alzheimer’s disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer’s disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer’s disease. We aimed to determine if periodontitis in Alzheimer’s disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer’s Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer’s Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation.

Increased consumption of omega-3 polyunsaturated fatty acids (PUFA) correlate significantly with lower plasma levels of beta-amyloid 42 (Aβ-42) in elderly individuals without dementia, researchers found.

The association of higher omega-3 intake and lower plasma Aβ-42 they observed was independent of age, sex, ethnicity, education, and APOE genotype and has been “linked with reduced risk of incident Alzheimer’s disease (AD) and slower cognitive decline in our cohort,” they note.

The study, from Nikolaos Scarmeas, MD, MSc, associate professor of neurology, Columbia University Medical Center in New York City, and colleagues was published online May 2 in Neurology.

“We demonstrate here that there is an association between what we eat and levels of amyloid in our blood,” Dr. Scarmeas told Medscape Medical News. “The amount of omega-3 that we consume may relate to levels of amyloid in our system, an argument suggesting a possible direct relation with Alzheimer’s type of pathology,” he added.

The WHICAP Cohort

The findings stem from the Washington Heights/Hamilton Heights Columbia Aging Project (WHICAP), a large community-based project investigating the antecedents, biologic risk factors, genetics, and course of cognitive aging and dementia. A total of 1219 cognitively healthy multiethnic participants older than age 65 years provided information on their diet 1.2 years, on average, before plasma levels of Aβ were assessed.

The study team used linear regression models adjusted for relevant confounders to analyze associations between Aβ-40 and Aβ-42 levels and dietary intake of 10 nutrients, including saturated fatty acids, monounsaturated fatty acids (MUFA), omega-3 PUFA, omega-6 PUFA, vitamin E, vitamin C, beta-carotene, vitamin B12, folate, and vitamin D.

They report that participants with higher plasma levels of Aβ-40 and Aβ-42 were older and less educated and had lower intakes of omega-3 PUFA, omega-6 PUFA, and MUFA. Participants with higher omega-3 or omega-6 PUFA or MUFA intake had higher education, were more likely to be white or black and less likely to be Hispanic, and had lower levels of Aβ-42. Those with higher omega-3 PUFA also had lower levels of Aβ-40.

In unadjusted models that simultaneously included all nutrients, higher intake of omega-3 PUFA was associated with lower levels of Aβ-40 (? = -24.74; P < .001) and Aβ-42 (? = -12.31; P < .001).

In the fully adjusted model, omega-3 PUFA remained a strong predictor of Aβ-42 (? = -7.70; P = .02), whereas its association with Aβ-40 was attenuated (? = -10.13; P = .13).

The other investigated nutrients were not associated with plasma Aβ levels.

Mounting Evidence

Dr. Scarmeas and his colleagues say their observations are consistent with results observed in animal studies, “pointing to a beneficial role of dietary omega-3 PUFA in brain pathology.”

They also note that in a prior study using the WHICAP cohort, also reported by Medscape Medical News, they observed a lower risk of incident AD, mild cognitive impairment (MCI) and progression from MCI to AD in subjects who adhered more to a Mediterranean-style diet, characterized by a high intake of omega-3-rich fish.

They also showed previously that a “dietary pattern” characterized by high omega-3 PUFA (and other nutrients) was associated with a 40% reduced risk for incident AD. They also reported recently that increasing intake of omega-3 PUFAs was associated with a 20% to 30% lower risk for dementia (Alzheimer Dement. 2011;7:S296-S297).

The researchers conclude that the “potential beneficial effects of omega-3 PUFA intake on AD and cognitive function in the literature might be at least partly explained by an Aβ-related mechanism.”

In terms of clinical implications, Dr. Scarmeas cautioned that he’s “not sure about direct clinical applications because we are not sure about causality (not a clinical trial) and we relate aspects of diet to blood, not brain levels of amyloid (but they are related to a certain extent).”

“Determining through further research whether omega-3 fatty acids or other nutrients relate to spinal fluid or brain beta-amyloid levels or levels of other (AD) related proteins can strengthen our confidence on beneficial effects of parts of our diet in preventing dementia,” Dr. Scarmeas said in a statement.

The study was supported by the National Institute on Aging. The authors have disclosed no relevant financial relationships.

PET scanning involves the introduction of a radioactive tracer into the human body, usually with an intravenous injection. A tracer is essentially a biologic compound of interest that is labeled with a positron-emitting isotope, such as carbon-11 (¹¹ C), fluorine-18 (¹⁸ F), or oxygen-15 (¹⁵ O). These isotopes are used because they have relatively short half-lives (from minutes to < 2h), allowing the tracers to reach equilibrium in the body without exposing the subjects to prolonged radiation.

The 2 most common physiologic process measurements performed using PET scanning are glucose with [¹⁸ F]FDG and cerebral blood flow using water.^[23]

FDG-PET has been used extensively to study Alzheimer disease, and it is evolving into an effective tool for early diagnosis and for differentiation of Alzheimer disease from other types of dementia. FDG-PET has been used to detect persons at risk for Alzheimer disease even before the onset of symptoms.^[36]

Patients with Alzheimer disease have characteristic temporoparietal glucose hypometabolism, the degree of which is correlated with the severity of dementia.^[37] (Temporal and parietal glucose hypometabolism is widely seen on PET images in patients with Alzheimer disease.) With disease progression, frontal involvement may be evident. Glucose hypometabolism in Alzheimer disease is likely to be caused by a combination of neuronal cell loss and decreased synaptic activity.^[38]

In control subjects, entorhinal cortex hypometabolism on FDG-PET has predictive value in the progression of dementia to MCI or, even, to Alzheimer disease.^{[39, 40]} The identification of asymptomatic individuals at risk will have an enormous role in the treatment strategy for Alzheimer disease.^[41] Individuals at high risk for Alzheimer disease (asymptomatic carriers of the APOE*E4 allele) exhibit a pattern of glucose hypometabolism similar to that of patients with Alzheimer disease. After a mean follow-up of 2 years, the cortical metabolic abnormality continues to decline despite preservation of cognitive performance.^{[42, 40]}

In patients with Alzheimer disease, PET performed with ligand PK11195 labeled with¹¹ C, or (R)-[¹¹ C] PK11195, showed increased binding in the entorhinal, temporoparietal, and cingulate cortices. This finding corresponded to the postmortem distribution of Alzheimer disease pathology.^[43]

Degree of confidence

Despite the technical differences, results from PET and SPECT scanning are comparable, although data suggest that PET scanning is more sensitive than SPECT scanning.^[44] On PET or SPECT scanning, mild Alzheimer disease may be more difficult to detect than moderate or severe disease. In Alzheimer disease, FDG-PET has a sensitivity of 94% and a specificity of 73%. It can also be used to correctly predict a progressive course of dementia with a 91% sensitivity and a nonprogressive course with a 75% specificity.^[45] Efforts to develop a specific ligand for Aß plaques may further enhance the sensitivity of PET scanning for early diagnosis of Alzheimer disease and may provide a biologic marker of disease progression.^[43]

In their study, Boxer et al reported that different amyloid-binding PET scan agents—Pittsburgh Compound-B and FDDNP—may have differential sensitivity to prion-related brain pathology and that a combination of amyloid imaging agents may be useful in the diagnosis of early onset dementia.^[46]

Florbetapir F 18 (AMYViD) was approved by the FDA in April 2012 as a diagnostic imaging agent. It is indicated for PET brain imaging of beta-amyloid neuritic plagues in adults being evaluated for Alzheimer disease or other cognitive decline.

Approval for florbetapir F 18 was based on 3 clinical studies that examined images from healthy adult patients as well as patients with a range of cognitive disorders, including some terminally ill patients who had agreed to participate in a postmortem brain donation program. Measurements from postmortem cortical amyloid burden correlated with median florbetapir F 18 scores (r=0.78; P< 0.0001).^[47]

In a study by Clark et al, the presence and density of beta amyloid correlated closely in individuals who had florbetapir-PET imaging within 99 days before death and then upon autopsy.^[48] Patients with probably Alzheimer disease, mild cognitive impairment, or older healthy controls showed significantly different mean cortical florbetapir uptake value ratios in a study by Fleisher et al.^[49]

SPECT instrumentation is highly variable; therefore, use of a SPECT scanner with poor resolution can result in poor clinical performance. Positron-emission tomography (PET) scanning uses tracers that measure regional glucose metabolism (rCMRGlc). SPECT imaging is most commonly used for blood-flow measurement.

Early SPECT studies of blood flow replicated findings of functional reductions in the posterior temporal and parietal cortex. The severity of temporoparietal hypofunction has been correlated with the severity of dementia in a number of studies.

Reductions of blood flow and oxygen use can be found in the temporal and parietal neocortex in patients with Alzheimer disease and moderate to severe symptoms.^[16] Early reductions of glucose metabolism are seen in the posterior cingulate cortex.

SPECT scanning is not commonly used to assess Alzheimer disease. SPECT scanning is useful in the diagnostic assessment of Alzheimer disease if standardized and semiquantitative techniques are used.

Trollor et al examined 18 patients with early Alzheimer disease and 10 healthy, elderly control subjects with high-resolution SPECT scanning during their performance of a simple word-discrimination task and observed a gradation of regional cerebral blood flow (rCBF) values in both groups. The lowest values were in the hippocampus and the highest in the striatum, thalamus, and cerebellum. In the study, SPECT images were coregistered with individual MRI scans, allowing for the delineation of predetermined neuroanatomic regions of interest (ROI).^[17]

Compared with healthy control subjects, patients with Alzheimer disease had low relative rCBF in the parietal and prefrontal cortices. Analysis of individual the ROI demonstrated bilateral reduction of rCBF in the prefrontal poles and posterior temporal and anterior parietal cortex, with unilateral reduction of rCBF in the left dorsolateral prefrontal cortex, right posterior parietal cortex, and left cingulate body. No significant differences in hippocampal, occipital, or basal ganglia rCBF were found. Discriminant function analysis indicated that rCBF in the prefrontal polar regions permitted the best classification.^[17]

In class II studies, the sensitivity of SPECT scanning was lower than that of the clinical diagnosis.^[29] Sensitivity increased as the severity of dementia worsened, but the pretest probability of Alzheimer disease increased as well.^[30]

The added value of SPECT scanning was greatest for a positive test among patients with mild dementia in whom the diagnosis of Alzheimer disease was substantially doubted.^[31] In this situation, a positive SPECT scan result would have increased the posttest probability of Alzheimer disease by 30%, whereas a negative test result would have increased the likelihood of the absence of Alzheimer disease by only 10%.^[32]

Degree of confidence

Without surprise, clinically validated SPECT scan studies showing differences between patients with Alzheimer disease (Alzheimer’s disease) and control subjects reveal high sensitivities and specificities of 80-90%.^[32]

In one study, investigators compared patients from a dementia clinic with a community sample of control subjects using quantitative SPECT scanning and reported a 63% sensitivity and an 87% specificity. Alzheimer disease was defined in the study as temporal-lobe perfusion more than 2 standard deviations below control values.

Holman et al found that bilateral temporoparietal hypoperfusion had a positive predictive value of 82% for Alzheimer disease.^[33] Using inhaled xenon-133 (¹³³ Xe) and injected technetium-99m [^99m Tc]hexamethylpropyleneamine oxime, researchers reported a sensitivity of 76% and a specificity of 73%, with a positive predictive value of 92% and a negative predictive value of 57%.^[34] These studies may assist in the early and late diagnosis of Alzheimer disease and with the differential diagnosis of dementias.

Coronal, T1-weighted magnetic resonance imaging (MRI) scan in a patient with moderate Alzheimer disease. Brain image reveals hippocampal atrophy, especially on the right side. Axial, T2-weighted magnetic resonance imaging (MRI) scan of the brain reveals atrophic changes in the temporal lobes. Axial, T2-weighted magnetic resonance imaging (MRI) scan shows dilated sylvian fissure resulting from adjacent cortical atrophy, especially on the right side. Axial, T1-weighted magnetic resonance imaging (MRI) scan shows a dilated sylvian fissure caused by adjacent cortical atrophy. Axial, T1-weighted magnetic resonance imaging (MRI) scan shows bilateral cortical atrophy with accentuated cortical sulci; there is decreased involvement in the posterior aspect. Axial, T1-weighted magnetic resonance imaging (MRI) scan shows bilateral cortical atrophy with accentuated cortical sulci; there is decreased involvement in the posterior aspect.

Fox et al used an automated technique that is potentially applicable in the clinical setting to subtract MRI scans obtained an average of 1 year apart. They observed that there was a significant difference between the rate of change in patients with Alzheimer disease and the rate in control subjects. With MRI, sensitivity and specificity were approximately 90% for predicting the decline in dementia.[18]

Early MRI studies to evaluate the size of the hippocampus in patients with Alzheimer disease relative to control subjects showed large reductions in hippocampal volumes (approximately 50%) and high sensitivity and specificity for classification.[19] Over time, enlargement of the temporal horns, as well as of the third and lateral ventricles, was noted in patients with Alzheimer disease compared with control subjects.

On structural MRI, atrophy of the entorhinal cortex is already present in MCI. In the autosomal-dominant forms of Alzheimer disease, the rate of atrophy of the medial temporal structures differentiates affected individuals from control subjects as early as 3 years before the clinical onset of cognitive impairment. The accelerated annual rate of brain atrophy is a surrogate tool for evaluating new therapies in small samples that saves time and resources.

MRI measurements of the hippocampus, amygdala, cingulate gyrus, head of the caudate nucleus, temporal horn, lateral ventricles, third ventricle, and basal forebrain yield a prediction rate of 77% for conversion to Alzheimer disease from questionable Alzheimer disease.[20, 21]

Functional MRI (fMRI) techniques can be used to measure cerebral perfusion. Dynamic susceptibility contrast (DSC) MRI consists of the passage of a concentrated bolus of a paramagnetic contrast agent that sufficiently distorts the local magnetic field to cause a transient loss of signal with pulse sequences, especially T2-weighted sequences. The passage of contrast material is imaged over time by sequential rapid imaging of the same section. In animal studies, the rate of change of signal intensity over time gives a measure directly proportional to cerebral blood volume. Studies in humans have shown a correlation between PET and DSC MRI scan results, as well as between cerebral blood volumes measured with DSC MRI and perfusion on single-photon emission computed tomography (SPECT) scanning.

Studies have been performed using MRI with echo-planar imaging and signal targeting with attenuation radiofrequency (EPISTAR) in patients with Alzheimer disease. Focal areas of hypoperfusion were in the posterior temporoparietooccipital regions. Ratios of signal intensity in the parieto-occipital and temporo-occipital areas to signal intensity on whole section signal intensity were significantly lower in the patients with Alzheimer disease than in those without it. The parieto-occipital ratios were not correlated with the severity of dementia, as measured by using the Blessed Dementia Scale Information Memory Concentration subset.

With fMRI, structural imaging can be done by using the same imaging plane, field of view, and section thickness. Activational fMRI studies have included blood oxygenation level–dependent (BOLD) imaging, which uses changes in the level of oxygenated hemoglobin in capillary beds to depict areas of regional brain activation. In Alzheimer disease, fMRI activation in the hippocampal and prefrontal regions is decreased.

On fMRI, paradigms activate a larger area of parietotemporal association cortex in persons at high risk for Alzheimer disease than in others, whereas the entorhinal cortex activation is relatively low in MCI.[22]

The techniques are reasonably sensitive and specific in differentiating Alzheimer disease from changes resulting from normal aging, and studies with pathologic confirmation show good sensitivity and specificity in differentiating Alzheimer disease from other dementias. These techniques can also be used to detect abnormalities in asymptomatic or presymptomatic individuals, and they may help in predicting the decline to dementia.
Degree of confidence

MRI findings of hippocampal atrophy are highly associated with Alzheimer disease (Alzheimer’s disease), but the specificity is not well established.[23] Studies have shown that in patients with Alzheimer disease and moderate dementia, hippocampal volumes permitted correct classification in 85% of patients.[24] In patients with Alzheimer disease and mild dementia, sensitivity was 77%, and specificity, 80%.[25] Hippocampal volume was the best discriminator, although a number of medical temporal-lobe structures were studied, including the amygdala and the parahippocampal gyrus.
False positives/negatives

Hippocampal atrophy appears to be a feature of vascular disease (multi-infarct dementia) and Parkinson disease, even in patients with Parkinson disease without dementia. Hippocampal and entorhinal cortical atrophy are features of frontotemporal dementia, but they do not appear to be as profound as atrophy is in Alzheimer disease (Alzheimer’s disease).[26] ]]> https://www.luciazamorano.com/alzheimer-disease-imaging-mri/feed/ 0 https://www.luciazamorano.com/alzheimer-disease-workup/ https://www.luciazamorano.com/alzheimer-disease-workup/#respond Sun, 06 May 2012 03:45:09 +0000 http://www.natemat.com/alzheimer-disease-workup/ [Continue Reading]]]> Alzheimer disease (AD) is a clinical diagnosis. However, ancillary imaging studies (eg, computed tomography [CT]; magnetic resonance imaging [MRI]; and, in selected cases, single-photon emission CT [SPECT] or positron emission tomography [PET]) and laboratory tests may be used. These tests help exclude other possible causes for dementia (eg, cerebrovascular disease, cobalamin [vitamin B12] deficiency, syphilis, thyroid disease).

Diagnostic criteria established by the National Institute on Aging (NIA) and the Alzheimer’s Association are intended principally to facilitate research. However, the NIA-AA also proposed “core clinical criteria” for diagnosis of mild cognitive impairment (MCI) by health care providers without access to cerebrospinal fluid (CSF) testing or advanced imaging.[51] The NIA-AA criteria for diagnosis of dementia due to AD are clinical, with biomarkers in an assisting, nonessential role.[52] ]]> https://www.luciazamorano.com/alzheimer-disease-workup/feed/ 0 https://www.luciazamorano.com/alzheimer-disease-differential-diagnoses/ https://www.luciazamorano.com/alzheimer-disease-differential-diagnoses/#respond Sun, 06 May 2012 03:42:02 +0000 http://www.natemat.com/alzheimer-disease-differential-diagnoses/ [Continue Reading]]]> Depression is an important consideration in the differential diagnosis of Alzheimer disease (AD). The clinical manifestations of depression overlap with those of AD. In addition, an estimated 30-50% of AD patients have comorbid depression.[53]

Depression in patients with AD appears to differ from depression in cognitively intact elderly patients. Depression in AD more often features motivational disturbances (eg, fatigue, psychomotor slowing, apathy), whereas depression in geriatric patients without cognitive impairment tends to feature mood symptoms (eg, depressed mood, anxiety, suicidality, sleep and appetite disturbances).[53]

Commonly used instruments for assessing depression (eg, Hamilton Scale for Depression, Beck Depression Inventory, Geriatric Depression Scale) were designed for use in other patient populations and may be less reliable in patients with AD. Consequently, the National Institute of Mental Health has developed provisional diagnostic criteria for depression in AD.[53]

Chronic traumatic encephalopathy

Repetitive head trauma has long been recognized as a cause of brain degeneration in boxers (ie, dementia pugilistica). More recently, progressive degenerative brain disease (chronic traumatic encephalopathy [CTE] has been recognized in athletes with a history of multiple concussions, as well as milder blows to the head that do not cause concussion. Neuropathologically confirmed CTE has been reported in retired professional football and hockey players and other athletes with a history of repeated head injuries.

Pathological hallmarks of CTE, which may not appear until long after the end of active athletic involvement, include the following[54] :

Tau-positive neurofibrillary tangles (NFTs) in the neocortex, concentrated around penetrating parenchymal vessels
Neuropil threads
Neocortical diffuse amyloid plaques, with or without neuritic plaques
Sparing of the hippocampus

The distribution of NFTs in CTE differs markedly from that in normal aging and AD, in which there is early involvement of the entorhinal cortex and hippocampus with later involvement of the neocortex in advanced stages.

The symptoms of CTE may include the following[54] :

Recurrent headaches
Dizziness
Mood disorders
Aggression
Impaired judgment and impulse control
Parkinsonian movement disorders
Progressive dementia

For more information, see the Medscape Reference article Repetitive Head Injury Syndrome.

Other disorders

Other disorders to consider in the differential diagnosis of AD include the following:

• Age-associated memory impairment
• Alcohol or drug abuse
• Depression
• Vitamin B12 deficiency
• Cerebrovascular disease
• Hearing or visual impairment
• Hypernatremia
• Hypoglycemia
• Hypothyroidism or hyperthyroidism
• Polypharmacy
• Volume depletion

Patients with mild AD usually have somewhat less obvious executive, language, and/or visuospatial dysfunction. In atypical presentations, dysfunction in cognitive domains other than memory may be most apparent. In later stages, many patients develop extrapyramidal dysfunction.

Substantially less common, but biopsy or autopsy-proven, presentations include right parietal lobe syndrome, progressive aphasia, spastic paraparesis, and impaired visuospatial skills, which is subsumed under the visual variant of AD.

It is important to obtain a complete history not only from the patient but also from someone who knows the patient well. In addition, a family history of AD or other forms of dementia should be noted.

Physical Examination

At the time of initial diagnosis, a complete physical examination, including a detailed neurologic examination and a mental status examination, should be performed to evaluate disease stage and rule out comorbid conditions. Initial mental status testing should include evaluation of the following:

Attention and concentration
Recent and remote memory
Language
Praxis (ie, ability to perform skilled motor tasks without nonverbal prompting)
Executive function
Visuospatial function

Cognitive features of early AD include memory loss, mild anomic aphasia, and visuospatial dysfunction. At all subsequent follow-up visits, a full mental status examination should be performed to evaluate disease progression and identify the development of any new neuropsychiatric symptoms.

Brief standardized examinations, such as the Mini-Mental Status Examination (MMSE), are less sensitive and specific than longer batteries that are specifically tailored to individual patients. Other examples include the Montreal Cognitive Assessment (MoCA) and the Saint Louis University Mental Status (SLUMS) examination. Nonetheless, screening exams have a role, particularly as a baseline. For more information, see the Medscape Reference article Screening for Cognitive Impairment.

A complete neurologic examination is performed to look for signs of other diseases that could cause dementia, such as Parkinson disease or multiple strokes.In patients with AD, the neurologic exam is generally normal but may reveal minor abnormalities such as hyposmia or anosmia.
Stages of Alzheimer Disease

AD can be classified into the following stages:

Preclinical
Mild
Moderate
Severe

Preclinical Alzheimer disease

The pathologic changes associated with AD begin in the entorhinal cortex, which is near the hippocampus and directly connected to it. AD then proceeds to the hippocampus, which is the structure that is essential to the formation of short-term and long-term memories (see the images below). Affected regions begin to atrophy. These brain changes probably start 10-20 years before any visible signs or symptoms appear.

Memory loss, the first visible sign, is the main feature of amnestic mild cognitive impairment (MCI). Many scientists think MCI is often an initial, transitional clinical phase between normal brain aging and AD. For more information, see the Medscape Reference article Mild Cognitive Impairment.
Preclinical Alzheimer disease. Image courtesy of NPreclinical Alzheimer disease. Image courtesy of NIH. Preclinical Alzheimer disease. Image courtesy of NPreclinical Alzheimer disease. Image courtesy of NIH.

A patient with preclinical AD may appear completely normal on physical examination and mental status testing. At this stage, there is normally no alteration in judgment or the ability to perform activities of daily living.
Mild Alzheimer disease

As AD begins to affect the cerebral cortex, memory loss continues and impairment of other cognitive abilities emerges. This stage is referred to as mild AD. The clinical diagnosis of AD is usually made during this stage. Signs of mild AD can include the following:

Memory loss
Confusion about the location of familiar places (getting lost begins to occur)
Taking longer to accomplish normal daily tasks
Trouble handling money and paying bills
Compromised judgment often leading to bad decisions
Loss of spontaneity and sense of initiative
Mood and personality changes; increased anxiety

The growing number of plaques and tangles first damage areas of the brain that control memory, language, and reasoning (see the images below). Later in the disease, physical abilities decline. This leads to a situation in mild AD in which a person seems to be healthy but is actually having more and more trouble making sense of the world around him or her. The realization that something is wrong often comes gradually because the early signs can be confused with changes that can happen normally with aging.
Mild Alzheimer disease. The disease begins to affeMild Alzheimer disease. The disease begins to affect the cerebral cortex, memory loss continues, and changes in other cognitive abilities emerge. The clinical diagnosis of AD is usually made during this stage. Image courtesy of NIH. Mild-to-moderate Alzheimer disease. Image courtesyMild-to-moderate Alzheimer disease. Image courtesy of NIH.

Acknowledging these signs of AD and deciding to seek diagnostic testing can be a hurdle for patients and their families to cross. In many cases, the family has a more difficult time handling the diagnosis than the patient does, probably because of apathy from the AD. Following the initial diagnosis, patients should be carefully monitored for depressed mood. Although it is common for patients with early AD to be depressed about the diagnosis, they rarely become suicidal.
Moderate Alzheimer disease

By the time AD reaches the moderate stage, damage has spread further to the areas of the cerebral cortex that control language, reasoning, sensory processing, and conscious thought. Affected regions continue to atrophy, and signs and symptoms of the disease become more pronounced and widespread. Behavior problems, such as wandering and agitation, can occur. More intensive supervision and care become necessary, and this can be difficult for many spouses and families.

The symptoms of this stage can include the following:

Increasing memory loss and confusion
Shortened attention span
Problems recognizing friends and family members
Difficulty with language; problems with reading, writing, working with numbers
Difficulty organizing thoughts and thinking logically
Inability to learn new things or to cope with new or unexpected situations
Restlessness, agitation, anxiety, tearfulness, wandering, especially in the late afternoon or at night
Repetitive statements or movement; occasional muscle twitches
Hallucinations, delusions, suspiciousness or paranoia, irritability
Loss of impulse control (shown through behavior such as undressing at inappropriate times or places or vulgar language)
Perceptual-motor problems (such as trouble getting out of a chair or setting the table)

Behavior is the result of complex brain processes, all of which take place in a fraction of a second in the healthy brain. In AD, many of these processes are disturbed, and this is the basis for many distressing or inappropriate behaviors. For example, patients may angrily refuse to take a bath or get dressed because they do not understand what the caregiver has asked them to do. If they do understand, they may not remember how to do what was asked.

This anger is a mask for underlying confusion and anxiety. Consequently, the risk for violent and homicidal behavior is highest at this stage of disease progression. Patients should be carefully monitored for any behavior that may compromise the safety of those around them.

For a person who cannot remember the past or anticipate the future, the world around them can be strange and frightening. Staying close to a trusted and familiar caregiver may be the only thing that makes sense and provides security. A person with AD may constantly follow his or her caregiver and fret when the person is out of sight.

Judgment and impulse control continue to decline at this stage. For example, taking off clothes may seem reasonable to a person with AD who feels hot and does not understand or remember that undressing in public is not acceptable.
Severe Alzheimer disease

In the last stage, severe AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further (see the images below). Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish.
Severe Alzheimer disease. In the last stage of AD,Severe Alzheimer disease. In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further. Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish. Image courtesy of NIH. Severe Alzheimer disease. Image courtesy of NIH. Severe Alzheimer disease. Image courtesy of NIH.

Other symptoms can include the following:

Weight loss
Seizures, skin infections, difficulty swallowing
Groaning, moaning, or grunting
Increased sleeping
Lack of bladder and bowel control

In end-stage AD, patients may be in bed much or all of the time. Death is often the result of other illnesses, frequently aspiration pneumonia.
Clinical Guidelines for Diagnosis

Clinical guidelines for the diagnosis of AD have been formulated by the National Institutes of Health-Alzheimer’s Disease and Related Disorders Association (NIH-ADRDA); the American Psychiatric Association, in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision, Text Revision (DSM-IV-TR); and the Consortium to Establish a Registry in Alzheimer’s Disease (CERAD). In 2011, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) workgroup released new research and clinical diagnostic criteria for AD.[49]

The NIH-ADRDA criteria for the diagnosis of AD require the finding of a slowly progressive memory loss of insidious onset in a fully conscious patient. AD cannot be diagnosed in patients with clouded consciousness or delirium. Toxic metabolic conditions and brain neoplasms must also be excluded as potential causes of the patient’s dementia.

The focus of the 2011 NIA-AA criteria is the need to create a more accurate diagnosis of preclinical disease so that treatment can begin before neurons are significantly damaged, while they are more likely to respond. Therefore, the report includes criteria for diagnosis of the following:

Asymptomatic, preclinical AD (for purposes of research, not clinical diagnosis)[50] Mild cognitive impairment (MCI), an early symptomatic but predementia phase of AD[51] AD dementia[52]

DSM-IV-TR criteria

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision(DSM-IV-TR) lists 6 diagnostic criteria, labeled A-F, for dementia of the Alzheimer type (see Table 1, below). These guidelines are widely believed to be 90-95% accurate (as histopathologically verified) when followed carefully. They are important not only for routine management but also for selecting and enrolling patients in therapeutic trials.

Class Summary

Cholinesterase inhibitors (ChEIs) are used to palliate cholinergic deficiency. All 4 currently approved ChEIs (ie, tacrine, donepezil, rivastigmine, galantamine) inhibit acetylcholinesterase (AChE) at the synapse (specific cholinesterase). Tacrine was the first agent that was approved for AD, but because of its potential to cause hepatotoxicity, it is now rarely used.

Tacrine and rivastigmine also inhibit butyrylcholinesterase (BuChE). Although BuChE levels may be increased in AD, it is not clear that rivastigmine and tacrine have greater clinical efficacy than donepezil and galantamine.

Galantamine has a different second mechanism of action; it is also a presynaptic nicotinic modulator. No data exist to indicate that this second mechanism is of clinical importance.

Rivastigmine is indicated for the treatment of mild to moderate dementia of the Alzheimer type. Initial dosing recommendations are 1.5 mg given twice daily, with a maximum dose of 12 mg/day. Rivastigmine is a potent, selective inhibitor of brain AChE and BChE. Rivastigmine is considered a pseudo-irreversible inhibitor of AChE.

While the precise mechanism of rivastigmine’s action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase.

Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer type. It enhances central cholinergic function and likely inhibits AChE. There is no evidence that galantamine alters the course of the underlying dementing process. The dosing recommendation for the immediate-release formulation is 4 mg twice daily. The extended-release formulation is given at a dose of 8 mg once daily. The maintenance dose after dose titration is 16-24 mg/day.

The only drug in the N -methyl-D-aspartate (NMDA) antagonist class that is approved by the US Food and Drug Administration is memantine. This agent may be used alone or in combination with AChE inhibitors.

Namenda is approved for the treatment of moderate to severe dementia in patients with AD. The initial dose for the immediate-release formulation is 5 mg once daily, and it can be titrated to a maximum dose of 20 mg/day. The initial dose for the extended-release formulation is 7 mg once daily, and it can be titrated to a maximum dose of 28 mg/day.

Medical foods are dietary supplements intended to compensate specific nutritional problems caused by a disease or condition. Caprylidene is a prescription medical food that is metabolized into ketone bodies. The brain can use these ketone bodies for energy when its ability to process glucose is impaired, which brain-imaging scans suggest is the case in AD.

Caprylidene is indicated for clinical dietary management of metabolic processes associated with mild to moderate AD. General dosing recommendations include administering 40 g/day (1 packet of caprylidene powder, containing 20 g of medium-chain triglycerides) during breakfast.

Radioactive diagnostic agent for use with PET brain imaging. Binds to beta-amyloid neuritic plaques and the F 18 isotope produces a positron signal that is detected by a PET scanner.